Controlled Diabetics Have New Reason to Smile 2002.

AAP. Chicago, IL: American Academy of Peridontology (http://www.perio.org/consumer/diabetes.htm or abcnews.go.com/sections/wnt/WorldNewsTonight/wnt010427_stemcell_feature.html).

First Human Studies Promising for Popular Nutritional Supplement 2000.

ACS. Washington, D.C.: American Chemical Society (http://www.seacoastvitamins.com/Information/cla3.html).

Effect of altered nutritional states on insulin receptors.

Adamo M, LeRoith D, Simon J, Roth J. Diabetes Branch, National Institute of Diabetes, and Digestive and Kidney Diseases, Bethesda, MD 20892.

Annu Rev Nutr 1988;8:149-66

No abstract available.

[Antiplatelet properties of nitrogen monoxide] [Article in French]

Adrie C. Service de reanimation medicale, hopital Saint-Louis, Paris.

Arch Mal Coeur Vaiss 1996 Nov;89(11 Suppl):1527-32

Nitric (correction of nitrous) oxide (NO) plays a fundamental part in the haemostatic equilibrium between the endothelium and platelets, an equilibrium of established clinical importance in cardiovascular disease. NO stimulates the enzyme guanylate cyclase which is responsible for synthesis of GMPc, the increase of which results in platelet inhibition. Synthesis of NO may have endogenous auto or paracrine origine from platelets or endothelial cells and participates in the local regulation of platelet function in association with other products of endothelial or platelet synthesis. Exogenous administration is common in therapeutics either in molecules which release NO (nitrate derivatives, sodium nitropruside, molsidomine, etc) or by NO gas administered by inhalation. The antiplatelet effect of NO has been clearly demonstrated in vitro, in vivo or ex vivo, in animals and humans, and probably explains, at least partially, the efficacy of nitrate derivatives in ischaemic coronary artery disease. Nevertheless, the platelet inhibition observed with intravenous NO releasing drugs is associated with potentially harmful systemic hypotension. Platelet inhibition by inhalation of NO could be an alternative means of avoiding this unwanted effect.

Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes.

Anderson RA, Cheng N, Bryden NA, Polansky MM, Cheng N, Chi J, Feng J. Beltsville Human Nutrition Research Center, U.S. Department of Agriculture, Beltsville, MD 20705-2350, USA. anderson@307.bhnrc.usda.gov

Diabetes 1997 Nov;46(11):1786-91

Chromium is an essential nutrient involved in normal carbohydrate and lipid metabolism. The chromium requirement is postulated to increase with increased glucose intolerance and diabetes. The objective of this study was to test the hypothesis that the elevated intake of supplemental chromium is involved in the control of type 2 diabetes. Individuals being treated for type 2 diabetes (180 men and women) were divided randomly into three groups and supplemented with: 1) placebo, 2) 1.92 micromol (100 microg) Cr as chromium picolinate two times per day, or 3) 9.6 micromol (500 microg) Cr two times per day. Subjects continued to take their normal medications and were instructed not to change their normal eating and living habits. HbA1c values improved significantly after 2 months in the group receiving 19.2 pmol (1,000 microg) Cr per day and was lower in both chromium groups after 4 months (placebo, 8.5 +/- 0.2%; 3.85 micromol Cr, 7.5 +/- 0.2%; 19.2 micromol Cr, 6.6 +/- 0.1%). Fasting glucose was lower in the 19.2-micromol group after 2 and 4 months (4-month values: placebo, 8.8 +/- 0.3 mmol/l; 19.2 micromol Cr, 7.1 +/- 0.2 mmol/l). Two-hour glucose values were also significantly lower for the subjects consuming 19.2 micromol supplemental Cr after both 2 and 4 months (4-month values: placebo, 12.3 +/- 0.4 mmo/l; 19.2 micromol Cr, 10.5 +/- 0.2 mmol/l). Fasting and 2-h insulin values decreased significantly in both groups receiving supplemental chromium after 2 and 4 months. Plasma total cholesterol also decreased after 4 months in the subjects receiving 19.2 micromol/day Cr. These data demonstrate that supplemental chromium had significant beneficial effects on HbA1c, glucose, insulin, and cholesterol variables in subjects with type 2 diabetes. The beneficial effects of chromium in individuals with diabetes were observed at levels higher than the upper limit of the Estimated Safe and Adequate Daily Dietary Intake.

The effects of inorganic chromium and brewer's yeast supplementation on glucose tolerance, serum lipids and drug dosage in individuals with type 2 diabetes.

Bahijiri SM, Mira SA, Mufti AM, Ajabnoor MA. Department of Clinical Biochemistry, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.

Saudi Med J 2000 Sep;21(9):831-7

OBJECTIVE: To study the effects of supplementation with organic and inorganic chromium on glucose tolerance, serum lipids, and drug dosage in type 2 diabetes patients, in the hope of finding a better and more economical method of control. METHODS: Seventy eight type 2 diabetes patients were divided randomly into two groups and given Brewer's yeast (23.3ug Cr/day), and CrCl3 (200ug Cr/day) sequentially with placebo in between, in a double blind cross-over design of four stages, each lasting 8 weeks. At the beginning and end of each stage, subjects were weighed, their dietary data and drug dosage recorded, and blood and urine samples were collected for analysis of glucose (fasting and 2 hour post 75g glucose load) fructosamine, triglycerides, total and HDL-cholesterol, and serum and urinary chromium. RESULTS: Both supplements caused a significant decrease in the means of glucose (fasting and 2 hour post glucose load), fructosamine and triglycerides. The means of HDL-cholesterol, and serum and urinary chromium were all increased. The mean drug dosage decreased slightly (and significantly in case of Glibenclamide) after both supplements and some patients no longer required insulin. No change was noted in dietary intakes or Body Mass Index. A higher percentage of subjects responded positively to Brewer's yeast chromium, which was retained more by the body, with effects on fructosamine, triglycerides, and HDL-cholesterol maintained in some subjects when placebo followed it, and mean urinary chromium remaining significantly higher than zero time mean. CONCLUSION: Chromium supplementation gives better control of glucose and lipid variables while decreasing drug dosage in type 2 diabetes patients. A larger scale study is needed to help decide on the convenient chemical form, and dosage required to achieve optimal response.

Chromium supplements tied to glucose control.

Baker, B.

Fam. Pract. News 1996 Jul 15; p. 5, 2C.

No abstract available.

Bacteria from Gum Infections Associated with Diabetes, Chronic Lung Disease, UB Studies Find 1999a.

Baker, L.

Buffalo, NY: University at Buffalo/School of Dental Medicine (http://www.sdm.buffalo.edu/news/19990313_diab.html).

UB Oral Geologists Find Link between Gum Disease and Passive Exposure to Tobacco Smoke 1999b.

Baker, L.

Buffalo, NY: University at Buffalo/School of Dental Medicine (http://www.sdm.buffalo.edu/news/19990312_smoke.html).

Persistent elevation of plasma insulin levels is associated with increased cardiovascular risk in children and young adults. The Bogalusa Heart Study.

Bao W, Srinivasan SR, Berenson GS. Tulane National Center for Cardiovascular Health, Tulane School of Public Health and Tropical Medicine, New Orleans, LA 70112-2824, USA.

Circulation 1996 Jan 1;93(1):54-9

BACKGROUND: Hyperinsulinemia has been considered to be a potent cardiovascular risk factor. The present investigation examines persistently elevated fasting insulin levels from childhood to young adulthood and its influence on cardiovascular risk factors. METHODS AND RESULTS: A longitudinal cohort was constructed from two cross-sectional surveys in a community-based population over an 8-year period: 1606 individuals (39% were black) aged 5 to 23 years participated in the first survey. Stability in rankings (persistence) of insulin levels was shown by the presence of significant correlations between year 1 and year 8 values (r=.23 to .36, < 0001), with a greater magnitude in older subjects. Compared with subjects with levels of insulin consistently in the lowest quartile, those with levels always in the highest quartile showed higher (<001) levels of body mass index (+9 kg/m2), triglycerides (+58 mg/dL), LDL cholesterol (+11 mg/dL), VLDL cholesterol (+8 mg/dL), glucose (+9 mg/dL), systolic blood pressure (+7 mm Hg), and diastolic blood pressure (+3 mm Hg); lower (<001) levels of HDL cholesterol (-4 mg/dL): and higher (<05) prevalence of parental history of diabetes (3.3-fold) and hypertension (1.2-fold). There were 739 young adults aged 20 to 31 years at follow-up. As adults, individuals with consistently elevated insulin versus those with consistently decreased insulin had increased (<05) prevalence of obesity (36-fold), hypertension (2.5-fold), and dyslipidemia (3-fold), which was attributed to both baseline insulin and change of insulin from baseline to follow-up. In addition, clustering of these risk factors was stronger (<05) in adults with persistent insulin elevation. CONCLUSIONS: Elevated insulin levels persist from childhood through young adulthood, resulting in a clinically relevant adverse cardiovascular risk profile in young adults.

Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss.

Bastard JP, Jardel C, Bruckert E, Blondy P, Capeau J, Laville M, Vidal H, Hainque B. Service de Biochimie, Hopital de la Salpetriere, Paris, France. jean-philippe.bastard@tnn.ap-hop-paris.fr

J Clin Endocrinol Metab 2000 Sep;85(9):3338-42

The aim of this study was to investigate the potential role of adipose cytokines in the obesity-associated insulin resistance. To that end, we compared: 1) serum concentrations of interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalpha), and leptin in eight healthy lean control females and in android obese female without (n = 14) and with (n = 7) type 2 diabetes; and 2) the levels of these cytokines both in serum and in sc adipose tissue in the 14 obese nondiabetic women before and after 3 weeks of a very low-calorie diet (VLCD). As compared with lean controls, obese nondiabetic and diabetic patients were more insulin resistant and presented increased values for leptin, IL-6, TNFalpha, and C-reactive protein. In the whole group, IL-6 values were more closely related to the parameters evaluating insulin resistance than leptin or TNFalpha values. VLCD resulted in weight loss and decreased body fat mass (approximately 3 kg). Insulin sensitivity was improved with no significant change in both serum and adipose tissue TNFalpha levels. In contrast, VLCD induced significant decreases in IL-6 and leptin levels in both adipose tissue and serum. These results suggest that, as for leptin, circulating IL-6 concentrations reflect, at least in part, adipose tissue production. The reduced production and serum concentrations after weight loss could play a role in the improved sensitivity to insulin observed in these patients.

Role of diet and exercise in the management of hyperinsulinemia and associated atherosclerotic risk factors.

Barnard RJ, Ugianskis EJ, Martin DA, Inkeles SB. Department of Kinesiology, University of California, Los Angeles, CA 90024-1527.

Am J Cardiol 1992 Feb 15;69(5):440-4

Hyperinsulinemia, hypertension, hypertriglyceridemia and obesity are independent risk factors for coronary artery disease and are often found in the same person. This study investigated the effects of an intensive, 3-week, dietary and exercise program on these risk factors. The group was divided into diabetic patients (non-insulin-dependent diabetes mellitus [NIDDM], n = 13), insulin-resistant persons (n = 29) and those with normal insulin, less than or equal to 10 microU/ml (n = 30). The normal groups had very small but statistically significant decreases in all of the risk factors. The patients with NIDDM had the greatest decreases. Insulin was reduced from 40 +/- 15 to 27 +/- 11 microU/ml, blood pressure from 142 +/- 9/83 +/- 3 to 132 +/- 6/71 +/- 3 mm Hg, triglycerides from 353 +/- 76 to 196 +/- 31 mg/dl and body mass index from 31.1 +/- 4.0 to 29.7 +/- 3.7 kg/m2. Although there was a significant weight loss for the group with NIDDM, resulting in the decrease in body mass index, 8 of 9 patients who were initially overweight were still overweight at the end of the program, and 5 of the 8 were still obese (body mass index greater than 30 kg/m2), indicating that normalization of body weight is not a requisite for a reduction or normalization of other risk factors. Insulin was reduced from 18.2 +/- 1.8 to 11.6 +/- 1.2 microU/ml in the insulin-resistant group, with 17 of the 29 subjects achieving normal fasting insulin (less than 10 microU/ml). (ABSTRACT TRUNCATED AT 250 WORDS.)

Caffeine: a cause of insulin resistance?

Biaggioni I, Davis SN.

Diabetes Care 2002 Feb;25(2):399-400

No abstract available.

Exercise: The Miracle Remedy? 2002

Blake, M.

(http://www.co.sutter.ca.us/human_services/diabetes/exercise_miracle_remedy.htm).

Medical Applications of Clinical Nutrition 1983.

Bland, J.

New Canaan, CT: Keats Publishing.

Starting Insulin in Type 2 Diabetes (response).

Bloomgarden, Z.T.

Medscape Diabetes & Endocrinology 2001; 3(2) (http://www.Medscape.com/viewarticle/412404).

Relationship between degree of obesity and in vivo insulin action in man.

Bogardus C, Lillioja S, Mott DM, Hollenbeck C, Reaven G.

Am J Physiol 1985 Mar;248(3 Pt 1):E286-91

Previous studies have demonstrated reduced in vivo insulin action in obese subjects compared with lean controls. However, little data is available on the relationship between degree of obesity and insulin action, and this relationship has not been shown to be independent of individual differences in maximal aerobic capacity. We studied 55 male Pima Indians and 35 male Caucasians with normal glucose tolerance. In vivo insulin action was measured using the hyperinsulinemic, euglycemic clamp technique at a plasma insulin concentration of approximately 100 microU/ml. Body composition was determined by densitometry, and maximal aerobic capacity was estimated using a graded exercise test. The results showed that degree of obesity was nonlinearly related to in vivo insulin action. In both Indians and Caucasians there was a significant decline in insulin action with increasing obesity up to a percent body fat of approximately 28-30%. Further increases in obesity in the Indians were not associated with significant changes in insulin action. Maximal aerobic capacity was positively linearly correlated with insulin action over the entire range of insulin action in both racial groups. Degree of obesity and maximal aerobic capacity were each independently associated with insulin action although these independent relationships were of marginal significance in the Caucasians. Surprisingly, individual differences in obesity and maximal aerobic capacity accounted for only half the variability observed in insulin action in these glucose tolerant subjects.

Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials.

Boule NG, Haddad E, Kenny GP, Wells GA, Sigal RJ. Clinical Epidemiology Unit, Ottawa Health Research Institute, 1053 Carling Ave, Ottawa, Ontario, Canada K1Y 4E9.

JAMA 2001 Sep 12;286(10):1218-27

CONTEXT: Exercise is widely perceived to be beneficial for glycemic control and weight loss in patients with type 2 diabetes. However, clinical trials on the effects of exercise in patients with type 2 diabetes have had small sample sizes and conflicting results. OBJECTIVE: To systematically review and quantify the effect of exercise on glycosylated hemoglobin (HbA(1c)) and body mass in patients with type 2 diabetes. DATA SOURCES: Database searches of MEDLINE, EMBASE, Sport Discuss, Health Star, Dissertation Abstracts, and the Cochrane Controlled Trials Register for the period up to and including December 2000. Additional data sources included bibliographies of textbooks and articles identified by the database searches. STUDY SELECTION: We selected studies that evaluated the effects of exercise interventions (duration < /=8 weeks) in adults with type 2 diabetes. Fourteen (11 randomized and 3 nonrandomized) controlled trials were included. Studies that included drug cointerventions were excluded. DATA EXTRACTION: Two reviewers independently extracted baseline and postintervention means and SDs for the intervention and control groups. The characteristics of the exercise interventions and the methodological quality of the trials were also extracted. DATA SYNTHESIS: Twelve aerobic training studies (mean [SD], 3.4 [0.9] times/week for 18 [15] weeks) and 2 resistance training studies (mean [SD], 10 [0.7] exercises, 2.5 [0.7] sets, 13 [0.7] repetitions, 2.5 [0.4] times/week for 15 [10] weeks) were included in the analyses. The weighted mean postintervention HbA(1c) was lower in the exercise groups compared with the control groups (7.65% vs 8.31%; weighted mean difference, -0.66%; < 001). The difference in postintervention body mass between exercise groups and control groups was not significant (83.02 kg vs 82.48 kg; weighted mean difference, 0.54; P =.76). CONCLUSION: Exercise training reduces HbA(1c) by an amount that should decrease the risk of diabetic complications, but no significantly greater change in body mass was found when exercise groups were compared with control groups.

Dr. Braly's Optimum Health Program 1985.

Braly, J.

New York: Random House/Times Books.

Dehydroepiandrosterone prevents lipid peroxidation and cell growth inhibition induced by high glucose concentration in cultured rat mesangial cells.

Brignardello E, Gallo M, Aragno M, Manti R, Tamagno E, Danni O, Boccuzzi G. Department of Clinical Pathophysiology, University of Turin, via Genova 3, 10126 Turin, Italy.

J Endocrinol 2000 Aug;166(2):401-6

The oxidative stress induced by high glucose concentration contributes to tissue damage associated with diabetes, including renal injury. Dehydroepiandrosterone (DHEA), the major secretory product of the human adrenal gland, has been shown to possess a multi-targeted antioxidant activity which is also effective against lipid peroxidation induced by high glucose. In this study we evaluated the effect of DHEA on the growth impairment which high glucose concentration induces in cultured rat mesangial cells. Primary cultures of rat mesangial cells were grown for 10 days in media containing either normal (i.e. 5.6 mmol/l) or high (i.e. 30 mmol/l) concentrations of glucose, without or with DHEA at different concentrations. The impairment of cell growth induced by high glucose was reversed by 100 nmol/l and 500 nmol/l DHEA, which had no effect on mesangial cells cultured in media containing glucose at the normal physiological concentration (5.6 mmol/l). In high-glucose cultured mesangial cells, DHEA also attenuated the lipid peroxidation, as measured by thiobarbituric acid reactive substances (TBARS) generation and 4-hydroxynonenal (HNE) concentration, and preserved the cellular content of reduced glutathione as well as the membrane Na+/K+ ATPase activity. The data further support the protective effect of DHEA against oxidative damage induced by high glucose concentrations, and bring into focus its possible effectiveness in preventing chronic complications of diabetes.

Nonenzymatic glycosylation and the pathogenesis of diabetic complications.

Brownlee M, Vlassara H, Cerami A.

Ann Intern Med 1984 Oct;101(4):527-37

Glucose chemically attaches to proteins and nucleic acids without the aid of enzymes. Initially, chemically reversible Schiff base and Amadori product adducts form in proportion to glucose concentration. Equilibrium is reached after several weeks, however, and further accumulation of these early nonenzymatic glycosylation products does not continue beyond that time. Subsequent reactions of the Amadori product slowly give rise to nonequilibrium advanced glycosylation end-products which continue to accumulate indefinitely on longer-lived molecules. Excessive formation of both types of nonenzymatic glycosylation product appears to be the common biochemical link between chronic hyperglycemia and a number of pathophysiologic processes potentially involved in the development of long-term diabetic complications. The major biological effects of excessive nonenzymatic glycosylation include: inactivation of enzymes; inhibition of regulatory molecule binding; crosslinking of glycosylated proteins and trapping of soluble proteins by glycosylated extracellular matrix (both may progress in the absence of glucose); decreased susceptibility to proteolysis; abnormalities of nucleic acid function; altered macromolecular recognition and endocytosis; and increased immunogenicity.

Get on Your Feet 2001

Cafazzo, D.

(http://www.reporternews.com/2001/features/feet0424.html).

Syndrome X 2000.

Challem, J., Berkson, B., Smith, M.

New York: John Wiley & Sons.

Beneficial effects of high dietary fiber intake in patients with type 2 diabetes mellitus.

Chandalia M, Garg A, Lutjohann D, von Bergmann K, Grundy SM, Brinkley LJ. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

N Engl J Med 2000 May 11;342(19):1392-8

BACKGROUND: The effect of increasing the intake of dietary fiber on glycemic control in patients with type 2 diabetes mellitus is controversial. METHODS: In a randomized, crossover study, we assigned 13 patients with type 2 diabetes mellitus to follow two diets, each for six weeks: a diet containing moderate amounts of fiber (total, 24 g; 8 g of soluble fiber and 16 g of insoluble fiber), as recommended by the American Diabetes Association (ADA), and a high-fiber diet (total, 50 g; 25 g of soluble fiber and 25 g of insoluble fiber), containing foods not fortified with fiber (unfortified foods). Both diets, prepared in a research kitchen, had the same macronutrient and energy content. We compared the effects of the two diets on glycemic control and plasma lipid concentrations. RESULTS: Compliance with the diets was excellent. During the sixth week, the high-fiber diet, as compared with the the sixth week of the ADA diet, mean daily preprandial plasma glucose concentrations were 13 mg per deciliter [0.7 mmol per liter] lower (95 percent confidence interval, 1 to 24 mg per deciliter [0.1 to 1.3 mmol per liter]; P=0.04) and mean median difference, daily urinary glucose excretion 1.3 g (0.23; 95 percent confidence interval, 0.03 to 1.83 g; P= 0.008). The high-fiber diet also lowered the area under the curve for 24-hour plasma glucose and insulin concentrations, which were measured every two hours, by 10 percent (P=0.02) and 12 percent (P=0.05), respectively. The high-fiber diet reduced plasma total cholesterol concentrations by 6.7 percent (P=0.02), triglyceride concentrations by 10.2 percent (P=0.02), and very-low-density lipoprotein cholesterol concentrations by 12.5 percent (P=0.01). CONCLUSIONS: A high intake of dietary fiber, particularly of the soluble type, above the level recommended by the ADA, improves glycemic control, decreases hyperinsulinemia, and lowers plasma lipid concentrations in patients with type 2 diabetes.

Prevention of type 2 diabetes: role of metformin.

Charles MA, Eschwege E. National Institute of Health and Medical Research (INSERM) Unit 21, Villejuif, France. charles@vjf.inserm.fr

Drugs 1999;58 Suppl 1:71-3; discussion 75-82

Metformin lowers moderate (nondiabetic) fasting hyperglycaemia in individuals at risk for type 2 diabetes without causing hypoglycaemia. In addition, it has demonstrated favourable action on several cardiovascular risk factors that are often present in these individuals: it favours the maintenance of diet-induced weight loss and its associated improvement in fibrinolysis; and it lowers plasma concentrations of fasting insulin, total and low density lipoprotein-cholesterol, free fatty acids, and of two markers of endothelial damage--tissue plasminogen activator antigen and von Willebrand factor. These effects together with the good tolerability profile of the drug position metformin as a first-line agent for the prevention of type 2 diabetes.

Novel lipid-lowering properties of Vaccinium myrtillus L. leaves, a traditional antidiabetic treatment, in several models of rat dyslipidaemia: a comparison with ciprofibrate.

Cignarella A, Nastasi M, Cavalli E, Puglisi L. Institute of Pharmacological Sciences, University of Milano, Italy.

Thromb Res 1996 Dec 1;84(5):311-22

Vaccinium myrtillus L. (blueberry) leaf infusions are traditionally used as a folk medicine treatment of diabetes. To further define this therapeutical action, a dried hydroalcoholic extract of the leaf was administered orally to streptozotocin-diabetic rats for 4 days. Plasma glucose levels were consistently found to drop by about 26% at two different stages of diabetes. Unexpectedly, plasma triglyceride (TG) were also decreased by 39% following treatment. Subsequent to the latter observation, possible lipid-lowering properties of the extract were investigated on other models of hyperlipidaemia and ciprofibrate, a well-established hypolipidaemic drug, was used as a reference compound. Both drug reduced TG levels of rats on hyperlipidaemic diet in a dose-dependent fashion. When administered at single doses over the same experimental period, blueberry and ciprofibrate were effective in lowering TG concentrations in ethanol-treated normolipidaemic animals and in genetically hyperlipidaemic Yoshida rats. Unlike ciprofibrate, however, blueberry failed to prevent the rise in plasma TG elicited by fructose and did not affect free fatty acid levels in any of the above experimental conditions. In rats treated with Triton WR-1339, blueberry feeding induced an hypolipidaemic activity one hour after injection but proved to be ineffective at later time points, thus suggesting that its hypolipidaemic action may reflect improved TG-rich lipoprotein catabolism. In addition, ciprofibrate and the extract were tested for antithrombotic activity using a collagen-triggered model of venous thrombosis in diabetic and Yoshida rats. Only ciprofibrate, however, significantly reduced thrombus formation in diabetics, possibly because of its effects on free fatty acid metabolism, whereas no effect was observed in Yoshida rats. In conclusion, the present findings indicate that active consituent(s) of Vaccinium myrtillus L. leaves may prove potentially useful for treatment of dyslipidaemiae associated with impaired TG-rich lipoprotein clearance.

Biotin status and plasma glucose in diabetes.

Coggeshall J C; Heggers J P; Robson M C; Baker H

Ann. N.Y. Acad. Sci. 1985; 447: 389 92.

No abstract available.

Weight as a risk factor for clinical diabetes in women.

Colditz GA, Willett WC, Stampfer MJ, Manson JE, Hennekens CH, Arky RA, Speizer FE. Channing Laboratory, Harvard Medical School, Boston, MA 02115.

Am J Epidemiol 1990 Sep;132(3):501-13

To determine the relation of body mass index (weight/height2) with the risk of clinical non-insulin-dependent diabetes, the authors analyzed data from a cohort of 113,861 US women aged 30-55 years in 1976. During 8 years of follow-up (826,010 person-years), 873 definite cases were identified among women initially free from diagnosed diabetes. Among women of average body mass index, 23-23.9 kg/m2, the relative risk was 3.6 times that of women having a body mass index less than 22 kg/m2. The risk continued to increase above this level of body mass index. The authors observed a much weaker positive association with weight at age 18, and this association was eliminated after adjustment for current body mass index. Thus, weight gain after age 18 was a major determinant of risk. For an increase of 20-35 kg, the relative risk was 11.3, and for an increase of more than 35 kg, the relative risk was 17.3. Adjusting for family history did not appreciably alter the strong relation observed among women at average levels of body mass index. These data indicate that, at even average weight, women are at increased risk of clinical non-insulin-dependent diabetes and that the relation between body mass index and risk of diabetes is continuous.

Nitric oxide synthase: role in the genesis of vascular disease.

Cooke JP, Dzau VJ. Division of Cardiovascular Medicine, Stanford University, Stanford, CA 94305, USA.

Annu Rev Med 1997;48:489-509

The product of nitric oxide (NO) synthase is the most potent endogenous vasodilator known. No not only is a potent vasodilator, it also inhibits platelet adherence and aggregation, reduces adherence of leukocytes to the endothelium, and suppresses proliferation of vascular smooth muscle cells. A number of disorders are associated with reduced synthesis and/or increased degradation of vascular NO. These include hypercholesterolemia, diabetes mellitus, hypertension, and tobacco use. The endothelial dysfunction caused by these disorders contributes to the alterations in vascular function and structure observed in these conditions. A reduction in the activity of vascular NO likely plays a significant role in the development of atherosclerosis. Insights into the mechanisms by which NO production or activity is altered in these states will lead to new therapeutic strategies in the treatment of a number of vascular disorders, including hypertension, atherosclerosis, restenosis, and thrombosis.

The Carnitine Miracle 1999.

Crayhon, R.

New York: M. Evans.

Skin tags and the atherogenic lipid profile.

Crook MA. Department of Chemical Pathology, Guy's, St Thomas's, University Lewisham Hospital, London SE13 6LH, UK. martin.crook@gstt.sthames.nhs.uk

J Clin Pathol 2000 Nov;53(11):873-4

This report details four patients who had skin tags, mainly on their torso, neck, and axillae, and who also displayed an abnormal lipid profile. All showed an increased serum triglyceride (fasting < 1.70 mmol/litre) and a decreased high density lipoprotein (HDL) cholesterol (< 1.1 mmol/litre in women and 1.0 mmol/litre for men) concentration. The displayed lipid profile is also known as the atherogenic profile and is associated with insulin resistance, type 2 diabetes mellitus, and an increased risk of cardiovascular disease. Two of the patients had impaired glucose tolerance and one had type 2 diabetes mellitus. Three of the individuals had coronary artery disease. Skin tags might be a useful clinical sign that could alert clinicians to screen such individuals for abnormal lipids, type 2 diabetes mellitus, and cardiovascular disease.

Hyperzincuria in individuals with insulin-dependent diabetes mellitus: concurrent zinc status and the effect of high-dose zinc supplementation.

Cunningham JJ, Fu A, Mearkle PL, Brown RG. Department of Nutrition, University of Massachusetts, Amherst, MA 01003-1420.

Metabolism 1994 Dec;43(12):1558-62

The urinary excretion of zinc in individuals with insulin-dependent diabetes mellitus (IDDM) is approximately doubled. In the absence of a compensatory mechanism, this hyperzincuria should induce a deficient or marginal Zn status. We examined parameters of Zn status in plasma and in blood cells with respect to urinary Zn losses and Zn supplementation. We measured Zn levels in the urine, plasma, and erythrocytes of 14 IDDM subjects and 15 nondiabetics who kept dietary records for 3 consecutive days. Subsequently, six IDDM subjects and seven nondiabetics were supplemented with 50 mg Zn daily for 28 days. We measured the above parameters, as well as mononuclear leukocyte Zn (MNL-Zn) and the plasma subfraction of albumin-bound Zn (alb-Zn). The total plasma Zn-binding capacity was also assessed. Plasma copper and erythrocyte Cu were monitored as indicators of potential Zn toxicity. Individuals with IDDM displayed the expected hyperzincuria, but had normal blood Zn parameters. Zincuria increased by a similar amount in both groups during supplementation, as did the MNL-Zn content. However, erythrocyte Zn (e-Zn) was refractory, so a trend toward lower e-Zn among IDDM subjects persisted during Zn supplementation. Hemoglobin A1c (HbA1c) increased markedly in the Zn-supplemented IDDM group. Despite their chronic hyperzincuria, individuals with IDDM appear not to be Zn-deficient. Large-dose Zn supplementation increases MNL-Zn and induces an undesirable elevation of HbA1c in all individuals. This is especially disconcerting for those with IDDM, and may reflect an exacerbation of a chronic "Zn diabetes." These data suggest a potential for toxicity from large-dose Zn supplementation.

Heightened gingival inflammation and attachment loss in type 2 diabetics with hyperlipidemia.

Cutler CW, Machen RL, Jotwani R, Iacopino AM. Department of Periodontics, Baylor College of Dentistry-TAMUHSC, Dallas, TX 75266-0677, USA. ccutler@tambcd.edu

J Periodontol 1999 Nov;70(11):1313-21

BACKGROUND: Our previous studies in diabetic (DB) rats suggest that hyperlipidemia may cause a dysregulation of the cellular and local cytokine response to periodontitis (AP). The objective of the present study was to determine if diabetes has a similar dysregulatory effect on the gingival response to AP in humans. METHODS: Peripheral blood, as well as gingival tissue (GT) and gingival crevicular fluid (GCF), was obtained from a total of 35 patients who were categorized into the following groups based on level of diabetic (type 2) control and presence or absence of adult periodontitis (AP): group 1, systemically and periodontally healthy (n = 6); group 2, systemically healthy with adult periodontitis (n = 7); group 3, well-controlled diabetes and periodontally healthy (n = 6); group 4, well-controlled diabetes with adult periodontitis (n = 5); group 5, poorly controlled diabetes and periodontally healthy (n = 5); group 6, poorly controlled diabetes and adult periodontitis (n = 6). All subjects were given a thorough periodontal examination, including probing depths (PD), clinical attachment levels (CAL), gingival index (GI), plaque index (PI), and vertical bitewing radiographs. Blood studies included levels of glycated hemoglobin (HbA1c), triglycerides (TG), cholesterol (CHL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). The levels of interleukin-1 beta (IL-1beta) in GCF and GT, interleukin-6 (IL-6), and platelet-derived growth factor AB (PDGF-AB) in GT from patients in each experimental group were analyzed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our results indicate that all clinical indices except PI were significantly elevated in the poorly controlled and well-controlled diabetics, compared to systemically healthy patients, but only in the subjects without preexisiting AP (Tukey's multiple comparisons, < 0.05). Pairwise linear regression analysis revealed significant (< 0.01) positive associations between periodontal inflammation (PD, CAL, PI, GI) and levels of GCF IL-1beta, GT IL- 1beta GT IL-6, but not GT PDGF; moreover, GT IL-6 levels were significantly associated (< 0.05) with GT IL-1beta. As TG levels increased in the non-AP patients (group 1 < group 3 < group 5), there was a trend, not significant, for increased GCF IL-1beta levels and increased gingival inflammation. Interestingly, periodontitis resulted in increased PDGF-AB levels in the gingiva of systemically healthy and well-controlled diabetes patients, but this increase was obtunded in poorly controlled diabetes patients. CONCLUSIONS: This confirms our earlier work in the diabetic rat model. These studies indicate that decreased metabolic control in type 2 diabetics results in increased serum triglycerides and has a negative influence on all clinical measures of periodontal health, particularly in patients without preexisting periodontitis. Levels of the cytokine IL- 1beta showed a trend for increasing as diabetic control diminished. In contrast, levels of the growth factor PDGF, which normally increase in periodontitis, decreased in poorly controlled diabetics with periodontitis. These studies suggest a possible dysregulation of the normal cytokine/growth factor signaling axis in poorly controlled type 2 diabetics that may contribute to periodontal breakdown/diminished repair.

Deferoxamine therapy in high-ferritin diabetes.

Cutler P.

Diabetes 1989 Oct;38(10):1207-10

Serum ferritin and diabetes control were evaluated in 18 White patients with poorly controlled type II (non-insulin-dependent) diabetes who had no known causes of iron-storage disorder. Serum ferritin levels were found to be elevated with normal serum iron and total iron-binding capacity in 9 of the 18 patients studied. Because excess iron, typified by hemochromatosis, is associated with diabetes, and diabetes has been shown to improve after lowering total-body iron load through repeat venesection, I investigated whether regulating elevated ferritin levels could facilitate diabetes control. Deferoxamine (DFO), a known specific chelator of iron, was used because of its capacity to correct excess iron stores. All 9 patients in the high-ferritin diabetic group and 7 of 9 diabetic control subjects with normal serum ferritin levels were given DFO (10 mg/kg i.v.) twice weekly. Diabetic control, fasting glucose, triglyceride, cholesterol, HbA1c, and serum ferritin levels were monitored. Data show that lowering elevated ferritin levels correlated well with diabetes control and improved fasting glucose, triglyceride, and HbA1c in 8 of 9 patients with high ferritin levels. Lowering normal ferritin levels had no effect on diabetes control or on any of the other parameters in the 7 control subjects. This study shows there is a need to study iron metabolism in poorly controlled diabetes and demonstrates the value of DFO in controlling high-ferritin diabetes.

Insulin action and the regulation of hexose transport.

Czech MP.

Diabetes 1980 May;29(5):399-409

No abstract available.

Changes in Body Composition with Conjugated Linoleic Acid 2001

DeLany, J., West, D.

(www.am-coll-nutr.org/jacn/vol_19/no_4/pg487s.htm).

Vitamin E Shows Promise in Treating Diabetes 2001 Jun 5.

Devaraj, S.

Washington, D.C.: Hearst Newspapers (http://www.ithyroid.com/diabetes.htm).

Low-density lipoprotein postsecretory modification, monocyte function, and circulating adhesion molecules in type 2 diabetic patients with and without macrovascular complications: the effect of alpha-tocopherol supplementation.

Devaraj S, Jialal I. Division of Clinical Biochemistry and Human Metabolism, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75235-9073, USA.

Circulation 2000 Jul 11;102(2):191-6

BACKGROUND: Although diabetes confers an increased propensity toward accelerated atherogenesis, data are lacking on monocyte activity in type 2 diabetic patients with (DM2-MV) and without (DM2) macrovascular disease compared with control subjects. Thus, we tested whether (1) postsecretory modifications of LDL (glycation and oxidation), monocyte proatherogenic activity, and circulating levels of soluble cell adhesion molecules (sCAMs) are more pronounced in DM2-MV than in DM2 and control subjects and (2) RRR-alpha-tocopherol (AT) therapy, 1200 IU/d for 3 months, has a similar effect in the 3 groups (n=25 per group). METHODS AND RESULTS: Although LDL glycation was increased in both diabetic groups compared with control subjects, AT therapy had no significant effect on glycation. AT therapy significantly decreased LDL oxidizability in all 3 groups. Diabetic monocytes released significantly more superoxide anion (O(2)(-)) and interleukin-1beta (IL-1beta) and exhibited greater adhesion to endothelium than control subjects. AT therapy significantly decreased the release of O(2)(-), IL-1beta, tumor necrosis factor-alpha, and monocyte-endothelium adhesion in all 3 groups. There was no significant difference between the 2 diabetic groups for any of the above parameters. sICAM levels were significantly elevated in both diabetic groups compared with controls. AT therapy resulted in a significant decrease in sCAMs. CONCLUSIONS: This is the first demonstration of increased IL-1beta secretion and increased adhesion of monocytes to endothelium from normotriglyceridemic diabetic subjects and of decreased monocyte activity and sCAMs with AT therapy in diabetic subjects with and without macrovasculopathy.

Diabetes Forum/Gopi Memorial Hospital. Treatment Role of Silymarin (undated).

Salem, India: Gopi Memorial Hospital

(www.diabetesforum.net/eng_treatment_Role_Silymarin.htm).

Diabetes-induced nitrative stress in the retina, and correction by aminoguanidine.

Du Y, Smith MA, Miller CM, Kern TS. Department of Medicine, Center for Diabetes Research, Case Western Reserve University, University Hospitals, and Veterans Affairs Medical Center, Cleveland, OH 44106-4951, USA.

J Neurochem 2002 Mar;80(5):771-9

Aminoguanidine inhibits the development of retinopathy in diabetic animals, but the mechanism remains unclear. Inasmuch as aminoguanidine is a relatively selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), we have investigated the effects of hyperglycemia on the retinal nitric oxide (NO) pathway in the presence and absence of aminoguanidine. In vivo studies utilized retinas from experimentally diabetic rats treated or without aminoguanidine for 2 months, and in vitro studies used bovine retinal endothelial cells and a transformed retinal glial cell line (rMC-1) incubated in 5 mm and 25 mm glucose with and without aminoguanidine (100 microg/mL). NO was detected as nitrite and nitrate, and nitrotyrosine and iNOS were detected using immunochemical methods. Retinal homogenates from diabetic animals had greater than normal levels of NO and iNOS (< 0.05), and nitrotyrosine was greater than normal, especially in one band immunoprecipitated from retinal homogenates. Oral aminoguanidine significantly inhibited all of these increases. Nitrotyrosine was detected immunohistochemically only in the retinal vasculature of non-diabetic and diabetic animals. Retinal endothelial and rMC-1 cells cultured in high glucose increased NO and NT, and aminoguanidine inhibited both increases in rMC-1 cells, but only NT in endothelial cells. Hyperglycemia increases NO production in retinal cells, and aminoguanidine can inhibit this abnormality. Inhibition of diabetic retinopathy by aminoguanidine might be mediated in part by inhibition of sequelae of NO production.

Health and Wellness, Sixth Edition 1999.

Edlin, G. et al.

Sudbury, MA: Jones and Bartlett.

Magnesium and insulin-dependent diabetes mellitus.

Elamin A, Tuvemo T. Department of Paediatrics & Child Health, Faculty of Medicine, University of Khartoum, Sudan.

Diabetes Res Clin Pract 1990 Nov-Dec;10(3):203-9

There is accumulating evidence that the changes which occur in the metabolism of some micronutrients in diabetes mellitus might have a specific role in the pathogenesis and complications of this disease. Magnesium deficiency is the most evident disturbance of metal metabolism in insulin-dependent diabetes mellitus. Hypomagnesemia has been linked both to the acute metabolic and late chronic complication of diabetes. Of particular concern, is the association between hypomagnesemia and ischemic heart disease and severe retinopathy in humans with diabetes mellitus. Appropriate magnesium supplementation might prove beneficial in normalizing the low plasma and tissue magnesium levels and prevent or retard the development of vascular complications in diabetic patients. However, well designed and documented experiments need to be performed before the rationales for such therapy are well established.

Nonenzymatic glycosylation of tissue and blood proteins.

Emekli N. Department of Biochemistry, Faculty of Dentistry, Marmara University, Istanbul, Turkiye.

J Marmara Univ Dent Fac 1996 Sep;2(2-3):530-4

A brief description of the phenomenon of nonenzymatic glycosylation will be presented, some examples given from the literature and then a brief summary of the results of laboratory research conducted in this area by myself and coworkers since 1981. Excessive glycosylation causes undesirable changes in proteins. Such glycosylation also occurs to collagen in oral tissue. In a study on induced experimental diabetes in rats we observed a defective platelet aggregation curve for gingival collagen. Glycosylation of proteins is known to result in functional defects, for example hemoglobin acquires an increased affinity for oxygen. Glycosylation of rat and bovine lens crystallins has been reported as being an important genesis of cataracts in diabetes. Increased glycosylation of submandibular collagen has been shown to occur in diabetes. However collagen from normal subjects has also been found to show an age related advanced glycosylation end product pigment. Increased platelet membrane protein glycosylation has been reported and the hyperaggregation typically observed in these cases thought to be due to glycosylation. The presence of red cell membrane proteins has also been reported and the impairment of red cell function in diabetes has been reported in cases of excessive glycosylation. According to some investigators cataract formation is prevented by some specific drug which inhibits the glycosylation of lens crystallins. Vitamin C has lowering effects on nonenzymatic glycation. Dentists should take into account the possibility of glycosylation of oral proteins such as collagen in cases of impaired gingiva tooth connection.

Insulin resistance and cigarette smoking.

Facchini FS, Hollenbeck CB, Jeppesen J, Chen YD, Reaven GM. Department of Medicine, Stanford University School of Medicine, Stanford, CA. Lancet 1992 May 9;339(8802):1128-30

Cigarette smoking is associated with increases in plasma triglycerides and decreases in plasma high density-lipoprotein-cholesterol concentration. These changes not only increase risk of coronary heart disease but also are secondary to resistance to insulin-stimulated glucose uptake or hyperinsulinaemia. To see whether there is a relation between cigarette smoking and insulin-mediated glucose uptake we measured plasma lipid and lipoprotein concentrations, plasma glucose and insulin response to an oral glucose challenge, and insulin-mediated glucose uptake in 40 matched healthy volunteers (20 non-smokers, 20 smokers). Smokers had significantly higher mean (SEM) very-low-density-lipoprotein triglycerides (0.66 [0.10] vs 0.39 [0.03] mmol/l, p less than 0.02) and cholesterol (0.45 [0.06] vs 0.23 [0.04] mmol/l, p less than 0.005) concentrations and lower high-density-lipoprotein cholesterol concentrations (1.16 [0.05] vs 1.51 [0.08] mmol/l, p less than 0.001). Although plasma glucose concentrations in response to the oral glucose load were similar in the two groups, plasma insulin response of the smokers was significantly higher (p less than 0.001). Finally, smokers had higher steady-state plasma glucose concentrations in response to a continuous infusion of glucose, insulin, and somatostatin (8.4 [0.2] vs 5.0 [0.3] mmol/l, p less than 0.001), despite similar steady-state plasma insulin concentrations. The findings show that chronic cigarette smokers are insulin resistant, hyperinsulinaemic, and dyslipidaemic compared with a matched group of non-smokers, and may help to explain why smoking increases risk of coronary heart disease.

Zinc and insulin sensitivity.

Faure P, Roussel A, Coudray C, Richard MJ, Halimi S, Favier A. Laboratoire de Biochimie C, Hopital A. Michallon, Grenoble, France.

Biol Trace Elem Res 1992 Jan-Mar;32:305-10

Many studies have shown that zinc deficiency could decrease the response to insulin. In genetically diabetic animals, a low zinc status has been observed contrary to induced diabetic animals. The zinc status of human patients depends on the type of diabetes and the age. Zinc supplementation seems to have beneficial effects on glucose homeostasis. However, the mechanism of insulin resistance secondary to zinc depletion is yet unclear. More studies are therefore necessary to document better zinc metabolism in diabetes mellitus, and the antioxidant activity of zinc on the insulin receptor and the glucose transporter.

Insulin-dependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosylation modification of signaling proteins in human coronary endothelial cells.

Federici M, Menghini R, Mauriello A, Hribal ML, Ferrelli F, Lauro D, Sbraccia P, Spagnoli LG, Sesti G, Lauro R. Department of Internal Medicine, University of Tor Vergata, Rome, Italy. federicm@uniroma2.it

Circulation 2002 Jul 23;106(4):466-72

BACKGROUND: Hyperglycemia impairs functional properties of cytosolic and nuclear proteins via O-linked glycosylation modification (O-GlcNAcylation). We studied the effects of O-GlcNAcylation on insulin signaling in human coronary artery endothelial cells. METHODS AND RESULTS: O-GlcNAcylation impaired the metabolic branch of insulin signaling, ie, insulin receptor (IR) activation of the IR substrate (IRS)/phosphatidylinositol 3-kinase (PI3-K)/Akt, whereas it enhanced the mitogenic branch, ie, ERK-1/2 and p38 (mitogen-activated protein kinase). Both in vivo and in vitro phosphorylation of endothelial nitric oxide synthase (eNOS) by Akt were reduced by hyperglycemia and hexosamine activation. Insulin-induced eNOS activity in vivo was reduced by hyperglycemia and hexosamine activation, which was coupled to increased activation and expression of matrix metalloproteinase-2 and -9; these phenomena were reversed by inhibition of the hexosamine pathway. Finally, carotid plaques from type 2 diabetic patients showed increased endothelial O-GlcNAcylation with respect to nondiabetics. CONCLUSIONS: Our data show that hyperglycemia, through the hexosamine pathway, impairs activation of the IR/IRS/PI3-K/Akt pathway, resulting in deregulation of eNOS activity.

Effect of Glutamine on the Initiation and Promotion Phases of DMBA-Induced Mammary Tumor Development 1997.

Feng, Z. et al.

Little Rock, AR: University of Arkansas/Medical Sciences Department.

Cross-talk between iron metabolism and diabetes.

Fernandez-Real JM, Lopez-Bermejo A, Ricart W. Unit of Diabetes, Endocrinology and Nutrition, University Hospital of Girona Dr Josep Trueta, Girona, Spain. endocrino@htrueta.scs.es

Diabetes 2002 Aug;51(8):2348-54

Emerging scientific evidence has disclosed unsuspected influences between iron metabolism and type 2 diabetes. The relationship is bi-directional--iron affects glucose metabolism, and glucose metabolism impinges on several iron metabolic pathways. Oxidative stress and inflammatory cytokines influence these relationships, amplifying and potentiating the initiated events. The clinical impact of these interactions depends on both the genetic predisposition and the time frame in which this network of closely related signals acts. In recent years, increased iron stores have been found to predict the development of type 2 diabetes while iron depletion was protective. Iron-induced damage might also modulate the development of chronic diabetes complications. Iron depletion has been demonstrated to be beneficial in coronary artery responses, endothelial dysfunction, insulin secretion, insulin action, and metabolic control in type 2 diabetes. Here, we show that iron modulates insulin action in healthy individuals and in patients with type 2 diabetes. The extent of this influence should be tested in large-scale clinical trials, searching for the usefulness and cost-effectiveness of therapeutic measures that decrease iron toxicity. The study of individual susceptibility and of the mechanisms that influence tissue iron deposition and damage are proposed to be valuable in anticipating and treating diabetes complications.

Hormone replacement therapy is associated with better glycemic control in women with type 2 diabetes: The Northern California Kaiser Permanente Diabetes Registry.

Ferrara A, Karter AJ, Ackerson LM, Liu JY, Selby JV; Northern California Kaiser Permanente Diabetes Registry. Division of Research, Kaiser Permanente, Oakland, CA 94611, USA. azf@dor.kaiser.org

Diabetes Care 2001 Jul;24(7):1144-50

OBJECTIVE: In women with diabetes, the changes that accompany menopause may further diminish glycemic control. Little is known about how hormone replacement therapy (HRT) affects glucose metabolism in diabetes. The aim of this study was to examine whether HbA(1c) levels varied by current HRT among women with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a cohort of 15,435 women with type 2 diabetes who were members of a health maintenance organization, HbA(1c) and HRT were assessed by reviewing records in the health plan's computerized laboratory and pharmacy systems. Sociodemographic and clinical information were collected by survey. RESULTS: The mean age was 64.7 years (SD +/- 8.7). The study cohort comprised 55% non-Hispanic whites, 14% non-Hispanic blacks, 12% Hispanics, 11% Asians, 4% "other" ethnic groups, and 4% with missing ethnicity data. Current HRT was observed in 25% of women. HbA(1c) levels were significantly lower in women currently using HRT than in women not using HRT (age-adjusted mean +/- SE: 7.9 +/- 0.03 vs. 8.5 +/- 0.02, respectively, P = 0.0001). No differences in HbA(1c) level were observed between women using unopposed estrogens and women using opposed estrogens. In a Generalized Estimating Equation model, which took into account patient clustering within physician and adjusted for age, ethnicity, education, obesity, hypoglycemic therapy, diabetes duration, self-monitoring of blood glucose, and exercise, HRT remained significantly and independently associated with decreased HbA(1c) levels (P = 0.0001). CONCLUSIONS: HRT was independently associated with decreased HbA(1c) level. Clinical trials will be necessary to understand whether HRT may improve glycemic control in women with diabetes.

Renoprotective effects of a novel inhibitor of advanced glycation.

Forbes JM, Soulis T, Thallas V, Panagiotopoulos S, Long DM, Vasan S, Wagle D, Jerums G, Cooper ME. Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, West Heidelberg, Australia.

Diabetologia 2001 Jan;44(1):108-14

AIMS/HYPOTHESIS: ALT-946, an inhibitor of advanced glycation with a minimal inhibitory effect on nitric oxide synthase, was compared with aminoguanidine in experimental diabetic nephropathy. METHODS: In vitro and in vivo assays were used to assess the ability of ALT-946 to inhibit AGE-protein cross-link formation. Diabetic animals were randomly allocated into groups receiving aminoguanidine for 32 weeks, ALT-946 or vehicle (untreated). As a delayed intervention protocol, an additional diabetic group was treated with ALT-946 from week 16 to week 32 of the study. Non-diabetic rats were studied concurrently. Systolic blood pressure, body weight, plasma glucose, glycated haemoglobin and urinary albumin excretion were measured serially. Accumulation of advanced-glycation end products in the kidney was assessed by immunohistochemistry. RESULTS: The ALT-946 inhibitor was more potent than aminoguanidine in inhibiting AGE-protein cross-linking both in vitro and in vivo. Increased albuminuria observed in diabetic rats was attenuated in all three treatment groups. We found no difference in body weight, blood pressure or glycaemic control with any of the treatments. The untreated diabetic group had a twofold increase in glomerular staining for advanced-glycation end products compared with the diabetic groups which received treatment. CONCLUSION/INTERPRETATION: ALT-946 is a potent inhibitor of advanced renal glycation end-product accumulation and reproduces the renoprotective effects of aminoguanidine. Therefore, ALT-946 should be considered as a treatment for preventing or retarding diabetic nephropathy.

Sleep Deprivation Promotes Insulin Resistance 2001

Ford-Martin, P.

(http://diabetes.about.com/library/blnews/blnsleep601.htm).

Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study.

Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, Isles C, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ, Shepherd J, Gaw A. Department of Biological Sciences, University of Durham, Durham, UK.

Circulation 2001 Jan 23;103(3):357-62

BACKGROUND: We examined the development of new diabetes mellitus in men aged 45 to 64 years during the West of Scotland Coronary Prevention Study. METHODS AND RESULTS: Our definition of diabetes mellitus was based on the American Diabetic Association threshold of a blood glucose level of < =7.0 mmol/L. Subjects who self-reported diabetes at baseline or had a baseline glucose level of < =7.0 mmol/L were excluded from the analyses. A total of 5974 of the 6595 randomized subjects were included in the analysis, and 139 subjects became diabetic during the study. The baseline predictors of the transition from normal glucose control to diabetes were studied. In the univariate model, body mass index, log triglyceride, log white blood cell count, systolic blood pressure, total and HDL cholesterol, glucose, and randomized treatment assignment to pravastatin were significant predictors. In a multivariate model, body mass index, log triglyceride, glucose, and pravastatin therapy were retained as predictors of diabetes in this cohort. CONCLUSIONS: We concluded that the assignment to pravastatin therapy resulted in a 30% reduction (P:=0.042) in the hazard of becoming diabetic. By lowering plasma triglyceride levels, pravastatin therapy may favorably influence the development of diabetes, but other explanations, such as the anti-inflammatory properties of this drug in combination with its endothelial effects, cannot be excluded with these analyses.

Aminoguanidine prolongs survival in azotemic-induced diabetic rats.

Friedman EA, Distant DA, Fleishhacker JF, Boyd TA, Cartwright K. Department of Medicine, State University of New York, Health Science Center at Brooklyn, NY 11203-2098, USA. elifreidmn@aol.com

Am J Kidney Dis 1997 Aug;30(2):253-9

Toxic effects of hyperglycemia-induced advanced glycosylated end products (AGEs) may explain some vasculopathic complications of diabetes. Aminoguanidine, a known inhibitor of AGE formation, was administered by gavage to Sprague-Dawley streptozotocin-induced diabetic rats made azotemic by surgical reduction of renal mass. All rats became hyperglycemic. Renal ablation caused renal insufficiency, as evidenced by markedly reduced endogenous creatinine clearances at days 7 and 14. Aminoguanidine-treated rats had significantly (< 0.04) superior survival to that of untreated azotemic diabetic rats. We infer from the extended life in a rat model of uremia in diabetic nephropathy that aminoguanidine may prove beneficial in human diabetes.

Effects of varying carbohydrate content of diet in patients with non-insulin-dependent diabetes mellitus.

Garg A, Bantle JP, Henry RR, Coulston AM, Griver KA, Raatz SK, Brinkley L, Chen YD, Grundy SM, Huet BA et al. Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75235-9052.

JAMA 1994 May 11;271(18):1421-8

OBJECTIVE--To study effects of variation in carbohydrate content of diet on glycemia and plasma lipoproteins in patients with non-insulin-dependent diabetes mellitus (NIDDM). DESIGN--A four-center randomized crossover trial. SETTING--Outpatient and inpatient evaluation in metabolic units. PATIENTS--Forty-two NIDDM patients receiving glipizide therapy. INTERVENTIONS--A high-carbohydrate diet containing 55% of the total energy as carbohydrates and 30% as fats was compared with a high-monounsaturated-fat diet containing 40% carbohydrates and 45% fats. The amounts of saturated fats, polyunsaturated fats, cholesterol, sucrose, and protein were similar. The study diets, prepared in metabolic kitchens, were provided as the sole nutrients to subjects for 6 weeks each. To assess longer-term effects, a subgroup of 21 patients continued the diet they received second for an additional 8 weeks. MAIN OUTCOME MEASURES--Fasting plasma glucose, insulin, lipoproteins, and glycosylated hemoglobin concentrations. Twenty-four-hour profiles of glucose, insulin, and triglyceride levels. RESULTS--The site of study as well as the diet order did not affect the results. Compared with the high-monounsaturated-fat diet, the high-carbohydrate diet increased fasting plasma triglyceride levels and very low-density lipoprotein cholesterol levels by 24% (< .0001) and 23% (P = .0001), respectively, and increased daylong plasma triglyceride, glucose, and insulin values by 10% (P = .03), 12% (< .0001), and 9% (P = .02), respectively. Plasma total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels remained unchanged. The effects of both diets on plasma glucose, insulin, and triglyceride levels persisted for 14 weeks. CONCLUSIONS--In NIDDM patients, high-carbohydrate diets compared with high-monounsaturated-fat diets caused persistent deterioration of glycemic control and accentuation of hyperinsulinemia, as well as increased plasma triglyceride and very-low-density lipoprotein cholesterol levels, which may not be desirable.

Diabetes mellitus, hypertension, and cardiovascular disease: which role for oxidative stress?

Giugliano D, Ceriello A, Paolisso G. Department of Geriatrics and Metabolic Diseases, Second University of Naples, Italy.

Metabolism 1995 Mar;44(3):363-8

Accelerated atherosclerotic vascular disease is the leading cause of mortality in patients with diabetes mellitus. Endothelium-derived nitric oxide (NO) is a potent endogenous nitrovasodilator and plays a major role in modulation of vascular tone. Selective impairment of endothelium-dependent relaxation has been demonstrated in aortas of both nondiabetic animals exposed to elevated concentrations of glucose in vitro and insulin-dependent diabetic animals. The impaired NO release in experimentally induced diabetes may be prevented by a number of antioxidants. It has been hypothesized that oxygen-derived free radicals (OFR) generated during both glucose autoxidation and formation of advanced glycosylation end products may interfere with NO action and attenuate its vasodilatory activity. The oxidative injury may also be increased in diabetes mellitus because of a weakened defense due to reduced endogenous antioxidants (vitamin E, reduced glutathione [GSH]). A defective endothelium-dependent vascular relaxation has been found in animal models of hypertension and in hypertensive patients. An imbalance due to reduced production of NO or increased production of free radicals, mainly superoxide anion, may facilitate the development of an arterial functional spasm. Treatment with different antioxidants increases blood flow in the forearm and decreases blood pressure and viscosity in normal humans; vitamin E inhibits nonenzymatic glycosylation, oxidative stress, and red blood cell microviscosity in diabetic patients. Long-term randomized clinical trials of adequate size in secondary and primary prevention could support the free-radical hypothesis for diabetic diabetic vascular complications and the use of antioxidants to reduce the risk of coronary heart disease.

Gopi Memorial Hospital. Role of Silymarin in Diabetes (undated).

Salem, India: Gopi Memorial Hospital/Diabetes Forum

(http://www.diabetesforum.net/eng_treatment_Role_Silymarin.htm).

Metabolic precursors and effects of obesity in children: a decade of progress, 1990-1999.

Goran MI. Institute for Prevention Research, the Department of Preventive Medicine, University of Southern California, Los Angeles, CA USA. goran@usc.edu

Am J Clin Nutr 2001 Feb;73(2):158-71

Current data suggest that 20% of US children are overweight. An analysis of secular trends suggested a clear upward trend in body weight in children of 0.2 kg/y between 1973 and 1994. In addition, childhood obesity is more prevalent among minority subgroups, such as African Americans. Obesity that begins early in life persists into adulthood and increases the risk of obesity-related conditions later in life. Obesity is now considered a disease of epidemic proportions, not just in the United States but also worldwide. In the past 10 y there has been a tremendous increase in the number of studies examining the etiology and health effects of obesity in children. The major objectives of this article are to 1) review highlights in pediatric obesity research from 1990 to 1999; 2) summarize our research on the roles of energy expenditure, physical activity, and aerobic capacity in the etiology of pediatric obesity, and on ethnic differences in the relation between obesity and type 2 diabetes risk factors in children; and 3) discuss areas of future study that will require greater emphasis as the field of childhood obesity research evolves over future years.

Treatment of periodontal disease in diabetics reduces glycated hemoglobin.

Grossi SG, Skrepcinski FB, DeCaro T, Robertson DC, Ho AW, Dunford RG, Genco RJ. Periodontal Disease Research Center, Department of Oral Biology, School of Dental Medicine, Buffalo, NY 14214, USA.

J Periodontol 1997 Aug;68(8):713-9

Periodontal disease is a common infection-induced inflammatory disease among individuals suffering from diabetes mellitus. The purpose of this study was to assess the effects of treatment of periodontal disease on the level of metabolic control of diabetes. A total of 113 Native Americans (81 females and 32 males) suffering from periodontal disease and non-insulin dependent diabetes mellitus (NIDDM) were randomized into 5 treatment groups. Periodontal treatment included ultrasonic scaling and curettage combined with one of the following antimicrobial regimens: 1) topical water and systemic doxycycline, 100 mg for 2 weeks; 2) topical 0.12% chlorhexidine (CHX) and systemic doxycycline, 100 mg for 2 weeks; 3) topical povidone-iodine and systemic doxycycline, 100 mg for 2 weeks; 4) topical 0.12% CHX and placebo; and 5) topical water and placebo (control group). Assessments were performed prior to and at 3 and 6 months after treatment and included probing depth (PD), clinical attachment level (CAL), detection of Porphyromonas gingivalis in subgingival plaque and determination of serum glucose and glycated hemoglobin (HbA1c). After treatment all study groups showed clinical and microbial improvement. The doxycycline-treated groups showed the greatest reduction in probing depth and subgingival Porphyromonas gingivalis compared to the control group. In addition, all 3 groups receiving systemic doxycycline showed, at 3 months, significant reductions (< or = 0.04) in mean HbA1c reaching nearly 10% from the pretreatment value. Effective treatment of periodontal infection and reduction of periodontal inflammation is associated with a reduction in level of glycated hemoglobin. Control of periodontal infections should thus be an important part of the overall management of diabetes mellitus patients.

Clinical and experimental study on the long-term effect of dietary gamma-linolenic acid on plasma lipids, platelet aggregation, thromboxane formation, and prostacyclin production.

Guivernau M, Meza N, Barja P, Roman O. Department of Medicine, School of Medicine, University of Chile, Santiago.

Prostaglandins Leukot Essent Fatty Acids 1994 Nov;51(5):311-6

Effects of a dietary intake of the polyunsaturated omega-6 essential fatty acids (EFAs) linoleic and gamma-linolenic acids (GLA) on blood lipids, platelet function, and vascular prostacyclin production were studied 12 hyperlipidemic patients (doses of 3 g/day) and 12 male Wistar rats (doses of 3 mg/kg/day) for 4 months. In humans, GLA supplementation decreased plasma triglyceride (TG) levels by 48% (< 0.001) and increased HDL-cholesterol concentration by 22% (< 0.01). Total cholesterol and LDL-cholesterol levels were significantly decreased by omega-6 EFAs. Platelet aggregation induced by low concentrations of adenosine diphosphate (ADP) and epinephrine, and serum thromboxane B2 decreased by 45% both in humans and animals after GLA supplementation. Bleeding time increased 40% (p , 0.01). In rats, vascular prostacyclin production measured by radioimmunoassay of 6-keto-PGF1 alpha was enhanced by GLA intake. These effects of omega-6 EFAs may contribute to cardiovascular protection and prevention of the atherosclerotic disease.

Leptin concentrations are increased in subjects treated with clozapine or conventional antipsychotics.

Hagg S, Soderberg S, Ahren B, Olsson T, Mjorndal T. Division of Clinical Pharmacology, Norrland University Hospital, Umea, Sweden. staffan.hagg@pharm.umu.se

J Clin Psychiatry 2001 Nov;62(11):843-8

BACKGROUND: Overweight is a considerable clinical problem in patients treated with antipsychotic agents. Recent results suggest that insulin resistance with increased insulin levels is also associated with treatment with the atypical antipsychotic agent clozapine. Leptin is important for the control of body weight and has been proposed to be a link between obesity and the insulin resistance syndrome. This study examined if clozapine-treated subjects and subjects treated with conventional antipsychotics had increased leptin levels compared with the general population and whether there was a gender difference in this respect. METHOD: Clozapine-treated patients (N = 41), patients treated with conventional antipsychotic drugs (N = 62), and healthy subjects from the Northern Sweden Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) project (N = 189) were investigated with a cross-sectional study design. Weight, body mass index (BMI), and plasma leptin concentrations were measured, and all study subjects were investigated for the presence of diabetes mellitus. Drug treatment, health status, and smoking habits were registered. RESULTS: After adjustment for gender, BMI, smoking habits, age, and diabetes, hyperleptinemia was independently (< .001) associated with clozapine treatment and with treatment with conventional antipsychotics (< .005) within a multiple regression analysis. In separate multiple regression analyses, leptin levels were significantly associated with clozapine treatment in men (p = .002) and women (p =.023) and with conventional antipsychotic treatment in men (p = .027) but not in women. CONCLUSION: Treatment with clozapine as well as with conventional antipsychotics is associated with increased levels of circulating leptin. Hyperleptinemia can be an important link in the development of overweight and the insulin resistance syndrome in subjects receiving antipsychotic drugs, especially atypical agents like clozapine.

Nutrition: Concepts & Controversies, Fourth Edition 1988.

Hamilton, E.M., Whitney, E., Sizer, F.

St. Paul, MN: West.

DHEA treatment reduces fat accumulation and protects against insulin resistance in male rats.

Han DH, Hansen PA, Chen MM, Holloszy JO. Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.

J Gerontol A Biol Sci Med Sci 1998 Jan;53(1):B19-24

The purpose of this study was to determine whether administration of dehydroepiandrosterone (DHEA) protects male rats against the accumulation of body fat the development of insulin resistance with advancing age. We found that supplementation of the diet with 0.3% DHEA between the ages of 5 months and approximately 25 months resulted in a significantly lower final body weight (DHEA, 593 +/- 18 g vs control, 668 +/- 12 g, < 0.02), despite no decrease in food intake. Lean body mass was unaffected by the DHEA, and the lower body weight was due to a approximately 25% reduction in body fat. The rate of glucose disposal during a euglycemic, hyperinsulinemic clamp was 30% higher in the DHEA group than in the sedentary controls due to a greater insulin responsiveness. The DHEA administration was as effective in reducing body fat content and maintaining insulin responsiveness as exercise in the form of voluntary wheel running. The DHEA had no significant effect on muscle GLUT4 content. A preliminary experiment provided evidence suggesting that muscle insulin signaling, as reflected in binding of phosphatidylinositol 3-kinase to the insulin receptor substrate-1, was enhanced in the DHEA-treated and wheel running groups as compared to controls. These results provide evidence that DHEA, like exercise, protects against excess fat accumulation and development of insulin resistance in rats.

Favorable Facts About Fiber 2001

Hayes, C.

(http://www.dailycarconline.com/diabetes_fw_00/01_favorable_facts.htm).

Energy restriction and weight loss on very-low-fat diets reduce C-reactive protein concentrations in obese, healthy women.

Heilbronn LK, Noakes M, Clifton PM. Department of Physiology, Adelaide University, Adelaide, South Australia. leonie.heilbronn@hsn.csiro.au

Arterioscler Thromb Vasc Biol 2001 Jun;21(6):968-70

C-reactive protein (CRP) is an inflammatory-response protein that is a strong, independent predictor of cardiovascular mortality. CRP is positively associated with body mass index (BMI). In this study, we investigated the effects of dynamic weight loss on CRP in 83 healthy, obese women (mean BMI, 33.8+/-0.4 kg/m(2); range, 28.2 to 43.8 kg/m(2)). Subjects were placed on very-low-fat, energy-restricted diets (5700 kJ, 15% fat) for 12 weeks. Weight, waist and hip circumferences, plasma lipids, glucose, and CRP were measured at baseline and after 12 weeks. CRP was positively associated with BMI (r=0.281, P=0.01) and waist circumference (r=0.278, P=0.01) but was not related to other atherosclerosis risk factors. BMI was significantly different between groups split above or below the median for CRP (34.8+/-0.6 kg/m(2) vs 33.0+/-0.5 kg/m(2), P=0.02). After 12 weeks, weight loss was 7.9+/-0.3 kg. CRP was significantly decreased by 26% (<0.001), and a correlation was observed between weight loss and the change in CRP (r=0.309, P=0.005). The variance in the change in CRP was partly explained by initial CRP (13.6%), energy intake (5.4%), and percentage weight loss (4.6%, P=0.001). This study confirms recent observations that BMI is associated with CRP, a marker for low-grade systemic inflammation. Furthermore, we observed that CRP was lowered in proportion to weight loss.

Profactor-H (elevated circulating insulin): the link to health risk factors and diseases of civilization.

Heller RF, Heller RF. Department of Pathology, Mount Sinai School of Medicine, New York, NY 10029, USA.

Med Hypotheses 1995 Oct;45(4):325-30

We propose the term Profactor-H for chronic elevated circulating insulin. Profactor-H is common in atherosclerosis, essential hypertension, non-insulin dependent diabetes mellitus, some forms of obesity, some forms of cancer, cardiovascular disease, peripheral vascular disease and some forms of stroke. Profactor-H appears to be the central pathophysiologic consideration in the etiology of many diseases and health risk factors. Profactor-H's impact depends on genetic predisposition, frequency consumption of refined simple and complex carbohydrates, deficiency in dietary chromium, sedentary life style and stresses of modern day living. In many obese individuals, Profactor-H disturbs metabolic balance, favoring anabolic metabolism, and is exacerbated through chronic insulin production and impairment of insulin action. This vicious cycle also appears to be common in many apparently healthy, non-obese individuals destined to develop health risks and diseases in response to long-term adverse consequences of Profactor-H. We believe that a four-pronged program which 1) reduces the daily frequency of carbohydrate consumption, particularly refined foods and simple sugars, 2) supplements the daily dietary intake of chromium, 3) encourages activity, and 4) reduces stress, will minimize the impact of Profactor-H and thereby reduce health risks and result in improved health.

Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus.

Helmrich SP, Ragland DR, Leung RW, Paffenbarger RS Jr. School of Public Health, University of California, Berkeley, CA.

N Engl J Med 1991 Jul 18;325(3):147-52

BACKGROUND. Physical activity is recommended by physicians to patients with non-insulin-dependent diabetes mellitus (NIDDM), because it increases sensitivity to insulin. Whether physical activity is effective in preventing this disease is not known. METHODS. We used questionnaires to examine patterns of physical activity and other personal characteristics in relation to the subsequent development of NIDDM in 5990 male alumni of the University of Pennsylvania. The disease developed in a total of 202 men during 98,524 man-years of follow-up from 1962 to 1976. RESULTS. Leisure-time physical activity, expressed in kilocalories expended per week in walking, stair climbing, and sports, was inversely related to the development of NIDDM. The incidence rates declined as energy expenditure increased from less than 500 kcal to 3500 kcal. For each 500-kcal increment in energy expenditure, the age-adjusted risk of NIDDM was reduced by 6 percent (relative risk, 0.94; 95 percent confidence interval, 0.90 to 0.98). This association remained the same when the data were adjusted for obesity, hypertension, and a parental history of diabetes. The association was weaker when we considered weight gain between the time of college attendance and 1962 (relative risk, 0.95; 95 percent confidence interval, 0.90 to 1.00). The protective effect of physical activity was strongest in persons at highest risk for NIDDM, defined as those with a high body-mass index, a history of hypertension, or a parental history of diabetes. These factors, in addition to weight gain since college, were also independent predictors of the disease. CONCLUSIONS. Increased physical activity is effective in preventing NIDDM, and the protective benefit is especially pronounced in persons at the highest risk for the disease.

Antioxidants: Alpha Lipoic Acid 2002

Hinderliter, L.

(http://vitaminlady.com/Articles/ALA.art.htm).

A possible new role for the anti-ageing peptide carnosine.

Hipkiss AR, Brownson C. Biomolecular Sciences Division, GKT School of Biomedical Sciences, King's College London, UK. alan.hipkiss@kcl.ac.uk

Cell Mol Life Sci 2000 May;57(5):747-53

The naturally occurring dipeptide carnosine (beta-alanyl-L-histidine) is found in surprisingly large amounts in long-lived tissues and can delay ageing in cultured human fibroblasts. Carnosine has been regarded largely as an anti-oxidant and free radical scavenger. More recently, an anti-glycating potential has been discovered whereby carnosine can react with low-molecular-weight compounds that bear carbonyl groups (aldehydes and ketones). Carbonyl groups, arising mostly from the attack of reactive oxygen species and low-molecular-weight aldehydes and ketones, accumulate on proteins during ageing. Here we propose, with supporting evidence, that carnosine can react with protein carbonyl groups to produce protein-carbonyl-carnosine adducts ('carnosinylated' proteins). The various possible cellular fates of the carnosinylated proteins are discussed. These proposals may help explain anti-ageing actions of carnosine and its presence in non-mitotic cells of long-lived mammals.

Cinnamon Helps Stop Type 2 Diabetes 2000

Hodge, M.

(http://chetday.com/type2diabetes.htm).

Dietary conjugated linoleic acid normalizes impaired glucose tolerance in the Zucker diabetic fatty fa/fa rat.

Houseknecht KL, Vanden Heuvel JP, Moya-Camarena SY, Portocarrero CP, Peck LW, Nickel KP, Belury MA. Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA.

Biochem Biophys Res Commun 1998 Mar 27;244(3):678-82

Conjugated linoleic acid (CLA) is a naturally occurring fatty acid which has anti-carcinogenic and anti-atherogenic properties. CLA activates PPAR alpha in liver, and shares functional similarities to ligands of PPAR gamma, the thiazolidinediones, which are potent insulin sensitizers. We provide the first evidence that CLA is able to normalize impaired glucose tolerance and improve hyperinsulinemia in the pre-diabetic ZDF rat. Additionally, dietary CLA increased steady state levels of aP2 mRNA in adipose tissue of fatty ZDF rats compared to controls, consistent with activation of PPAR gamma. The insulin sensitizing effects of CLA are due, at least in part, to activation of PPAR gamma since increasing levels of CLA induced a dose-dependent transactivation of PPAR gamma in CV-1 cells cotransfected with PPAR gamma and PPRE X 3-luciferase reporter construct. CLA effects on glucose tolerance and glucose homeostasis indicate that dietary CLA may prove to be an important therapy for the prevention and treatment of NIDDM.

Diet, lifestyle, and the risk of type 2 diabetes mellitus in women.

Hu FB, Manson JE, Stampfer MJ, Colditz G, Liu S, Solomon CG, Willett WC. Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA. frank.hu@channing.harvard.edu

N Engl J Med 2001 Sep 13;345(11):790-7

BACKGROUND: Previous studies have examined individual dietary and lifestyle factors in relation to type 2 diabetes, but the combined effects of these factors are largely unknown. METHODS: We followed 84,941 female nurses from 1980 to 1996; these women were free of diagnosed cardiovascular disease, diabetes, and cancer at base line. Information about their diet and lifestyle was updated periodically. A low-risk group was defined according to a combination of five variables: a bodymass index (the weight in kilograms divided by the square of the height in meters) of less than 25; a diet high in cereal fiber and polyunsaturated fat and low in trans fat and glycemic load (which reflects the effect of diet on the blood glucose level); engagement in moderate-to-vigorous physical activity for at least half an hour per day; no current smoking; and the consumption of an average of at least half a drink of an alcoholic beverage per day. RESULTS: During 16 years of follow-up, we documented 3300 new cases of type 2 diabetes. Overweight or obesity was the single most important predictor of diabetes. Lack of exercise, a poor diet, current smoking, and abstinence from alcohol use were all associated with a significantly increased risk of diabetes, even after adjustment for the body-mass index. As compared with the rest of the cohort, women in the low-risk group (3.4 percent of the women) had a relative risk of diabetes of 0.09 (95 percent confidence interval, 0.05 to 0.17). A total of 91 percent of the cases of diabetes in this cohort (95 percent confidence interval, 83 to 95) could be attributed to habits and forms of behavior that did not conform to the low-risk pattern. CONCLUSIONS: Our findings support the hypothesis that the vast majority of cases of type 2 diabetes could be prevented by the adoption of a healthier lifestyle.

Can Cinnamon Help Control Blood Sugar? 2000.

IBN.

Winter Park, FL: Ivanhoe Broadcast News (http://www.newsmakingnews.com/contents9%2C13%2C00.htm).

In vivo and in vitro evidence for the glycoxidation of low density lipoprotein in human atherosclerotic plaques.

Imanaga Y, Sakata N, Takebayashi S, Matsunaga A, Sasaki J, Arakawa K, Nagai R, Horiuchi S, Itabe H, Takano T. Second Department of Pathology, School of Medicine, Fukuoka University, 45-1, 7-chome Nanakuma, Jonan-ku, 814-0180, Fukuoka, Japan.

Atherosclerosis 2000 Jun;150(2):343-55

Although there have been suggestions that the glycation and oxidation of low density lipoprotein (LDL) might increase its atherogenic potential, little is known about the presence of glycoxidative LDL in human atherosclerotic lesions. We developed specific antibodies against different immunological epitopes of AGE structures, including N(varepsilon)-(carboxymethyl)lysine-protein adduct (CML), a glycoxidation product, and structure(s) other than CML (nonCML), and a monoclonal antibody against oxidized phosphatidylcholine (oxPC), as an epitope of oxidized LDL. Immunohistochemical analysis demonstrated that the CML- and oxPC-epitopes were accumulated mainly in macrophage-derived foam cells in atherosclerotic lesions, including fatty streaks and atherosclerotic plaques. On the other hand, the nonCML-epitope and apolipoprotein B were localized mainly in extracellular matrices of atherosclerotic lesions. The CML- and oxPC-epitopes were characterized by a model antigen-generating system using the copper ion-induced peroxidation and/or glucose-induced glycation of LDL. The glycoxidation of LDL caused the formation of CML-epitope with increasing concentrations of copper ion and glucose. It was also formed to some extent in LDL incubated with high concentrations (500 mM) of glucose. However, no CML-epitope was observed in oxidized LDL induced by copper ion alone. On the other hand, the formation of oxPC-epitope in LDL was dependent on copper ion-induced peroxidation, but independent of glucose-induced glycation. The addition of chelators, ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid, reduced the increase in electrophoretic mobility and TBARS caused by the peroxidation and glycoxidation of LDL, but had no effects on the formation of fructosamine caused by the glycation and glycoxidation of LDL. Chelators as well as aminoguanidine protected the formation of CML-epitope in glycated or glycoxidative LDL. Although the formation of oxPC-epitope was completely inhibited by the addition of chelators, it was partially protected by aminoguanidine. These in vitro results suggest that the glycoxidative modification of LDL may occur in the arterial intima, and may contribute to the development of human atherosclerotic lesions.

Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid.

Jacob S, Henriksen EJ, Schiemann AL, Simon I, Clancy DE, Tritschler HJ, Jung WI, Augustin HJ, Dietze GJ. Department of Internal Medicine, City Hospital, Baden-Baden, Germany.

Arzneimittelforschung 1995 Aug;45(8):872-4

Insulin resistance of skeletal muscle glucose uptake is a prominent feature of Type II diabetes (NIDDM); therefore pharmacological interventions should aim to improve insulin sensitivity. Alpha-lipoic acid (CAS 62-46-4, thioctic acid, ALA), a natural occurring compound frequently used for treatment of diabetic polyneuropathy, enhances glucose utilization in various experimental models. To see whether this compound also augments insulin mediated glucose disposal in NIDDM, 13 patients received either ALA (1000 mg/Thioctacid/500 ml NaCl, n = 7) or vehicle only (500 ml NaCl, n = 6) during a glucose-clamp study. Both groups were comparable in age, body-mass index and duration of diabetes and had a similar degree of insulin resistance at baseline. Acute parenteral administration of ALA resulted in a significant increase of insulin-stimulated glucose disposal; metabolic clearance rate (MCR) for glucose rose by about 50% (3.76 ml/kg/min = pre vs. 5.82 ml/kg/min = post, p &lt; 0.05), whereas the control group did not show that alpha-lipoic acid increases insulin stimulated glucose disposal in NIDDM. The mode of action of ALA and its potential use as an antihyperglycemic agent require further investigation.

The antioxidant alpha-lipoic acid enhances insulin-stimulated glucose metabolism in insulin-resistant rat skeletal muscle.

Jacob S, Streeper RS, Fogt DL, Hokama JY, Tritschler HJ, Dietze GJ, Henriksen EJ. Department of Physiology, University of Arizona College of Medicine, Tucson, AZ, USA.

Diabetes 1996 Aug;45(8):1024-9

Insulin resistance of muscle glucose metabolism is a hallmark of NIDDM. The obese Zucker (fa/fa) rat--an animal model of muscle insulin resistance--was used to test whether acute (100 mg/kg body wt for 1 h) and chronic (5-100 mg/kg for 10 days) parenteral treatments with a racemic mixture of the antioxidant alpha-lipoic acid (ALA) could improve glucose metabolism in insulin-resistant skeletal muscle. Glucose transport activity (assessed by net 2-deoxyglucose [2-DG] uptake), net glycogen synthesis, and glucose oxidation were determined in the isolated epitrochlearis muscles in the absence or presence of insulin (13.3 nmol/l). Severe insulin resistance of 2-DG uptake, glycogen synthesis, and glucose oxidation was observed in muscle from the vehicle-treated obese rats compared with muscle from vehicle-treated lean (Fa/-) rats. Acute and chronic treatments (30 mg.kg-1.day-1, a maximally effective dose) with ALA significantly (P &lt; 0.05) improved insulin-mediated 2-DG uptake in epitrochlearis muscles from the obese rats by 62 and 64%, respectively. Chronic ALA treatment increased both insulin-stimulated glucose oxidation (33%) and glycogen synthesis (38%) and was associated with a significantly greater (21%) in vivo muscle glycogen concentration. These adaptive responses after chronic ALA administration were also associated with significantly lower (15-17%) plasma levels of insulin and free fatty acids. No significant effects on glucose transporter (GLUT4) protein level or on the activities of hexokinase and citrate synthase were observed. Collectively, these findings indicate that parenteral administration of the antioxidant ALA significantly enhances the capacity of the insulin-stimulatable glucose transport system and of both oxidative and nonoxidative pathways of glucose metabolism in insulin-resistant rat skeletal muscle.

The radical scavenger a-lipoic acid enhances insulin sensitivity in patients with NIDDM; a placebo-controlled trial.

Jacob, S. et al.

Presented at Oxidants and Antioxidants in Biology, Santa Barbara, California, February 27 March 1, 1997.

Lipoic acid (LA) decreases protein glycation and increases (NA++K+)- and Ca++ATPases activities in high glucose (G)-treated red blood cells (RBC)

Jain SK, Lim G. Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA, USA

Free Radical Biol. Med. 1998; 25: S94 (Abstr. 268)

Lipoic acid supplementation has been found to be beneficial in preventing neurovascular abnormalities in diabetic neuropathy. Insufficient (Na+ + K+)-ATPase activity has been suggested as a contributing factor in the development of diabetic neuropathy. This study was undertaken to test the hypothesis that lipoic acid reduces lipid peroxidation and glycosylation and can increase the (Na+ + K+)- and Ca++-ATPase activities in high glucose-exposed red blood cells (RBC). Washed normal human RBC were treated with normal (6 mM) and high glucose concentrations (45 mM) with 0-0.2 mM lipoic acid (mixture of S and R sterioisomers) in a shaking water bath at 37°C for 24 h. There was a significant stimulation of glucose consumption by RBC in the presence of lipoic acid both in normal and high glucose-treated RBC. Lipoic acid significantly lowered the level of glycated hemoglobin (GHb) and lipid peroxidation in RBC exposed to high glucose concentrations. High glucose treatment significantly lowered the activities of (Na+ + K+)- and Ca++-ATPases of RBC membranes. Lipoic acid addition significantly blocked the reduction in activities of (Na+ + K+)- and Ca++-ATPases in high glucose- treated RBC. There were no differences in lipid peroxidation, GHb and (Na+ + K+)- and Ca++-ATPase activity levels in normal glucose-treated RBC with and without lipoic acid. Thus, lipoic acid can lower lipid peroxidation and protein glycosylation, and increase (Na+ + K+)- and Ca++-ATPase activities in high-glucose exposed RBC, which provides a potential mechanism by which lipoic acid may delay or inhibit the development of neuropathy in diabetes.

Lipoic acid decreases lipid peroxidation and protein glycosylation and increases (Na(+) + K(+))- and Ca(++)-ATPase activities in high glucose-treated human erythrocytes.

Jain SK, Lim G. Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA. sjain@lsuhsc.edu

Free Radic Biol Med 2000 Dec;29(11):1122-8

Lipoic acid supplementation has been found to be beneficial in preventing neurovascular abnormalities in diabetic neuropathy. Insufficient (Na(+) + K(+))-ATPase activity has been suggested as a contributing factor in the development of diabetic neuropathy. This study was undertaken to test the hypothesis that lipoic acid reduces lipid peroxidation and glycosylation and can increase the (Na(+) + K(+))- and Ca(++)-ATPase activities in high glucose-exposed red blood cells (RBC). Washed normal human RBC were treated with normal (6 mM) and high glucose concentrations (45 mM) with 0-0.2 mM lipoic acid (mixture of S and R sterioisomers) in a shaking water bath at 37 degrees C for 24 h. There was a significant stimulation of glucose consumption by RBC in the presence of lipoic acid both in normal and high glucose-treated RBC. Lipoic acid significantly lowered the level of glycated hemoglobin (GHb) and lipid peroxidation in RBC exposed to high glucose concentrations. High glucose treatment significantly lowered the activities of (Na(+) + K(+))- and Ca(++)-ATPases of RBC membranes. Lipoic acid addition significantly blocked the reduction in activities of (Na(+) + K(+))- and Ca(++)-ATPases in high glucose- treated RBC. There were no differences in lipid peroxidation, GHb and (Na(+) + K(+))- and Ca(++)-ATPase activity levels in normal glucose-treated RBC with and without lipoic acid. Thus, lipoic acid can lower lipid peroxidation and protein glycosylation, and increase (Na(+) + K(+))- and Ca(++)-ATPase activities in high-glucose exposed RBC, which provides a potential mechanism by which lipoic acid may delay or inhibit the development of neuropathy in diabetes.

A hydroxychalcone derived from cinnamon functions as a mimetic for insulin in 3T3-L1 adipocytes.

Jarvill-Taylor KJ, Anderson RA, Graves DJ. Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011, USA.

J Am Coll Nutr 2001 Aug;20(4):327-36

OBJECTIVES: These studies investigated the ability of a hydroxychalcone from cinnamon to function as an insulin mimetic in 3T3-LI adipocytes. METHODS: Comparative experiments were performed with the cinnamon methylhydroxychalcone polymer and insulin with regard to glucose uptake, glycogen synthesis. phosphatidylinositol-3-kinase dependency, glycogen synthase activation and glycogen synthase kinase-3beta activity. The phosphorylation state of the insulin receptor was also investigated. RESULTS: MHCP treatment stimulated glucose uptake and glycogen synthesis to a similar level as insulin. Glycogen synthesis was inhibited by both wortmannin and LY294002, inhibitors directed against the PI-3-kinase. In addition, MHCP treatment activated glycogen synthase and inhibited glycogen synthase kinase-3beta activities, known effects of insulin treatment. Analysis of the insulin receptor demonstrated that the receptor was phosphorylated upon exposure to the MHCP. This supports that the insulin cascade was triggered by MHCP. Along with comparing MHCP to insulin, experiments were done with MHCP and insulin combined. The responses observed using the dual treatment were greater than additive, indicating synergism between the two compounds. CONCLUSION: Together, these results demonstrate that the MHCP is an effective mimetic of insulin. MHCP may be useful in the treatment of insulin resistance and in the study of the pathways leading to glucose utilization in cells.

Obesity as a disease.

Jung RT. Diabetic Centre, Ninewells Hospital, Dundee, UK.

Br Med Bull 1997;53(2):307-21

Obesity is associated with the development of some of the most prevalent diseases of modern society. The greatest risk is for diabetes mellitus where a body mass index above 35 kg/m2 increases the risk by 93-fold in women and by 42-fold in men. The risk of coronary heart disease is increased 86% by a 20% rise in weight in males, whereas in obese women the risk is increased 3.6-fold. Elevation of blood pressure, hyperlipidaemia and altered haemostatic factors are implicated in this high risk from coronary heart disease. Gallbladder disease is increased 2.7-fold with an enhanced cancer risk especially for colorectal cancer in males and cancer of the endometrium and biliary passages in females. Endocrine changes are associated with metabolic diseases and infertility, and respiratory problems result in sleep apnoea, hypoventilation, arrhythmias and eventual cardiac failure. Obesity is not a social stigma but an actual disease with a major genetic component to its aetiology and a financial cost estimated at $69 billion for the USA alone.

Skin tags: a cutaneous marker for diabetes mellitus.

Kahana M, Grossman E, Feinstein A, Ronnen M, Cohen M, Millet MS.

Acta Derm Venereol 1987;67(2):175-7

Two hundred and sixteen non hospitalized patients with skin tags (ST) were studied for the presence of diabetes mellitus (DM) and obesity. Overt DM was found in 57 (26.3%) patients and impaired glucose tolerance test was found in 17 (7.9%) patients. Sixteen new cases of DM were found among this group. All the diabetic patients in the study population had non-insulin dependent DM. Sixty-two (28.7%) of the patients were obese. No correlation was found between the localization, size, colour and number of the ST and the presence of DM. Our study indicates that ST are not associated with increased incidence of obesity compared to the general population. On the other hand, ST are associated with impaired carbohydrate metabolism, and may serve as means for identifying patients at increasing risk of having DM.

Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity.

Kaneto H, Kajimoto Y, Miyagawa J, Matsuoka T, Fujitani Y, Umayahara Y, Hanafusa T, Matsuzawa Y, Yamasaki Y, Hori M. Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan.

Diabetes 1999 Dec;48(12):2398-406

Oxidative stress is produced under diabetic conditions and possibly causes various forms of tissue damage in patients with diabetes. The aim of this study was to examine the involvement of oxidative stress in the progression of pancreatic beta-cell dysfunction in type 2 diabetes and to evaluate the potential usefulness of antioxidants in the treatment of type 2 diabetes. We used diabetic C57BL/KsJ-db/db mice, in whom antioxidant treatment (N-acetyl-L-cysteine [NAC], vitamins C plus E, or both) was started at 6 weeks of age; its effects were evaluated at 10 and 16 weeks of age. According to an intraperitoneal glucose tolerance test, the treatment with NAC retained glucose-stimulated insulin secretion and moderately decreased blood glucose levels. Vitamins C and E were not effective when used alone but slightly effective when used in combination with NAC. No effect on insulin secretion was observed when the same set of antioxidants was given to nondiabetic control mice. Histologic analyses of the pancreases revealed that the beta-cell mass was significantly larger in the diabetic mice treated with the antioxidants than in the untreated mice. As a possible cause, the antioxidant treatment suppressed apoptosis in beta-cells without changing the rate of beta-cell proliferation, supporting the hypothesis that in chronic hyperglycemia, apoptosis induced by oxidative stress causes reduction of beta-cell mass. The antioxidant treatment also preserved the amounts of insulin content and insulin mRNA, making the extent of insulin degranulation less evident. Furthermore, expression of pancreatic and duodenal homeobox factor-1 (PDX-1), a beta-cell-specific transcription factor, was more clearly visible in the nuclei of islet cells after the antioxidant treatment. In conclusion, our observations indicate that antioxidant treatment can exert beneficial effects in diabetes, with preservation of in vivo beta-cell function. This finding suggests a potential usefulness of antioxidants for treating diabetes and provides further support for the implication of oxidative stress in beta-cell dysfunction in diabetes.

Caffeine can decrease insulin sensitivity in humans.

Keijzers GB, De Galan BE, Tack CJ, Smits P. Department of Internal Medicine, University Medical Center Nijmegen, 6500 HB Nijmegen, the Netherlands.

Diabetes Care 2002 Feb;25(2):364-9

OBJECTIVE: Caffeine is a central stimulant that increases the release of catecholamines. As a component of popular beverages, caffeine is widely used around the world. Its pharmacological effects are predominantly due to adenosine receptor antagonism and include release of catecholamines. We hypothesized that caffeine reduces insulin sensitivity, either due to catecholamines and/or as a result of blocking adenosine-mediated stimulation of peripheral glucose uptake. RESEARCH DESIGN AND METHODS: Hyperinsulinemic-euglycemic glucose clamps were used to assess insulin sensitivity. Caffeine or placebo was administered intravenously to 12 healthy volunteers in a randomized, double-blind, crossover design. Measurements included plasma levels of insulin, catecholamines, free fatty acids (FFAs), and hemodynamic parameters. Insulin sensitivity was calculated as whole-body glucose uptake corrected for the insulin concentration. In a second study, the adenosine reuptake inhibitor dipyridamole was tested using an identical protocol in 10 healthy subjects. RESULTS: Caffeine decreased insulin sensitivity by 15% (P &lt; 0.05 vs. placebo). After caffeine administration, plasma FFAs increased (P &lt; 0.05) and remained higher than during placebo. Plasma epinephrine increased fivefold (P &lt; 0.0005), and smaller increases were recorded in plasma norepinephrine (P &lt; 0.02) and blood pressure (P &lt; 0.001). Dipyridamole did not alter insulin sensitivity and only increased plasma norepinephrine (P &lt; 0.01). CONCLUSIONS: Caffeine can decrease insulin sensitivity in healthy humans, possibly as a result of elevated plasma epinephrine levels. Because dipyridamole did not affect glucose uptake, peripheral adenosine receptor antagonism does not appear to contribute to this effect.

Pharmacotherapy Update: Newsletter Excerpts from the Department of Pharmacology. A Review of Oral Antidiabetic Drugs 2001

Ketz, J.

(http://www.clevelandclinicmeded.com/medical_info/pharmacy/MayJune2001/oral_anitdiabetic.htm).

Lipoic acid acutely induces hypoglycemia in fasting nondiabetic and diabetic rats.

Khamaisi M, Rudich A, Potashnik R, Tritschler HJ, Gutman A, Bashan N. Department of Clinical Biochemistry, Faculty of Health Sciences, Soroka Medical Center and Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Metabolism 1999 Apr;48(4):504-10

Lipoic acid (LA) is a unique antioxidant that increases peripheral glucose utilization in diabetic patients. This study was conducted to investigate whether the inhibition of glucose production could be an additional mechanism for the action of LA. Intravenous (i.v.) LA injection (100 or 60 mg/kg body weight) to fasting nondiabetic or streptozotocin (STZ)-induced diabetic rats caused a rapid reduction in blood glucose with no effect on circulating insulin levels. In vivo conversion of fructose to glucose was not inhibited by LA, whereas the gluconeogenesis flux from alanine was completely prevented. Reduced liver pyruvate carboxylase (PC) activity in vivo is suggested by the finding that LA induced a decrease in liver coenzyme A (CoA) content (44% and 28% reduction in nondiabetic and diabetic rats, respectively, compared with vehicle-treated animals) and liver acetyl CoA content (80% and 67% reduction in nondiabetic and diabetic rats, respectively). A reduction in plasma free carnitine (42% and 22% in nondiabetic and diabetic rats, respectively) was observed in LA-treated animals, and acylcarnitine levels were increased twofold. This could be attributed to elevated levels of C16 and C18 acylcarnitine, without a detectable accumulation of lipoylcarnitine. Under such conditions, a significant increase in the plasma free fatty acid (FFA) concentration (204% in nondiabetic and 151% in diabetic animals) with no elevation in beta-hydroxybutyrate levels was noted. In conclusion, this study suggests that short-term administration of LA at high dosage to normal and diabetic rats causes an inhibition of gluconeogenesis secondary to an interference with hepatic fatty acid oxidation. This may render LA an antihyperglycemic agent for the treatment of diabetic subjects, who display glucose overproduction as a major metabolic abnormality.

Infection, hemostatic factors and cardiovascular disease.

Khaw K T(a); Woodhouse P Clin. Gerontol. Unit, F and G level 2, Univ. Cambridge Sch. Clin. Med., Addenbrooke's Hosp., Cam**UK

Fibrinolysis &amp;amp; Proteolysis 1997 11 ( SUPPL. 1 ): p 149-153

While hemostatic factors such as fibrinogen and factor VIIc have been implicated as risk factors for cardiovascular disease, determinants of levels of these factors in the population are not well understood. We present data suggesting that infection may be an important determinant of fibrinogen and factor VII levels in the general population, and this may be one possible mechanism to explain the, now well-documented, association between chronic or acute infection and acute vascular events. We also present data indicating that vitamin C levels may influence markers of inflammation associated with infection as well as levels of hemostatic factors. Each winter in most countries, there is a 15%-30% increase in deaths from cardiovascular and respiratory disease. This observed seasonal variation may provide a means of examining the role of various cardiovascular risk factors and their possible environmental determinants. We followed 96 men and women over one year in the UK to examine determinants of the seasonal variation in cardiovascular risk factors. Our findings indicate that some of the excess winter cardiovascular mortality may be related to a winter rise in concentrations of hemostatic factors including fibrinogen and factor VII. The increase in fibrinogen concentrations in this cohort was related to an increase in winter infections measured both by self-reported symptoms and biologic markers including neutrophil count, C-reactive protein, and alpha-1-anti-chymotrypsin. Further, the winter increases in infection markers and hemostatic factors appeared to be due to a winter decline in dietary vitamin C intake (largely derived from fruit and vegetables), and corresponding serum levels. Raised levels of hemostatic factors, infection and inflammation, and low levels of vitamin C have separately been implicated in epidemiologic studies as risk factors for cardiovascular disease. Our data suggest that these factors are interrelated and has led to the hypothesis that vitamin C may influence cardiovascular risk by modulating the inflammatory response to infection, and hence, thrombotic tendency. This raises the possibility of potential new interventions to reduce cardiovascular risk.

Diabetes and depot medroxyprogesterone contraception in Navajo women.

Kim C, Seidel KW, Begier EA, Kwok YS. Robert Wood Johnson Clinical Scholars Program, Box 357183, University of Washington, Seattle, WA 98195-7183, USA. cathykim@u.washington.edu

Arch Intern Med 2001 Jul 23;161(14):1766-71

BACKGROUND: Depot medroxyprogesterone acetate contraception is widely used in Navajo women, a high-risk population for diabetes mellitus. However, depot medroxyprogesterone may lead to weight gain and independently decrease insulin sensitivity. We studied the association between depot medroxyprogesterone and development of diabetes in Navajo women. METHODS: We studied Navajo women aged 18 to 50 years who had seen a health care provider at a Navajo Area Indian Health Service clinic at least once in 1998. Diabetic cases (n = 284) and nondiabetic controls (n = 570) were matched by age. Medical records were reviewed to determine contraception use before the diagnosis date of diabetes. RESULTS: Users of depot medroxyprogesterone were more likely to develop diabetes than patients who had used combination estrogen-progestin oral contraception only (odds ratio [OR], 3.8; 95% confidence interval [CI], 1.8-7.9). The excess risk persisted after adjustment for body mass index (OR, 3.6; 95% CI, 1.6-7.9). Longer use was associated with greater risk of diabetes. Users of depot medroxyprogesterone were also more likely to develop diabetes than patients who had never used hormonal contraception, although excess risk was smaller (OR, 2.4; 95% CI, 1.4-3.6). CONCLUSIONS: Depot medroxyprogesterone contraception was associated with a greater risk of diabetes compared with combination oral contraceptive use only. Risk was associated with length of use and persisted after adjustment for body mass index. Additional research is needed for confirmation, but this risk should be considered in contraceptive choice for women at high risk for diabetes.

On the principles of functional ordering in biological membranes.

Kinnunen PK. Department of Medical Chemistry, University of Helsinki, Finland.

Chem Phys Lipids 1991 Mar;57(2-3):375-99

Integrating the available data on lipid-protein interactions and ordering in lipid mixtures allows to emanate a refined model for the dynamic organization of biomembranes. An important difference to the fluid mosaic model is that a high degree of spatiotemporal order should prevail also in liquid crystalline, "fluid" membranes and membrane domains. The interactions responsible for ordering the membrane lipids and proteins are hydrophobicity, coulombic forces, van der Waals dispersion, hydrogen bonding, hydration forces and steric elastic strain. Specific lipid-lipid and lipid-protein interactions result in a precisely controlled yet highly dynamic architecture of the membrane components, as well as in its selective modulation by the cell and its environment. Different modes of organization of the compositionally and functionally differentiated domains would correspond to different functional states of the membrane. Major regulators of membrane architecture are proposed to be membrane potential controlled by ion channels, intracellular Ca2+, pH, changes in lipid composition due to the action of phospholipase, cell-cell coupling, as well as coupling of the membrane with the cytoskeleton and the extracellular matrix. Membrane architecture is additionally modulated due to the membrane association of ions, lipo- and amphiphilic hormones, metabolites, drugs, lipid-binding peptide hormones and amphitropic proteins. Intermolecular associations in the membrane and in the membrane-cytoskeleton interface are further selectively controlled by specific phosphorylation and dephosphorylation cascades involving both proteins and lipids, and regulated by the extracellular matrix and the binding of growth factors and hormones to their specific receptor tyrosine kinases. A class of proteins coined architectins is proposed, as a notable example the pp60src kinase. The functional role of architectins would be in causing specific changes in the cytoskeleton-membrane interface, leading to specific configurational changes both in the membrane and cytoskeleton architecture and corresponding to (a) distinct metabolic/differentiation states of the cell, and (b) the formation and maintenance of proper three dimensional membrane structures such as neurites and pseudopods.

Dehydroepiandrosterone selectively inhibits production of tumor necrosis factor alpha and interleukin-6 [correction of interlukin-6] in astrocytes.

Kipper-Galperin M, Galilly R, Danenberg HD, Brenner T. Laboratory of Neuroimmunology, Hadassah University Hospital, Jerusalem, Israel.

Int J Dev Neurosci 1999 Dec;17(8):765-75

Dehydroepiandrosterone (DHEA) is a native neurosteroid with immunomodulating activity. DHEA effectively protects animals from several viral, bacterial and parasitic infections and it was suggested that its age-associated decline is related with immunosenescence. In the present study we examined the ability of DHEA to inhibit the production of inflammatory mediators by mycoplasma-stimulated glial cells and to change the course of acute central nervous system (CNS) inflammatory disease in vivo. Addition of DHEA (10 microg/ml) markedly inhibited tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) production (98 and 95%, respectively), whereas nitric oxide (NO) and prostaglandin E2 (PGE2) production was not affected. However, daily administration of 0.5 mg DHEA to mice or 5 mg to rats did not change the clinical outcome of experimental autoimmune encephalomyelitis (EAE).

[Metformin and contrast media-increased risk of lactic acidosis?] [Article in Norwegian]

Klow NE, Draganov B, Os I. Hjerte- og karradiologisk avdeling, Ulleval sykehus 0407 Oslo. n.e.klow@ioks.uio.no

Tidsskr Nor Laegeforen 2001 Jun 10;121(15):1829

A rare side effect from metformin is lactic acidosis. There have been much concern about the reported risk when metformin was combined with contrast medium. Almost all reported cases following combination with contrast media occurred when pre-existing poor renal function was present. A recent review of the literature has resulted in new recommendations in Europe and the USA. We suggest new guidelines for Norway with regard to the use of metformin in patients undergoing radiological examination with contrast media.

Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. VII. Mortality and selected nonfatal events with insulin treatment.

Knatterud GL, Klimt CR, Levin ME, Jacobson ME, Goldner MG.

JAMA 1978 Jul 7;240(1):37-42

The University Group Diabetes Program is a long-term prospective clinical trial designed to evaluate the effects of various hypoglycemic agents on vascular complications in patients with asymptomatic adult-onset diabetes. Mortality and blood glucose levels were determined as well as certain nonfatal events for patients assigned to diet alone or to either of two insulin treatment regimens. Lower levels of blood glucose with mean values close to normoglycemia were achieved in the treatment group in which the insulin dosage was adjusted to achieve normoglycemia compared with the levels achieved in patients treated with diet alone or with a fixed dose of insulin. In spite of differences in blood glucose levels among the treatment groups, there were only minor differences in the occurrence of fatal or nonfatal events.

Biotin for diabetic peripheral neuropathy.

Koutsikos D, Agroyannis B, Tzanatos-Exarchou H. University of Athens, Aretaieon University Hospital, Greece.

Biomed Pharmacother 1990;44(10):511-4

Biotin in high doses was given for 1-2 years to three diabetic patients suffering from severe diabetic peripheral neuropathy. Within 4-8 weeks there was a marked improvement in clinical and laboratory findings. It is suggested that in diabetes may exist a deficiency, inactivity or unavailability of Biotin, resulting in disordered activity of biotin-dependent enzyme, pyruvate carboxylase, leading to accumulation of pyruvate and/or depletion of aspartate, both of which play a significant role in nervous system metabolism. Based on our good results, regular biotin administration could be suggested for every diabetic patient for the prevention and management of peripheral neuropathy although extensive randomised clinical trials are required.

Activation of acetyl-CoA carboxylase by a glutamate- and magnesium-sensitive protein phosphatase in the islet beta-cell.

Kowluru A, Chen HQ, Modrick LM, Stefanelli C. Department of Pharmaceutical Sciences, 610 Shapero Hall, Wayne State University, Detroit, MI 48202, USA. akowluru@wizard.pharm.wayne.edu

Diabetes 2001 Jul;50(7):1580-7

Acetyl-CoA carboxylase (ACC) catalyzes the formation of malonyl-CoA, a precursor in the biosynthesis of long-chain fatty acids, which have been implicated in physiological insulin secretion. The catalytic function of ACC is regulated by phosphorylation (inactive)-dephosphorylation (active). In this study we investigated whether similar regulatory mechanisms exist for ACC in the pancreatic islet beta-cell. ACC was quantitated in normal rat islets, human islets, and clonal beta-cells (HIT-15 or INS-1) using a [(14)C]bicarbonate fixation assay. In the beta-cell lysates, ACC was stimulated by magnesium in a concentration-dependent manner. Of all the dicarboxylic acids tested, only glutamate, albeit ineffective by itself, significantly potentiated magnesium-activated ACC in a concentration-dependent manner. ACC stimulation by glutamate and magnesium was maximally demonstrable in the cytosolic fraction; it was markedly reduced by okadaic acid (OKA) in concentrations (&lt;50 nmol/l) that inhibited protein phosphatase 2A (PP2A). Furthermore, pretreatment of the cytosolic fraction with anti-PP2A serum attenuated the glutamate- and magnesium-mediated activation of ACC, thereby suggesting that ACC may be regulated by an OKA-sensitive PP2A-like enzyme. Streptavidin-agarose chromatography studies have indicated that glutamate- and magnesium-mediated effects on ACC are attributable to activation of ACC's dephosphorylation; this suggests that the stimulatory effects of glutamate and magnesium on ACC might involve activation of an OKA-sensitive PP2A-like enzyme that dephosphorylates and activates ACC. In our study, 5-amino-imidazolecarboxamide (AICA) riboside, a stimulator of AMP kinase, significantly inhibited glucose-mediated activation of ACC and insulin secretion from isolated beta-cells. Together, our data provide evidence for a unique regulatory mechanism for the activation of ACC in the pancreatic beta-cell, leading to the generation of physiological signals that may be relevant for physiological insulin secretion.

Food Nutrition and Diet Therapy, Seventh Edition 1984.

Krause, M. et al.

Philadelphia, PA: W.B. Saunders.

Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity.

Lemieux I, Pascot A, Prud'homme D, Almeras N, Bogaty P, Nadeau A, Bergeron J, Despres JP. Quebec Heart Institute, Laval Hospital Research Center, Sainte-Foy, Quebec, Canada.

Arterioscler Thromb Vasc Biol 2001 Jun;21(6):961-7

Recent studies have suggested that elevated plasma C-reactive protein (CRP) levels are associated with the features of insulin resistance syndrome. In the present study, we have examined the contribution of body composition measured by hydrostatic weighing and of abdominal adipose tissue (AT) accumulation assessed by computed tomography to the variation in plasma CRP levels associated with atherogenic dyslipidemia of the insulin resistance syndrome in a sample of 159 men, aged 22 to 63 years, covering a wide range of adiposity (body mass index values from 21 to 41 kg/m(2)). Plasma CRP levels showed positive and significant correlations with body fat mass (r=0.41, P&lt;0.0001), waist girth (r=0.37, P&lt;0.0001), and visceral AT accumulation measured by computed tomography at L4 to L5 (r=0.28, P&lt;0.0003). Although CRP levels were associated with plasma insulin levels measured in the fasting state and after a 75-g oral glucose load, no significant correlations were found with plasma lipoprotein levels. Finally, comparison of body fatness, of abdominal fat accumulation, and of the features of the insulin resistance syndrome across quintiles of CRP revealed major differences in body fatness and in indices of abdominal AT accumulation between the lowest and the highest CRP quintiles, whereas no significant differences were found for variables of the plasma lipoprotein-lipid profile. These results suggest that obesity and abdominal AT accumulation are the critical correlates of elevated plasma CRP levels found in men with atherogenic dyslipidemia of the insulin resistance syndrome.

Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.

Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I; Collaborative Study Group. Department of Medicine, Rush-Presbyterian-St Luke's Medical Center, Chicago, IL 60612, USA.

N Engl J Med 2001 Sep 20;345(12):851-60

BACKGROUND: It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure. METHODS: We randomly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan (300 mg daily), amlodipine (10 mg daily), or placebo. The target blood pressure was 135/85 mm Hg or less in all groups. We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration, the development of end-stage renal disease, or death from any cause. We also compared them with regard to the time to a secondary, cardiovascular composite end point. RESULTS: The mean duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group (P=0.02) and 23 percent lower than that in the amlodipine group (P=0.006). The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group (P=0.003) and 37 percent lower in the irbesartan group than in the amlodipine group (P&lt;0.001). Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups (P=0.07 for both comparisons). These differences were not explained by differences in the blood pressures that were achieved. The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group (P=0.008) and 21 percent more slowly than in the amlodipine group (P=0.02). There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point. CONCLUSIONS: The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes.

The multiple benefits of metformin.

Life Extension Foundation/Knorr, J.

Life Extension Magazine 2001 Sep; 7(9): 36-41. Ft. Lauderdale, FL: Life Extension Foundation.

(http://www.lef.org/magazine/mag2001/sep2001_report_metformin_01.html).

Delayed gastric emptying rate as a potential mechanism for lowered glycemia after eating sourdough bread: studies in humans and rats using test products with added organic acids or an organic salt.

Liljeberg HG, Bjorck IM. Department of Applied Nutrition and Food Chemistry, Chemical Center, University of Lund, Sweden. Helena.Liljeberg@inl.lth.se

Am J Clin Nutr 1996 Dec;64(6):886-93

The possible effects of organic acids or an organic salt on the rate of gastric emptying was studied to identify the cause for reduced postmeal responses of blood glucose and insulin to foods containing such components, eg, sourdough bread. Paracetamol was included in bread products with added lactic acid or sodium propionate and used as a marker for the rate of gastric emptying in healthy subjects. In parallel, postprandial glycemia, insulinemia, and satiety were evaluated. The influence of lactic acid, propionic acid, and sodium propionate was also studied in rats after they were tube-fed with glucose solutions. The bread products with lactic acid or sodium propionate both lowered blood glucose and insulin responses. The bread with sodium propionate also prolonged satiety. The reason for the lowered metabolic responses with sodium propionate was probably a lowered gastric emptying rate, as judged from reduced blood paracetamol concentrations; there was no such effect observed with bread with added lactic acid. A similar amount of lactic acid in solution tube-fed to rats did not affect the disappearance of glucose from the stomach. In contrast with the finding in humans, sodium propionate had no effect on the rate of gastric emptying in rats whereas an equimolar solution of propionic acid reduced gastric emptying rate in rats. Possibly, less of this acid was produced in the gastric contents after a bolus load of a sodium propionate solution (in rats) than in an eating situation. Also, the pH and/or the osmolarity may be important, and when provided in excessive amounts, lactic acid reduced the gastric emptying rate in rats. A hydrochloric acid solution of similar pH was much less effective in this respect.

Delayed gastric emptying rate may explain improved glycaemia in healthy subjects to a starchy meal with added vinegar.

Liljeberg H, Bjorck I. Department of Applied Nutrition and Food Chemistry, Chemical Center, Lund University, Sweden.

Eur J Clin Nutr 1998 May;52(5):368-71

OBJECTIVES: The aim of the study was to evaluate the possible influence of acetic acid (administered as vinegar) on the postprandial glucose and insulin responses, and the potential involvement of a modified gastric emptying rate was studied by use of paracetamol as a marker. DESIGN: The white bread reference meal as well as the corresponding meal supplemented with vinegar had the same content of starch, protein and fat. The meals were served in the morning after an over-night fast and in random order. Capillary blood samples for analysis of glucose, insulin and paracetamol were collected postprandially. SETTING: The study was performed at the Department of Applied Nutrition and Food Chemistry, Lund University, Sweden. SUBJECTS: Ten healthy volunteers, seven women and three men, aged 22-51 y, with normal body mass indices were recruited. RESULTS: The presence of acetic acid, given as vinegar, significantly reduced the postprandial glucose (GI=64) and insulin responses (II=65) to a starchy meal. As judged from lowered paracetamol levels after the test meal with vinegar, the mechanism is probably a delayed gastric emptying rate. CONCLUSIONS: Fermented foods or food products with added organic acids should preferably be included in the diet in order to reduce glycaemia and insulin demand.

Hyperinsulinemia, insulin resistance, and the treatment of hypertension.

Lithell HO. Institute of Geriatrics, Uppsala University, Sweden.

Am J Hypertens 1996 Nov;9(11):150S-154S

Treatment with beta-blockers and diuretics has been associated with an increased risk of developing diabetes mellitus in three prospective cohort studies. Prospective, randomized studies with antihypertensive drugs have demonstrated differences between different classes of drugs regarding effects on insulin sensitivity. Thus, treatment with beta-blockers or diuretics is associated with impairment in insulin sensitivity, whereas most modern calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors are neutral. However, there are exceptions within the different classes. Captopril seems to differ from the other ACE inhibitors and results in improvement of insulin sensitivity. The most pronounced improvements have been obtained with alpha 1-blockers. In populations at high risk for diabetes mellitus, it may be justified to se

Adjunctive Nutritional Support for Syndrome X: Clinical Practice Protocol 1999 May.

Lukaczer, D.

Gig Harbor, WA: Health-Comm International/Functional Medicine Research.

C-reactive protein, dietary n-3 fatty acids, and the extent of coronary artery disease.

Madsen T, Skou HA, Hansen VE, Fog L, Christensen JH, Toft E, Schmidt EB. Department of Cardiology, Aalborg Hospital, Aalborg, Denmark. austrine@hotmail.com

Am J Cardiol 2001 Nov 15;88(10):1139-42

The acute-phase reactant C-reactive protein (CRP) has emerged as an independent risk factor for coronary artery disease. Experimental and clinical studies provide evidence of anti-inflammatory effects of n-3 polyunsaturated fatty acids (PUFA) derived from fish. We have studied the effect of marine n-3 PUFA on CRP levels in 269 patients referred for coronary angiography because of clinical suspicion of coronary artery disease. All patients filled out a food questionnaire regarding fish intake. The n-3 PUFA content of granulocyte membranes was determined and the concentration of CRP in serum was measured using a highly sensitive assay. The results were related to angiographic findings. CRP was significantly higher in patients with significant coronary stenoses than in those with no significant angiographic changes (p &lt;0.001), but the CRP levels were not associated with the number of diseased vessels. Subjects with CRP levels in the lower quartile had a significantly higher content of docosahexaenoic acid (DHA) in granulocytes than subjects with CRP levels in the upper quartile (p = 0.02), and in a multivariate linear regression analysis, DHA was independently correlated to CRP (R(2) = 0.179; p = 0.003). The inverse correlation between CRP and DHA may reflect an anti-inflammatory effect of DHA in patients with stable coronary artery disease and suggest a novel mechanism by which fish consumption may decrease the risk of coronary artery disease.

Therapeutic evaluation of the effect of biotin on hyperglycemia in patients with non-insulin dependent diabetes mellitus.

Maebashi Masaru; Makino Yoshio; Furukawa Yuji(a); Ohinata Kosaku; Kimura Shuichi; Sato Takao Lab. Nutr., Dep. Appl. Biol. Chem., Fac. Agric., Tohoku Univ., Aoba-ku, Sendai 981**Japan

Journal of Clinical Biochemistry and Nutrition 1993 14 ( 3 ): p 211-218

The therapeutic efficacy of biotin was evaluated in 43 patients with non-insulin dependent diabetes mellitus. The serum biotin concentration in the patients was significantly lower than that in the 64 healthy control subjects and inversely correlated with the fasting blood glucose level. The oral administration of biotin, 9 mg daily, corrected the hyperglycemia in the patients with no change in their serum insulin level. The serum levels of pyruvate and lactate decreased to their normal ranges after the administration. These observations suggest that the biotin administration ameliorates abnormal glucose metabolism in diabetic patients, presumably by enhancing the activity of the biotin-dependent enzyme, pyruvate carboxylase, with a subsequent promotion of glucose utilization for the entry into the tricarboxylic acid cycle. The administration also enhanced the response to glibenclamide in patients who had been resistant to the agent, suggesting a significant increase in the potency of the endogenous insulin action. The result demonstrates that biotin administration is effective for the treatment of the patients. Neither a relapse of clinical symptoms nor an occurrence of undesirable side effects has been observed.

Glucose induces beta-cell apoptosis via upregulation of the Fas receptor in human islets.

Maedler K, Spinas GA, Lehmann R, Sergeev P, Weber M, Fontana A, Kaiser N, Donath MY. Division of Endocrinology and Diabetes, University Hospital, Zurich, Switzerland.

Diabetes 2001 Aug;50(8):1683-90

In autoimmune type 1 diabetes, Fas-to-Fas-ligand (FasL) interaction may represent one of the essential pro-apoptotic pathways leading to a loss of pancreatic beta-cells. In the advanced stages of type 2 diabetes, a decline in beta-cell mass is also observed, but its mechanism is not known. Human islets normally express FasL but not the Fas receptor. We observed upregulation of Fas in beta-cells of type 2 diabetic patients relative to nondiabetic control subjects. In vitro exposure of islets from nondiabetic organ donors to high glucose levels induced Fas expression, caspase-8 and -3 activation, and beta-cell apoptosis. The effect of glucose was blocked by an antagonistic anti-Fas antibody, indicating that glucose-induced apoptosis is due to interaction between the constitutively expressed FasL and the upregulated Fas. These results support a new role for glucose in regulating Fas expression in human beta-cells. Upregulation of the Fas receptor by elevated glucose levels may contribute to beta-cell destruction by the constitutively expressed FasL independent of an autoimmune reaction, thus providing a link between type 1 and type 2 diabetes.

Diabetic cardiomyopathy and carnitine deficiency.

Malone JI, Schocken DD, Morrison AD, Gilbert-Barness E. Department of Pediatrics, College of Medicine, the University of South Florida, Tampa, FL 33612, USA.

J Diabetes Complications 1999 Mar-Apr;13(2):86-90

This study was designed to study the pathogenesis of cardiomyopathy in animals with longstanding (6 months) diabetes mellitus. Male Wistar rats were made diabetic by the injection of streptozotocin (35 mg/kg) intraperitoneal at 6 months of age. Myocardial contractility was evaluated at 1 year of age by an echocardiogram. Blood was collected at that time to measure blood glucose and hemoglobin A1c as an indicator of metabolic control. Serum carnitine was also measured on the same sample to evaluate the availability of this substance so essential for fatty acid metabolism in the myocardium. Myocardial anatomy was evaluated by both light and electron microscopy after the animals had diabetes for 6 months. It was found that the left ventricular volume was greater at the end of systole and diastole. There was the suggestion of left ventricular fractional shortening and calculated reduced ejection fraction indicating decreased contractility consistent with cardiomyopathy. The hearts had no evidence of coronary vascular occlusion, and the serum cholesterol was normal. Myocardial ultrastructure revealed abnormal-appearing mitochondria consistent with carnitine deficiency. Serum and myocardial carnitine levels in the animals with diabetes and reduced myocardial function were low. Carnitine levels and metabolism could be important in the pathogenesis of diabetic cardiomyopathy.

Physical activity and incidence of non-insulin-dependent diabetes mellitus in women.

Manson JE, Rimm EB, Stampfer MJ, Colditz GA, Willett WC, Krolewski AS, Rosner B, Hennekens CH, Speizer FE. Channing Laboratory, Department of Medicine, Harvard Medical School, Boston, MA.

Lancet 1991 Sep 28;338(8770):774-8

The potential role of physical activity in the primary prevention of non-insulin-dependent diabetes mellitus (NIDDM) is largely unknown. We examined the association between regular vigorous exercise and the subsequent incidence of NIDDM in a prospective cohort of 87,253 US women aged 34-59 years and free of diagnosed diabetes, cardiovascular disease, and cancer in 1980. During 8 years of follow-up, we confirmed 1303 cases of NIDDM. Women who engaged in vigorous exercise at least once per week had an age-adjusted relative risk (RR) of NIDDM of 0.67 (p less than 0.0001) compared with women who did not exercise weekly. After adjustment for body-mass index, the reduction in risk was attenuated but remained statistically significant (RR = 0.84, p = 0.005). When analysis was restricted to the first 2 years after ascertainment of physical activity level and to symptomatic NIDDM as the outcome, age-adjusted RR of those who exercised was 0.5, and age and body-mass index adjusted RR was 0.69. Among women who exercised at least once per week, there was no clear dose-response gradient according to frequency of exercise. Family history of diabetes did not modify the effect of exercise, and risk reduction with exercise was evident among both obese and nonobese women. Multivariate adjustments for age, body-mass index, family history of diabetes, and other variables did not alter the reduced risk found with exercise. Our results indicate that physical activity may be a promising approach to the primary prevention of NIDDM.

A prospective study of exercise and incidence of diabetes among US male physicians.

Manson JE, Nathan DM, Krolewski AS, Stampfer MJ, Willett WC, Hennekens CH. Channing Laboratory, Department of Medicine, Harvard Medical School, Boston, MA.

JAMA 1992 Jul 1;268(1):63-7

OBJECTIVE--To examine prospectively the association between regular exercise and the subsequent development of non-insulin-dependent diabetes mellitus (NIDDM). DESIGN--Prospective cohort study including 5 years of follow-up. PARTICIPANTS--21,271 US male physicians participating in the Physicians' Health Study, aged 40 to 84 years and free of diagnosed diabetes mellitus, myocardial infarction, cerebrovascular disease, and cancer at baseline. Morbidity follow-up was 99.7% complete. MAIN OUTCOME MEASURE--Incidence of NIDDM. RESULTS--At baseline, information was obtained about frequency of vigorous exercise and other risk indicators. During 105,141 person-years of follow-up, 285 new cases of NIDDM were reported. The age-adjusted incidence of NIDDM ranged from 369 cases per 100,000 person-years in men who engaged in vigorous exercise less than once weekly to 214 cases per 100,000 person-years in those exercising at least five times per week (P, trend, less than .001). Men who exercised at least once per week had an age-adjusted relative risk (RR) of NIDDM of 0.64 (95% Cl, 0.51 to 0.82; P = .0003) compared with those who exercised less frequently. The age-adjusted RR of NIDDM decreased with increasing frequency of exercise: 0.77 for once weekly, 0.62 for two to four times per week, and 0.58 for five or more times per week (P, trend, .0002). A significant reduction in risk of NIDDM persisted after adjustment for both age and body-mass index: RR, 0.71 (95% Cl, 0.56 to 0.91; P = .006) for at least once per week compared with less than once weekly, and P, trend, .009, for increasing frequency of exercise. Further control for smoking, hypertension, and other coronary risk factors did not materially alter these associations. The inverse relation of exercise to risk of NIDDM was particularly pronounced among overweight men. CONCLUSIONS--Exercise appears to reduce the development of NIDDM even after adjusting for body-mass index. Increased physical activity may be a promising approach to the primary prevention of NIDDM.

Can correction of sub-optimal coenzyme Q status improve beta-cell function in type II diabetics?

McCarty MF. NutriGuard Research, Encinitas, CA 92024, USA.

Med Hypotheses 1999 May;52(5):397-400

A stimulus to mitochondrial respiratory activity is a crucial component of the signal transduction mechanism whereby increased plasma glucose evokes insulin secretion by beta-cells. Efficient function of the glycerol-3-phosphate shuttle is important in this regard, and the rate-limiting enzyme in this shuttle--the mitochondrial glycerol-3-phosphate dehydrogenase (G3PD)--is underexpressed in the beta cells of human type II diabetics as well of rodents that are models for this disorder. Suboptimal tissue levels of coenzyme Q10 (CoQ) could be expected to further impair G3PD activity. Clinical reports from Japan suggest that supplemental CoQ may often improve beta-cell function and glycemic control in type II diabetics. Thus, it is proposed that correction of suboptimal CoQ status, by aiding the efficiency of G3PD and of respiratory chain function, will improve the glucose-stimulated insulin secretion of diabetic beta-cells.

Toward a wholly nutritional therapy for type 2 diabetes.

McCarty MF. Helicon Foundation, San Diego, CA, USA.

Med Hypotheses 2000 Mar;54(3):483-7

It may now be feasible to target specific supplemental nutrients to each of the key dysfunctions which conspire to maintain hyperglycemia in type 2 diabetes: bioactive chromium for skeletal muscle insulin resistance, conjugated linoleic acid for adipocyte insulin resistance, high-dose biotin for excessive hepatic glucose output, and coenzyme Q(10) for beta cell failure. Nutritional strategies which disinhibit hepatic fatty acid oxidation (involving hydroxycitrate, carnitine, pyruvate, and other adjuvants) may likewise prove beneficial - in the short term, by decreasing serum free fatty acids and, in the longer term, by promoting regression of visceral obesity. The nutrients and food factors recommended here appear to be safe and well tolerated, and thus may have particular utility for diabetes prevention. Copyright 2000 Harcourt Publishers Ltd.

Effects of dietary supplementation of alpha-lipoic acid on early glomerular injury in diabetes mellitus.

Melhem MF, Craven PA, Derubertis FR. Department of Medicine, Veterans Affairs Medical Center and University of Pittsburgh, Pittsburgh, PA 15240, USA.

J Am Soc Nephrol 2001 Jan;12(1):124-33

Antioxidants, in particular vitamin E (VE), have been reported to protect against diabetic renal injury. alpha-Lipoic acid (LA) has been found to attenuate diabetic peripheral neuropathy, but its effects on nephropathy have not been examined. In the present study, parameters of glomerular injury were examined in streptozotocin diabetic rats after 2 mo on unsupplemented diets and in diabetic rats that received the lowest daily dose of dietary LA (30 mg/kg body wt), VE (100 IU/kg body wt), or vitamin C (VC; 1 g/kg body wt), which detectably increased the renal cortical content of each antioxidant. Blood glucose values did not differ among the diabetic groups. At 2 mo, inulin clearance, urinary albumin excretion, fractional albumin clearance, glomerular volume, and glomerular content of immunoreactive transforming growth factor-beta (TGF-beta) and collagen alpha1 (IV) all were significantly increased in unsupplemented D compared with age-matched nondiabetic controls. With the exception of inulin clearance, LA prevented or significantly attenuated the increase in all of these glomerular parameters in D, as well as the increases in renal tubular cell TGF-beta seen in D. At the dose used, VE reduced inulin clearance in D to control levels but failed to alter any of the other indices of glomerular injury or to suppress renal tubular cell TGF-beta in D. VC suppressed urinary albumin excretion, fractional albumin clearance, and glomerular volume but not glomerular or tubular TGF-beta or glomerular collagen alpha1 (IV) content. LA but not VE or VC significantly increased renal cortical glutathione content in D. These data indicate that LA is effective in the prevention of early diabetic glomerular injury and suggest that this agent may have advantages over high doses of either VE or VC.

Dietary Chromium: an Overview 1996

Mennen, B.

(www.healthfree.com/introchrom.htm).

Decrease Your Sleep and Increase Your Risk of Diabetes 2001

Mercola, J.

(http://www.mercola.com/2001/jul/7/diabetes_sleep.htm).

Cinnamon May Help Control Blood Sugar 2002

Mercola, J.

(http://www.mercola.com/2000/sept/3/cinnamon_insulin.htm).

The Route of All Evil: Bad Diseases Can Start in Your Mouth 2001

Millman, C.

(http://wwwabcnews.go.com/sections/living/MensHealth/menshealth_40.html).

Effect of eicosapentaenoic acid ethyl ester v. oleic acid-rich safflower oil on insulin resistance in type 2 diabetic model rats with hypertriacylglycerolaemia.

Minami A, Ishimura N, Sakamoto S, Takishita E, Mawatari K, Okada K, Nakaya Y. Department of Nutrition, School of Medicine, The University of Tokushima, Japan.

Br J Nutr 2002 Feb;87(2):157-62

The purpose of the present study was to test whether hyperlipidaemia and insulin resistance in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats can be improved by dietary supplementation with purified eicosapentaenoic acid (EPA) or oleic acid (OA). Male OLETF rats were fed powdered chow (510 g fat/kg) alone (n 8) or chow supplemented with 10 g EPA- (n 8) or OA- (n 8) rich oil/kg per d from 5 weeks until 30 weeks of age. An oral glucose tolerance test and hyperinsulinaemic euglycaemic clamp was performed at 25 and 30 weeks of age. EPA supplementation resulted in significantly (P&lt;0.05) reduced plasma lipids, hepatic triacylglycerols, and abdominal fat deposits, and more efficient in vivo glucose disposal compared with OA supplementation and no supplementation. OA supplementation was associated with significantly increased insulin response to oral glucose compared with EPA supplementation and no supplementation. Inverse correlation was noted between glucose uptake and plasma triacylglycerol levels (r -086, P&lt;0.001) and abdominal fat volume (r -0.80, P&lt;0.001). The result of oral glucose tolerance test study showed that the rats fed EPA tended to improve glucose intolerance, although this was not statistically significant. Levels of plasma insulin at 60 min after glucose was significantly increased in rats fed OA compared with the other two groups. The results indicate that long-term feeding of EPA might be effective in preventing insulin resistance in diabetes-prone rats, at least in part, due to improving hypertriacylglycerolaemia.

L-carnitine improves glucose disposal in type 2 diabetic patients.

Mingrone G, Greco AV, Capristo E, Benedetti G, Giancaterini A, De Gaetano A, Gasbarrini G. Istituto di Medicina Interna, Catholic University, Rome, Italy.

J Am Coll Nutr 1999 Feb;18(1):77-82

OBJECTIVE: Aim of the present study is to evaluate the effects of L-carnitine on insulin-mediated glucose uptake and oxidation in type II diabetic patients and compare the results with those in healthy controls. DESIGN: Fifteen type II diabetic patients and 20 healthy volunteers underwent a short-term (2 hours) euglycemic hyperinsulinemic clamp with simultaneous constant infusion of L-carnitine (0.28 micromole/kg bw/minute) or saline solution. Respiratory gas exchange was measured by an open-circuit ventilated hood system. Plasma glucose, insulin, non-esterified fatty acids (NEFA) and lactate levels were analyzed. Nitrogen urinary excretion was calculated to evaluate protein oxidation. RESULTS: Whole body glucose uptake was significantly (p&lt;0.001) higher with L-carnitine than with saline solution in the two groups investigated (48.66+/-4.73 without carnitine and 52.75+/-5.19 micromoles/kg(ffm)/minute with carnitine in healthy controls, and 35.90+/-5.00 vs. 38.90+/-5.16 micromoles/kg(ffm)/minute in diabetic patients). Glucose oxidation significantly increased only in the diabetic group (17.61+/-3.33 vs. 16.45+/-2.95 micromoles/kg(ffm)/minute, p&lt;0.001). On the contrary, glucose storage increased in both groups (controls: 26.36+/-3.25 vs. 22.79+/-3.46 micromoles/kg(ffm)/minute, p&lt;0.001; diabetics: 21.28+/-3.18 vs. 19.66+/-3.04 micromoles/kg(ffm)/minute, p&lt;0.001). In type II diabetic patients, plasma lactate significantly decreased during L-carnitine infusion compared to saline, going from the basal period to the end-clamp period (0.028+/-0.0191 without carnitine and 0.0759+/-0.0329 with carnitine, p&lt;0.0003). CONCLUSIONS: L-carnitine constant infusion improves insulin sensitivity in insulin resistant diabetic patients; a significant effect on whole body insulin-mediated glucose uptake is also observed in normal subjects. In diabetics, glucose, taken up by the tissues, appears to be promptly utilized as fuel since glucose oxidation is increased during L-carnitine administration. The significantly reduced plasma levels of lactate suggest that this effect might be exerted through the activation of pyruvate dehydrogenase, whose activity is depressed in the insulin resistant status.

Diabetes mellitus associated with atypical antipsychotic medications: new case report and review of the literature.

Muench J, Carey M. Department of Family Medicine, Oregon Health Sciences University, Portland, OR 97201, USA.

J Am Board Fam Pract 2001 Jul-Aug;14(4):278-82

BACKGROUND: Since the introduction of atypical antipsychotic medications, beginning with clozapine in 1990, several case reports in the psychiatric literature have suggested that they might be associated with new onset of diabetes mellitus as well as with diabetic ketoacidosis. METHODS: We report the case of a 38-year-old patient with schizophrenia who suddenly developed diabetes mellitus and ketoacidosis 12 months after starting olanzapine. Similar cases in the literature were found through a MEDLINE-assisted search using the key words "schizophrenia," "diabetes mellitus," "ketoacidosis," and "adverse drug reaction." RESULTS: Including this case, 30 patients have been reported in the literature to have developed diabetes or have lost diabetic control after starting clozapine, olanzapine, or quetiapine. Twelve of these 30 developed diabetic ketoacidosis. Two limited quantitative studies have added evidence toward this association. CONCLUSION: Although a causal relation has not been definitively proved, the number of cases reported in the literature suggests there might be an association between atypical antipsychotic medications and diabetes mellitus. Primary care physicians who care for patients with schizophrenia should be aware of this possible association.

Eating for Health 1992.

Murray, M.

Seattle, WA: Trillium.

The Healing Power of Herbs 1995.

Murray, M.

Rocklin, CA. Prima Publishing.

Diabetes. In Encyclopedia of Nutritional Supplements 1996, pp. 113 4.

Murray, M.

Rocklin, CA: Prima Publishing.

Encyclopedia of Natural Medicine 1991.

Murray, M., Pizzorno, J.

Rocklin, CA: Prima Publishing.

Polyol pathway hyperactivity is closely related to carnitine deficiency in the pathogenesis of diabetic neuropathy of streptozotocin-diabetic rats.

Nakamura J, Koh N, Sakakibara F, Hamada Y, Hara T, Sasaki H, Chaya S, Komori T, Nakashima E, Naruse K, Kato K, Takeuchi N, Kasuya Y, Hotta N. The Third Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, Japan.

J Pharmacol Exp Ther 1998 Dec;287(3):897-902

To investigate the relationship between polyol pathway hyperactivity and altered carnitine metabolism in the pathogenesis of diabetic neuropathy, the effects of an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl]acetic acid (TAT), and a carnitine analog, acetyl-L-carnitine (ALC), on neural functions and biochemistry and hemodynamic factors were compared in streptozotocin-diabetic rats. Significantly delayed motor nerve conduction velocity, decreased R-R interval variation, reduced sciatic nerve blood flow and decreased erythrocyte 2, 3-diphosphoglycerate concentrations in diabetic rats were all ameliorated by treatment with TAT (administered with rat chow containing 0.05% TAT, approximately 50 mg/kg/day) or ALC (by gavage, 300 mg/kg/day) for 4 weeks. Platelet hyperaggregation activity in diabetic rats was diminished by TAT but not by ALC. TAT decreased sorbitol accumulation and prevented not only myo-inositol depletion but also free-carnitine deficiency in diabetic nerves. On the other hand, ALC also increased the myo-inositol as well as the free-carnitine content without affecting the sorbitol content. These observations suggest that there is a close relationship between increased polyol pathway activity and carnitine deficiency in the development of diabetic neuropathy and that an aldose reductase inhibitor, TAT, and a carnitine analog, ALC, have therapeutic potential for the treatment of diabetic neuropathy.

Nutrients for the Control of Blood Sugar 2000

Natural Pharmacist.

(http://www.alternativediabetes.com/ciddiab/pg000082.html).

Metabolism and actions of dehydroepiandrosterone in humans.

Nestler JE, Clore JN, Blackard WG. Division of Endocrinology and Metabolism, Medical College of Virginia/Virginia Commonwealth University, Richmond, VA 23298-0111.

J Steroid Biochem Mol Biol 1991;40(4-6):599-605

Dehydroepiandrosterone (3 beta-hydroxy-5-androsten-17-one; DHA) and DHA-sulfate are abundantly produced adrenal steroids, whose serum concentrations exceed those of other adrenal steroids. Serum concentrations of DHA and DHA-sulfate, in contrast to other adrenal steroids, exhibit a progressive age-related decline. The mechanism(s) for this selective decline in serum DHA and DHA-sulfate levels and the biologic function of these steroids remain unknown. Studies examining insulin's regulation of adrenal androgens are reviewed. These studies show that experimentally-induced hyperinsulinemia lowers serum DHA and DHA-sulfate levels, and suggest that insulin reduces serum concentrations of these steroids by inhibiting production rather than by increasing clearance. Studies examining the actions of short-term pharmacologic DHA administration to young nonobese and obese men are also reviewed. These studies suggest that DHA may possess hypolipidemic and, possibly, anti-obesity properties. They have failed, however, to demonstrate any effect of DHA on tissue insulin sensitivity.

Insulin as an effector of human ovarian and adrenal steroid metabolism.

Nestler JE, Strauss JF III. Department of Medicine, Medical College of Virginia/Virginia Commonwealth University, Richmond, VA.

Endocrinol Metab Clin North Am 1991 Dec;20(4):807-23

Evidence is accumulating that insulin is a potent effector of human steroid hormone metabolism. In this article, we have reviewed primarily in vivo studies showing that physiologic elevations in serum insulin levels can increase circulating ovarian androgens, decrease serum levels of adrenal androgens, and decrease serum SHBG levels. In addition, insulin resistance at the level of the adrenals appears to be associated with loss of responsiveness to the suppressive effect on adrenal androgens. We have proposed an integrated hypothesis as to how these complex actions of insulin might all come into play in the genesis of a common endocrinopathy--PCO. At least one clinically relevant aspect of these findings is that therapies aimed at reducing the magnitude of hyperinsulinemic insulin resistance in women with PCO may ameliorate the hyperandrogenism. One example of this possibility is the well recognized observation that substantial weight loss is associated with a reduction in serum androgen levels and clinical manifestations of hyperandrogenism in this disorder.

Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome.

Nestler JE, Jakubowicz DJ. Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0111, USA.

N Engl J Med 1996 Aug 29;335(9):617-23

BACKGROUND: Insulin resistance and increased ovarian cytochrome P450c17 alpha activity are both features of the polycystic ovary syndrome. P450c17 alpha, which is involved in androgen biosynthesis, has both 17 alpha-hydroxylase and 17,20-lyase activities. Increased activity of this enzyme results in exaggerated conversion of progesterone to 17 alpha-hydroxyprogesterone in response to stimulation by gonadotrophin. We hypothesized that hyperinsulinemia stimulates ovarian P450c17 alpha activity. METHODS: We measured fasting serum steroid concentrations and the response of serum 17 alpha-hydroxyprogesterone to leuprolide, a gonadotrophin-releasing hormone agonist, and performed oral glucose-tolerance tests before and after oral administration of either metformin (500 mg three times daily) or placebo for four to eight weeks in 24 obese women with the polycystic ovary syndrome. RESULTS: In the 11 women given metformin, the mean (+/- SE) area under the serum insulin curve after oral glucose administration decreased from 9303 +/- 1603 to 4982 +/- 911 microU per milliliter per minute (56 +/- 10 to 30 +/- 6 nmol per liter per minute) (P = 0.004). This decrease was associated with a reduction in the basal serum 17 alpha-hydroxyprogesterone concentration from 135 +/- 21 to 66 +/- 7 ng per deciliter (4.1 +/- 0.6 to 2.0 +/- 0.2 nmol per liter) (P = 0.01) and a reduction in the leuprolide-stimulated peak serum 17 alpha-hydroxyprogesterone concentration from 455 +/- 54 to 281 +/- 52 ng per deciliter (13.7 +/- 1.6 to 8.5 +/- 1.6 nmol per liter) (P = 0.01). The serum 17 alpha-hydroxyprogesterone values increased slightly in the placebo group. In the metformin group, the basal serum luteinizing hormone concentration decreased from 8.5 +/- 2.2 to 2.8 +/- 0.5 mlU per milliliter (P = 0.01), the serum free testosterone concentration decreased from 0.34 +/- 0.07 to 0.19 +/- 0.05 ng per deciliter (12 +/- 3 to 7 +/- 2 pmol per liter) (P = 0.009), and the serum sex hormone-binding globulin concentration increased from 0.8 +/- 0.2 to 2.3 +/- 0.6 microgram per deciliter (29 +/- 7 to 80 +/- 21 nmol per liter) (P &lt; 0.001). None of these values changed significantly in the placebo group. CONCLUSIONS: In obese women with the polycystic ovary syndrome, decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates hyperandrogenism.

Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome.

Nestler JE, Stovall D, Akhter N, Iuorno MJ, Jakubowicz DJ. Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0111, USA. nestler@hsc.vcu.edu

Fertil Steril 2002 Feb;77(2):209-15

OBJECTIVE: Insulin resistance and its compensatory hyperinsulinemia play a key pathogenic role in the infertility of the polycystic ovary syndrome. Numerous studies indicate that insulin-sensitizing drugs can be used to enhance spontaneous ovulation and the induction of ovulation in the syndrome. The aim of this review is to summarize the studies in which insulin-sensitizing drugs were used to increase ovulation rate or improve fertility in women with the PCOS and to translate the information into practical guidelines for the use of these drugs by reproductive endocrinologists. DESIGN: Review and critique of studies in which an insulin-sensitizing drug was used to increase ovulation rate or improve infertility in women with the polycystic ovary syndrome. MAIN OUTCOME MEASURE(S): Ovulation rate and pregnancy rate. RESULT(S): Studies have demonstrated that insulin-sensitizing drugs can increase spontaneous ovulation, enhance the induction of ovulation with clomiphene citrate, and increase clinical pregnancy rates. CONCLUSION(S): An algorithmic approach is provided for the use of insulin-sensitizing drugs to treat the anovulation and infertility of women with the polycystic ovary syndrome.

Fitness and Sports Medicine, Third Edition 1995.

Nieman, D.C.

Palo Alto, CA: Bull Publishing.

Imprinting of female offspring with testosterone results in insulin resistance and changes in body fat distribution at adult age in rats.

Nilsson C, Niklasson M, Eriksson E, Bjorntorp P, Holmang A. Department of Heart and Lung Diseases, Goteborg University, Goteborg, Sweden. J Clin Invest 1998 Jan 1;101(1):74-8

In women, a relative hyperandrogenicity is statistically associated with insulin resistance and centralization of body fat, which are predictors for the development of non-insulin-dependent diabetes mellitus. The aim of this study was to evaluate the effect of androgenization of newborn female rats on insulin sensitivity at adult age. To mimic the neonatal androgen peak normally observed in male rats, female pups were administered one high dose of testosterone (T) subcutaneously within 3 h after birth. They were then given back to their mothers and followed to adult age. At the end of the week 9, tail samples were taken, showing no differences in fasting plasma concentrations of glucose, lactate, insulin, or free fatty acids between T-treated rats and controls. Plasma concentrations of T and progesterone were significantly lower in the T-treated rats, whereas no differences were found in the levels of corticosterone, estradiol, insulin-like growth factor I, or ACTH. After 10 wk, insulin sensitivity was studied with hyperglycemic and euglycemic hyperinsulinemic (5 mU insulin/kg/min) clamp techniques. The T-treated rats showed insulin resistance with both techniques, which was overcome with time and increasing insulin concentrations during the clamp measurements. The T-treated rats were also heavier and had increased relative weights of skeletal muscles and the spleen. Parametrial, retroperitoneal, and inguinal adipose tissues decreased in weight while mesenteric adipose tissue tended to increase, resulting in an approximately 30-50% larger mesenteric than other adipose tissues. It is concluded that neonatal T imprinting of female rats is followed by insulin resistance, changes in adipose tissue distribution, and an enlarged lean mass, without elevation of circulating T. Similar changes are seen in adult female rats or women receiving T.

Diabetes mellitus and the risk of dementia: The Rotterdam Study.

Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Department of Epidemiology &amp;amp; Biostatistics, Erasmus University Medical School, Rotterdam, The Netherlands.

Neurology 1999 Dec 10;53(9):1937-42

OBJECTIVE: To determine the influence of type 2 diabetes mellitus on the risk of dementia and AD. BACKGROUND: Both dementia and diabetes are frequent disorders in elderly people. METHODS: Prospective population-based cohort study among 6,370 elderly subjects. At baseline study participants were examined for presence of diabetes mellitus. Nondemented participants were followed up, on average, for 2.1 years. Incident dementia was diagnosed using a three-step screening and comprehensive diagnostic workup. To complete the follow-up, medical files were studied of persons who could not be reexamined. We estimated relative risks with proportional hazard regression, adjusting for age, sex, and possible confounders. RESULTS: During the follow-up, 126 patients became demented, of whom 89 had AD. Diabetes mellitus almost doubled the risk of dementia (relative risk [RR] 1.9 [1.3 to 2.8]) and AD (RR 1.9 [1.2 to 3.1]). Patients treated with insulin were at highest risk of dementia (RR 4.3 [1.7 to 10.5]). CONCLUSION: The diabetes attributable risk for dementia of 8.8% suggests that diabetes may have contributed to the clinical syndrome in a substantial proportion of all dementia patients.

Antioxidant properties of lipoic acid and its therapeutic effects in prevention of diabetes complications and cataracts.

Packer L. Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720.

Ann N Y Acad Sci 1994 Nov 17;738:257-64

No abstract available.

Dietary magnesium supplements improve B-cell response to glucose and arginine in elderly non-insulin dependent diabetic subjects.

Paolisso G, Passariello N, Pizza G, Marrazzo G, Giunta R, Sgambato S, Varricchio M, D'Onofrio F. Institute di Gerontalogia e Geriateria, Napoli, Italy.

Acta Endocrinol (Copenh) 1989 Jul;121(1):16-20

Hypomagnesemia and low erythrocyte magnesium content are both common findings in non-insulin-dependent diabetic subjects. Moreover, intracellular magnesium may play a crucial role in modulating B-cell response to glucose by interfering with potassium permeability. Eight elderly, moderately obese, non-insulin-dependent diabetic subjects were treated with either magnesium supplementation (3 g/day) to the diet or placebo. Both treatment schemes lasted 4-weeks and were separated by a 'wash-out' of 3 weeks. At the end of each treatment period, in glucose test (0.33 g/kg for 3 min) and an iv arginine (5 g) test were performed to determine the B-and A-cell responses. Dietary magnesium supplementation vs placebo produced a slight but significant decrease in basal plasma glucose (8.6 +/- 0.3 vs 8.0 +/- 0.1 mmol/l, p less than 0.05) and an increase in acute insulin response after iv glucose (3.7 +/- 2.3 vs - 14.7 +/- 0.9 pmol.l 1. (10 min)-1, p less than 0.01) and after iv arginine (151 +/- vs 81 +/- 15 pmol.l-1. (10 min)-1, p less than 0.01), respectively. Plasma glucagon levels were unaffected by chronic dietary magnesium supplementation as well under basal conditions as in response to arginine. Net increase in acute insulin response after iv glucose and after iv arginine was significantly correlated to the net increase in erythrocyte magnesium content after dietary magnesium supplementation. We conclude that magnesium administration may be a useful adjuvant to the classic hypoglycemic agents in the treatment of non-insulin-dependent diabetic subjects.

Daily magnesium supplements improve glucose handling in elderly subjects.

Paolisso G, Sgambato S, Gambardella A, Pizza G, Tesauro P, Varricchio M, D'Onofrio F. Department of Geriatric Medicine and Metabolic Diseases, 1st Medical School, University of Naples, Italy.

Am J Clin Nutr 1992 Jun;55(6):1161-7

We demonstrated similar plasma concentrations and urinary losses but lower erythrocyte magnesium concentrations (2.18 +/- 0.04 vs 1.86 +/- 0.03 mmol/L, P less than 0.01) in twelve aged (77.8 +/- 2.1 y) vs 25 young (36.1 +/- 0.4 y), nonobese subjects. Subsequently, aged subjects were enrolled in a double-blind, randomized, crossover study in which placebo (for 4 wk) and chronic magnesium administration (CMA) (4.5 g/d for 4 wk) were provided. At the end of each treatment period an intravenous glucose tolerance test (0.33 g/kg body wt) and a euglycemic glucose clamp with simultaneous [D-3H]glucose infusion and indirect calorimetry were performed. CMA vs placebo significantly increased erythrocyte magnesium concentration and improved insulin response and action. Net increase in erythrocyte magnesium significantly and positively correlated with the decrease in erythrocyte membrane microviscosity and with the net increase in both insulin secretion and action. In aged patients, correction of a low erythrocyte magnesium concentration may allow an improvement of glucose handling.

Pharmacologic doses of vitamin E improve insulin action in healthy subjects and non-insulin-dependent diabetic patients.

Paolisso G, D'Amore A, Giugliano D, Ceriello A, Varricchio M, D'Onofrio F. Department of Geriatric Medicine and Metabolic Diseases, First Medical School, University of Naples, Italy.

Am J Clin Nutr 1993 May;57(5):650-6

Ten control (healthy) subjects and 15 non-insulin-dependent diabetics underwent an oral glucose-tolerance test and a euglycemic hyperinsulinemic glucose clamp before and after vitamin E supplementation (900 mg/d for 4 mo). In control subjects (placebo-treated vs vitamin E-supplemented subjects, respectively) vitamin E reduced the area under the curve for glucose (344 +/- 21 vs 287 +/- 13 mmol.L-1 x min-1; P &lt; 0.05) and increased total body glucose disposal (39.0 +/- 0.3 vs 47.6 +/- 0.4 mumol.kg lean body mass-1 x min-1; P &lt; 0.05) and non-oxidative glucose metabolism (23.4 +/- 0.2 vs 30.8 +/- 0.3 mumol.kg lean body mass-1 x min-1; P &lt; 0.05). In diabetics (placebo-treated vs vitamin E-supplemented subjects, respectively) vitamin E supplementation reduced glucose area under the curve (614 +/- 129 vs 544 +/- 98 mmol.L-1 x min-1; P &lt; 0.03) and increased glucose disappearance (19.4 +/- 0.4 vs 26.4 +/- 0.7 mumol.kg lean body mass-1.min-1; P &lt; 0.03), total glucose disposal (19.0 +/- 0.7 vs 28.1 +/- 0.4 mumol.kg lean body mass-1 x min-1; P &lt; 0.02), and nonoxidative glucose metabolism (8.5 +/- 0.3 vs 13.9 +/- 0.3 mumol.kg lean body mass-1 x min-1; P &lt; 0.02). Therefore we conclude that administration of pharmacologic doses of vitamin E is a useful tool to reduce oxidative stress and improve insulin action.

First human studies promising for popular nutritional supplement: CLA could help control weight, fat, diabetes, and muscle loss.

Pariza, M.

Presented at the American Chemical Society Meeting, Washington, D.C., August 20, 2000 (www.acs.org/portal/Chemistry?PID=acsdisplay.html&amp;DOC=daily\sunday\weight.html).

Family Guide to Prescription Drugs 1999.

PDR.

New York: Three Rivers Press.

Dairy consumption, obesity, and the insulin resistance syndrome in young adults: the CARDIA Study.

Pereira MA, Jacobs DR Jr, Van Horn L, Slattery ML, Kartashov AI, Ludwig DS. Department of Medicine, Children's Hospital, 300 Longwood Ave, Boston, MA 02115, USA. mark.pereira@tch.harvard.edu

JAMA 2002 Apr 24;287(16):2081-9

CONTEXT: Components of the insulin resistance syndrome (IRS), including obesity, glucose intolerance, hypertension, and dyslipidemia, are major risk factors for type 2 diabetes and heart disease. Although diet has been postulated to influence IRS, the independent effects of dairy consumption on development of this syndrome have not been investigated. OBJECTIVE: To examine associations between dairy intake and incidence of IRS, adjusting for confounding lifestyle and dietary factors. DESIGN: The Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based prospective study. SETTING AND PARTICIPANTS: General community sample from 4 US metropolitan areas of 3157 black and white adults aged 18 to 30 years who were followed up from 1985-1986 to 1995-1996. MAIN OUTCOME MEASURE: Ten-year cumulative incidence of IRS and its association with dairy consumption, measured by diet history interview. RESULTS: Dairy consumption was inversely associated with the incidence of all IRS components among individuals who were overweight (body mass index &gt; or =25 kg/m(2)) at baseline but not among leaner individuals (body mass index &lt; 25 kg/m(2)). The adjusted odds of developing IRS (2 or more components) were 72% lower (odds ratio, 0.28; 95% confidence interval, 0.14-0.58) among overweight individuals in the highest (&gt; or =35 times per week, 24/102 individuals) compared with the lowest (&lt;10 times per week, 85/190 individuals) category of dairy consumption. Each daily occasion of dairy consumption was associated with a 21% lower odds of IRS (odds ratio, 0.79; 95% confidence interval, 0.70-0.88). These associations were similar for blacks and whites and for men and women. Other dietary factors, including macronutrients and micronutrients, did not explain the association between dairy intake and IRS. CONCLUSIONS: Dietary patterns characterized by increased dairy consumption have a strong inverse association with IRS among overweight adults and may reduce risk of type 2 diabetes and cardiovascular disease.

Prospective study of serum gamma-glutamyltransferase and risk of NIDDM.

Perry IJ, Wannamethee SG, Shaper AG. Department of Primary Care and Population Sciences, Royal Free Hospital School of Medicine, London, U.K. i.perry@ucc.i.e

Diabetes Care 1998 May;21(5):732-7

OBJECTIVE: Serum gamma-glutamyltransferase (GGT) levels are raised in obese individuals, and a particularly strong association with central obesity has been described. We hypothesized that elevated GGT levels are a marker for visceral fat, and specifically for hepatic steatosis (fatty liver), and that hepatic steatosis leads to hepatic insulin resistance. To test this hypothesis, we examined the association between GGT levels and risk of NIDDM. RESEARCH DESIGN AND METHODS: We carried out a prospective cohort study of incident cases of doctor-diagnosed NIDDM in a group of 7,458 nondiabetic men (aged 40-59 years) followed for a mean of 12.8 years (range 11.5-13.0). The men were randomly selected from general practice lists in 24 British towns. Cases of NIDDM were ascertained by repeated postal questionnaires to the men and by regular systematic review of primary care records. RESULTS: A total of 194 men developed NIDDM during follow-up. Mean serum GGT at baseline (geometric mean [95% CI]) was significantly higher in the NIDDM patients than in the rest of the cohort (20.9 [19.3-22.6] vs. 15.3 U/l [15.0-15.6], P &lt; 0.0001). There was a smooth, graded increase in the age-adjusted risk of NIDDM with increasing GGT levels, with a relative risk in the top fifth of the distribution of 6.8 (3.5-12.9) relative to the bottom fifth (trend P &lt; 0.0001). This association was independent of serum glucose and BMI and of other predictors of NIDDM with which GGT is associated, including alcohol intake and physical activity level (adjusted upper to lower fifth relative risk: 4.8 [2.0-11.8], trend P &lt; 0.0001]). CONCLUSIONS: These findings suggest that a raised serum GGT level is an independent risk factor for NIDDM. Serum GGT level may be a simple and reliable marker of visceral and hepatic fat and, by inference, of hepatic insulin resistance.

In experimental diabetes the decrease in the eye of lens carnitine levels is an early important and selective event.

Pessotto P, Liberati R, Petrella O, Romanelli L, Calvani M, Peluso G. Research, Sigma-Tau S.p.A., Pomezia, Rome, Italy.

Exp Eye Res 1997 Feb;64(2):195-201

Carnitine is present in the eye tissues of the rabbit and the highest concentration is found in the lens. In streptozotocin-diabetic rats, the carnitine loss of the lens is an initial and important event. At 8 days after the induction of diabetes, the carnitine content in the rat lens was reduced by 63% compared to control. The loss of lens carnitine continued at 15 and 45 days after the induction. Total carnitine level in the serum was diminished by 15 days, and the reduction in percentage term was much lower in comparison to the loss of lens carnitine. In the rabbit after alloxan-diabetes induction, there is an extensive loss of carnitine in the lens: -85% after 4 months. The carnitine levels in the other eye tissues seem substantially unaffected. The loss of lens carnitine was present even with an inconsistent hyperglycaemia. No difference was found in serum carnitine levels between controls and alloxan-treated rabbits. The role of carnitine in lens is still unclear, but its loss may be related to the appearance of cataract. A derivative of carnitine, acetylcarnitine, might prevent the processes involved in the formation of cataracts by a pharmacological action, as has been shown for aspirin.

Nutrition: An Integrated Approach 1984.

Pike, R. et al.

New York: MacMillan

Tumor-associated angiogenesis: mechanisms, clinical implications, and therapeutic strategies.

Pluda JM. Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD 20852, USA.

Semin Oncol 1997 Apr;24(2):203-18

Compelling data implicate angiogenesis and tumor-associated neovascularization as a central pathogenic step in the process of tumor growth, invasion, and metastasis. These complex processes involve multiple steps and pathways dependent on the local balance between positive and negative regulatory factors, as well as interactions among the tumor, its vasculature, and the surrounding extracellular tissue matrix. A tumor remains in a dormant state, the cellular proliferation rate balanced by the apoptotic rate, unable to grow in size beyond a few millimeters in the absence of the acquired angiogenic phenotype. The mechanism by which tumors switch to the angiogenic phenotype is unknown. Therapeutic agents and strategies are being devised either to interrupt or inhibit one or more of the pathogenic steps involved in the process of tumor neovascularization or to directly target and destroy the tumor vasculature. Therapies affecting an end target or pathway that cannot be circumvented by alternate mechanisms may significantly enhance efficacy and broaden applicability. These approaches may result in small, avascular tumors maintained in a dormant state or, perhaps in combination with cytotoxic therapies, they may potentiate shrinkage of tumors to, and maintain them, in a dormant state. As more powerful antiangiogenic agents are developed, perhaps even these dormant microscopic foci may be eradicated. Antiangiogenesis agents and strategies differ from the usual cancer therapeutic approaches; therefore, investigators must devise new paradigms for the clinical development of agents that may only have a static effect on tumors and require prolonged, chronic administration. Methods to assess the in vivo biologic activity of these compounds in patients are needed. Ultimately, antiangiogenic therapy may provide an additional novel cancer treatment suitable for combination with standard therapies.

C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus.

Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM.

JAMA 2001 Jul 18;286(3):327-34

CONTEXT: Inflammation is hypothesized to play a role in development of type 2 diabetes mellitus (DM); however, clinical data addressing this issue are limited. OBJECTIVE: To determine whether elevated levels of the inflammatory markers interleukin 6 (IL-6) and C-reactive protein (CRP) are associated with development of type 2 DM in healthy middle-aged women. DESIGN: Prospective, nested case-control study. SETTING: The Women's Health Study, an ongoing US primary prevention, randomized clinical trial initiated in 1992. PARTICIPANTS: From a nationwide cohort of 27 628 women free of diagnosed DM, cardiovascular disease, and cancer at baseline, 188 women who developed diagnosed DM over a 4-year follow-up period were defined as cases and matched by age and fasting status with 362 disease-free controls. MAIN OUTCOME MEASURES: Incidence of confirmed clinically diagnosed type 2 DM by baseline levels of IL-6 and CRP. RESULTS: Baseline levels of IL-6 (P&lt;.001) and CRP (P&lt;.001) were significantly higher among cases than among controls. The relative risks of future DM for women in the highest vs lowest quartile of these inflammatory markers were 7.5 for IL-6 (95% confidence interval [CI], 3.7-15.4) and 15.7 for CRP (95% CI, 6.5-37.9). Positive associations persisted after adjustment for body mass index, family history of diabetes, smoking, exercise, use of alcohol, and hormone replacement therapy; multivariate relative risks for the highest vs lowest quartiles were 2.3 for IL-6 (95% CI, 0.9-5.6; P for trend =.07) and 4.2 for CRP (95% CI, 1.5-12.0; P for trend =.001). Similar results were observed in analyses limited to women with a baseline hemoglobin A(1c) of 6.0% or less and after adjustment for fasting insulin level. CONCLUSIONS: Elevated levels of CRP and IL-6 predict the development of type 2 DM. These data support a possible role for inflammation in diabetogenesis.

Advanced glycation end products: a Nephrologist's perspective.

Raj DS, Choudhury D, Welbourne TC, Levi M. Department of Medicine, Lousiana State University Medical Center, Shreveport, LA,USA.

Am J Kidney Dis 2000 Mar;35(3):365-80

Advanced glycation end products (AGEs) are a heterogeneous group of molecules that accumulate in plasma and tissues with advancing age, diabetes, and renal failure. There is emerging evidence that AGEs are potential uremic toxins and may have a role in the pathogenesis of vascular and renal complications associated with diabetes and aging. AGEs are formed when a carbonyl of a reducing sugar condenses with a reactive amino group in target protein. These toxic molecules interact with specific receptors and elicit pleiotropic responses. AGEs accelerate atherosclerosis through cross-linking of proteins, modification of matrix components, platelet aggregation, defective vascular relaxation, and abnormal lipoprotein metabolism. In vivo and in vitro studies indicate that AGEs have a vital role in the pathogenesis of diabetic nephropathy and the progression of renal failure. The complications of normal aging, such as loss of renal function, Alzheimer's disease, skin changes, and cataracts, may also be mediated by progressive glycation of long-lived proteins. AGEs accumulate in renal failure as a result of decreased excretion and increased generation resulting from oxidative and carbonyl stress of uremia. AGE-modified beta(2)-microglobulin is the principal pathogenic component of dialysis-related amyloidosis in patients undergoing dialysis. Available dialytic modalities are not capable of normalizing AGE levels in patients with end-stage renal disease. A number of reports indicated that restoration of euglycemia with islet-cell transplantation normalized and prevented further glycosylation of proteins. Aminoguanidine (AGN), a nucleophilic compound, not only decreases the formation of AGEs but also inhibits their action. A number of studies have shown that treatment with AGN improves neuropathy and delays the onset of retinopathy and nephropathy. N-Phenacylthiazolium bromide is a prototype AGE cross-link breaker that reacts with and can cleave covalent AGE-derived protein cross-links. Thus, there is an exciting possibility that the complications of diabetes, uremia, and aging may be prevented with these novel agents.

Effects of coenzyme Q10 treatment on antioxidant pathways in normal and streptozotocin-induced diabetic rats.

Rauscher FM, Sanders RA, Watkins JB III. Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405-7005, USA.

J Biochem Mol Toxicol 2001;15(1):41-6

Coenzyme Q10 is an endogenous lipid soluble antioxidant. Because oxidant stress may exacerbate some complications of diabetes mellitus, this study investigated the effects of subacute treatment with exogenous coenzyme Q10 (10 mg/kg/day, i.p. for 14 days) on tissue antioxidant defenses in 30-day streptozotocin-induced diabetic Sprague-Dawley rats. Liver, kidney, brain, and heart were assayed for degree of lipid peroxidation, reduced and oxidized glutathione contents, and activities of catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase. All tissues from diabetic animals exhibited increased oxidative stress and disturbances in antioxidant defense when compared with normal controls. Treatment with the lipophilic compound coenzyme Q10 reversed diabetic effects on hepatic glutathione peroxidase activity, on renal superoxide dismutase activity, on cardiac lipid peroxidation, and on oxidized glutathione concentration in brain. However, treatment with coenzyme Q10 also exacerbated the increase in cardiac catalase activity, which was already elevated by diabetes, further decreased hepatic glutathione reductase activity, augmented the increase in hepatic lipid peroxidation, and further increased glutathione peroxidase activity in the heart and brain of diabetic animals. Subacute dosing with coenzyme Q10 ameliorated some of the diabetes-induced changes in oxidative stress. However, exacerbation of several diabetes-related effects was also observed.

The influence of zinc supplementation on glucose homeostasis in NIDDM.

Raz I, Karsai D, Katz M. Department of Medicine B, Hadassah University Hospital, Ein Karem, Israel.

Diabetes Res 1989 Jun;11(2):73-9

Decreased serum zinc levels and hyperzincuria occur in some non-insulin dependent diabetic subjects (NIDDM). Zinc deficiency was demonstrated in various tissues of animal models for NIDDM. Serum zinc and 24-hr urine zinc of subjects with NIDDM were compared with that of age- and sex-matched healthy volunteers. Zincuria was significantly increased in the diabetic group. Thirteen diabetic subjects with hyperzincuria and hypozincemia were supplemented with zinc sulfate 220 mg x 3/day for 7-8 weeks. At the end of the study, glucose disposal (evaluated by kg) decreased significantly from 0.562 +/- 0.03 to 0.414 +/- 0.05 (p less than 0.05) and fasting glucose and fructosamine were significantly increased from 177 +/- 10 mg/dl to 207 +/- 15 mg/dl (p less than 0.05) and from 2.7 +/- 0.2% to 3.2 +/- 0.28% (p less than 0.05), respectively. T-lymphocyte response to phytohemagglutinin was increased significantly. We conclude that zinc supplementation to NIDD patients with hypozincemia and hyperzincemia might aggravate their glucose intolerance. More accurate methods to assess zinc deficiency in NIDD patients is needed to justify the supplementation of zinc in these patients.

Syndrome X 2000.

Reaven, G.M.

New York: Simon &amp; Schuster.

Gum Disease Linked to Diabetes 2001

Reuters Health.

(www.heartcenteronline.com/myheartdr/home/research-detail_print.cfm?reutersid=1336).

Review of moderate alcohol consumption and reduced risk of coronary heart disease: is the effect due to beer, wine, or spirits.

Rimm EB, Klatsky A, Grobbee D, Stampfer MJ. Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA.

BMJ 1996 Mar 23;312(7033):731-6

OBJECTIVES: To review the effect of specific types of alcoholic drink on coronary risk. DESIGN: Systematic review of ecological, case-control, and cohort studies in which specific associations were available for consumption of beer, wine, and spirits and risk of coronary heart disease. SUBJECTS: 12 ecological, three case-control, and 10 separate prospective cohort studies. MAIN OUTCOME MEASURES: Alcohol consumption and relative risk of morbidity and mortality from coronary heart disease. RESULTS: Most ecological studies suggested that wine was more effective in reducing risk of mortality from heart disease than beer or spirits. Taken together, the three case-control studies did not suggest that one type of drink was more cardioprotective than the others. Of the 10 prospective cohort studies, four found a significant inverse association between risk of heart disease and moderate wine drinking, four found an association for beer, and four for spirits. CONCLUSIONS: Results from observational studies, where alcohol consumption can be linked directly to an individual's risk of coronary heart disease, provide strong evidence that all alcoholic drinks are linked with lower risk. Thus, a substantial portion of the benefit is from alcohol rather than other components of each type of drink.

Mechanisms behind insulin resistance in rat skeletal muscle after oophorectomy and additional testosterone treatment.

Rincon J, Holmang A, Wahlstrom EO, Lonnroth P, Bjorntorp P, Zierath JR, Wallberg-Henriksson H. Department of Clinical Physiology, Karolinska Hospital, Stockholm, Sweden.

Diabetes 1996 May;45(5):615-21

The absence of female sex hormones, as well as testosterone treatment of oophorectomized (OVX) female rats has been demonstrated to result in decreased whole-body insulin-mediated glucose uptake. The cellular mechanism behind this insulin resistance and the role of low levels of female sex hormones as a risk factor for development of peripheral insulin resistance are not yet fully clarified. We assessed the protein expression of GLUT4 and glycogen synthase, as well as insulin-induced translocation of GLUT4 to the plasma membrane, in soleus skeletal muscle from control rats, OVX rats, and OVX rats treated for 8 weeks with testosterone (OVX + T). Whole-body insulin-mediated glucose uptake assessed by the hyperinsulinemic-euglycemic clamp procedure was 25% lower in OVX rats (P &lt; 0.001) and addition of testosterone treatment further decreased insulin-mediated glucose uptake in OVX + T rats by 48% (P &lt; 0.001) compared with controls. GLUT4 protein expression in soleus muscles was unaltered in the OVX and OVX + T rats compared with controls. Insulin induced a 3.7-fold increase (P &lt; 0.05) in the plasma membrane content of GLUT4 in soleus muscle from control rats, whereas plasma membrane content of GLUT4 in soleus muscle from OVX or OVX + T rats was unaltered in response to insulin. Glycogen synthase protein expression in muscle homogenates was decreased by 25% in the OVX group (P &lt; 0.05) and by 37% in the OVX + T group (P &lt; 0.05) when compared with the control group. Insulin receptor and tyrosine kinase activities in the basal and insulin-stimulated states did not differ between the OVX and OVX + T rats. In conclusion, the absence of female sex hormones appears to decrease insulin-mediated whole-body glucose uptake via an impaired insulin-stimulated translocation of GLUT4 to the plasma membrane and by decreased protein expression of glycogen synthase. Testosterone treatment further impairs whole-body insulin-mediated glucose uptake, presumably by additional impairment of glycogen synthase expression.

Effect of variations in plasma magnesium concentration on resistance to insulin-mediated glucose disposal in nondiabetic subjects.

Rosolova H, Mayer O Jr, Reaven G. Department of Internal Medicine, Medical Faculty, Charles University Pilsen, Czech Republic.

J Clin Endocrinol Metab 1997 Nov;82(11):3783-5

Eighteen nondiabetic volunteers were selected for these studies on the basis of their plasma magnesium (Mg) concentrations defined as being either high (&gt; 0.83 mmol/L) or low (&lt; 0.80 mmol/L). Although different in Mg concentration (0.90 +/- 0.02 vs. 0.73 +/- 0.01 mmol/L), the 2 groups were comparable in terms of age, gender distribution, body mass index, and waist to hip girth. Measurements were made of their plasma glucose and insulin concentrations in response to a 75-g oral glucose load and the steady state plasma insulin and glucose (SSPG) concentrations at the end of an 180-min infusion of octreotide, insulin, and glucose. The low Mg group had significantly higher plasma glucose (P &lt; 0.001) and insulin (P &lt; 0.002) concentrations after the oral glucose challenge. Although the steady state plasma insulin concentrations were similar during the infusion study, the SSPG concentration was significantly (P &lt; 0.001) greater in the low Mg group (11.9 +/- 0.9 vs. 6.6 +/- 0.9 mmol/L). Finally, when the 18 patients were analyzed together, there were significant (P &lt; 0.05 to P &lt; 0.01) inverse correlations between Mg concentrations and glucose (r = -0.68) and insulin (r = -0.51) areas and SSPG concentrations (r = -0.60). Thus, a low Mg concentration in nondiabetic subjects was associated with relative insulin resistance, glucose intolerance, and hyperinsulinemia.

Relationship between acute insulin response and vitamin K intake in healthy young male volunteers.

Sakamoto N, Nishiike T, Iguchi H, Sakamoto K. Department of Hygiene, Hyogo College of Medicine, Nisinomiya, Japan. naomasas@hyo-med.ac.jp

Diabetes Nutr Metab 1999 Feb;12(1):37-41

To evaluate the effects of vitamin K (VK) on pancreatic function, especially on acute insulin response, 25 healthy young male volunteers were given an oral load of 75 g of glucose, and their mean daily VK intake was estimated by a one-week food check list. After excluding low (&lt;20) and high (&gt; or =25) body mass index (BMI) subjects, the remaining 16 participants were divided into three semi-equal groups according to VK intake. Blood VK status of the low VK intake group tended to be poorer than that of the high intake group (median of 5 samples: prothrombin time; 12.5 vs 12.2s and protein-induced VK absence-factor-II; 23 vs 15 mAU/ml), but fasting plasma glucose status was not markedly different between both groups: [plasma glucose (PG); 87 vs 86 mg/dl, immunoreactive insulin (IRI); 6.7 vs 5.3 microU/ml, HbA1c; 4.8 vs 4.9%]. However, at 30 min after glucose loading, PG of the low VK intake group tended to be higher than those of the high intake group (160 vs 145 mg/dl) and IRI was lower (36.1 vs 52.3 microU/ml). Insulinogenic index (incremental IRI/incremental PG, 0-30 min) of the low VK intake group was significantly lower than that of the high intake group (0.4 vs 0.9). These results suggested that VK may play an important role on the acute insulin response in glucose tolerance.

Dietary fat intake and risk of type 2 diabetes in women.

Salmeron J, Hu FB, Manson JE, Stampfer MJ, Colditz GA, Rimm EB, Willett WC. Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.

Am J Clin Nutr 2001 Jun;73(6):1019-26

BACKGROUND: The long-term relations between specific types of dietary fat and risk of type 2 diabetes remain unclear. OBJECTIVE: Our objective was to examine the relations between dietary fat intakes and the risk of type 2 diabetes. DESIGN: We prospectively followed 84204 women aged 34-59 y with no diabetes, cardiovascular disease, or cancer in 1980. Detailed dietary information was assessed at baseline and updated in 1984, 1986, and 1990 by using validated questionnaires. Relative risks of type 2 diabetes were obtained from pooled logistic models adjusted for nondietary and dietary covariates. RESULTS: During 14 y of follow-up, 2507 incident cases of type 2 diabetes were documented. Total fat intake, compared with equivalent energy intake from carbohydrates, was not associated with risk of type 2 diabetes; for a 5% increase in total energy from fat, the relative risk (RR) was 0.98 (95% CI: 0.94, 1.02). Intakes of saturated or monounsaturated fatty acids were also not significantly associated with the risk of diabetes. However, for a 5% increase in energy from polyunsaturated fat, the RR was 0.63 (0.53, 0.76; P &lt; 0.0001) and for a 2% increase in energy from trans fatty acids the RR was 1.39 (1.15, 1.67; P = 0.0006). We estimated that replacing 2% of energy from trans fatty acids isoenergetically with polyunsaturated fat would lead to a 40% lower risk (RR: 0.60; 95% CI: 0.48, 0.75). CONCLUSIONS: These data suggest that total fat and saturated and monounsaturated fatty acid intakes are not associated with risk of type 2 diabetes in women, but that trans fatty acids increase and polyunsaturated fatty acids reduce risk. Substituting nonhydrogenated polyunsaturated fatty acids for trans fatty acids would likely reduce the risk of type 2 diabetes substantially.

Vitamin C and hyperglycemia in the European Prospective Investigation into Cancer--Norfolk (EPIC-Norfolk) study: a population-based study.

Sargeant LA, Wareham NJ, Bingham S, Day NE, Luben RN, Oakes S, Welch A, Khaw KT. Department of Community Medicine, University of Cambridge, Institute of Public Health, UK. lincoln.sargeant@srl.cam.ac.uk

Diabetes Care 2000 Jun;23(6):726-32

OBJECTIVE: To examine the cross-sectional association between plasma vitamin C, self-reported diabetes, and HbA1c. RESEARCH DESIGN AND METHODS: Data from a population-based study of diet, cancer, and chronic disease were analyzed. A total of 2,898 men and 3,560 women 45-74 years of age who were registered with general practices in Norfolk, U.K., were recruited to the European Prospective Investigation Into Cancer-Norfolk study between 1995 and 1998. RESULTS: Mean plasma vitamin C levels were significantly higher in individuals with HbA1c levels &lt; 7% than in those with self-reported diabetes or prevalent undiagnosed hyperglycemia (HbA1c &gt; or = 7%). An inverse gradient of mean plasma vitamin C was found in both sexes across quintiles of HbA1c distribution &lt; 7%. The odds ratio (95% CI) of having prevalent undiagnosed hyperglycemia per 20 micromol/l (or 1 SD) increase in plasma vitamin C was 0.70 (0.52-0.95) (adjusted for sex, age, BMI, waist-to-hip ratio, tertiary education, any use of dietary supplements, vegetarian diet, alcohol consumption, physical activity, dietary vitamin E, dietary fiber, dietary saturated fat, and smoking history). The unadjusted change in HbA1c per 20 micromol/l increase in vitamin C estimated by linear regression was -0.12% (-0.14 to -0.09) in men and -0.09% (-0.11 to -0.07) in women. After adjusting for the possible confounders, these values were -0.08% (-0.11 to -0.04) in men and -0.05% (-0.07 to -0.03) in women. CONCLUSIONS: An inverse association was found between plasma vitamin C and HbA1c. Dietary measures to increase plasma vitamin C may be an important public health strategy for reducing the prevalence of diabetes.

Postprandial hyperinsulinaemia, insulin resistance and inappropriately high phosphaturia are features of younger males with idiopathic calcium urolithiasis: attenuation by ascorbic acid supplementation of a test meal.

Schwille PO, Schmiedl A, Herrmann U, Wipplinger J. Department of Surgery, University of Erlangen, Germany.

Urol Res 1997;25(1):49-58

In idiopathic recurrent calcium urolithiasis (RCU) the state of insulin and carbohydrate metabolism, and relationships to minerals such as phosphate, are insufficiently understood. Therefore, in two groups of males with RCU (n = 30) and healthy controls (n = 8) the response to an oral carbohydrate- and calcium-rich test meal was studied with respect to glucose, insulin, and C-peptide in peripheral venous blood (taken before and up to 180 min post-load), and phosphate and glucose in fasting and post-load urine. In one RCU group (n = 16) the meal was supplemented with ascorbic acid (ASC; 5 mg/kg body weight). The mean age (RCU 29, RCU + ASC 30, controls 27 years) and mean body mass index [RCU 24.4, RCU + ASC 25.0, controls 24.0 kg/m2] were similar. Insulin resistance (synonymous sensitivity of peripheral organs to insulin) was calculated from insulin serum concentration, as was also integrated insulin, C-peptide, and glucose. Untreated stone patients (RCU) developed hyperinsulinaemia between 60 and 120 min post-load, increased integrated insulin, and insulin resistance (P &lt; or = 0.05 vs controls), whereas the rise of C-peptide and glycaemia (absolute and integrated values) was only of borderline significance. Fasting phosphaturia was low in both RCU subgroups vs controls; however, phosphaturia in untreated RCU rose in response to the meal, contrasting sharply with a decrease in controls. ASC supplementation of the meal (in the RCU + ASC subgroup) normalized insulin, failed to normalize post-load phosphaturia, but reduced post-load glucosuria and urinary pH significantly (mean pH values 5.55 vs 5.93 in untreated RCU, controls 5.50). Postprandial urinary oxalate, calcium, protein, and supersaturation products were not changed. The postprandial changes in phosphaturia and insulin sensitivity were inversely correlated (n = 38, r = -0.44, P = 0.007). It was concluded that in younger RCU males: (1) postprandial hyperinsulinaemia, the failure to reduce phosphaturia and - within limits - glucosuria, appropriately, as well as poor urine acidification are important features of the metabolism; (2) these phenomena are probably caused by insulin resistance of organs, the kidney included; and (3) the addition of a supraphysiological dose of ASC to a meal, the subsequent abolition of hyperinsulinaemia, and the restoration of normal urine acidification suggest that this antioxidant is capable of counteracting some pre-existing basic abnormality of cell metabolism in RCU.

Enter the Zone 1995.

Sears, B.

New York: Regan Books.

The Anti-Aging Zone 1999.

Sears, B.

New York: Regan Books.

Low plasma ascorbate levels in patients with type 2 diabetes mellitus consuming adequate dietary vitamin C.

Sinclair AJ, Taylor PB, Lunec J, Girling AJ, Barnett AH. University Department of Geriatric Medicine, Cardiff Royal Infirmary, UK.

Diabet Med 1994 Nov;11(9):893-8

Low ascorbate concentrations in diabetes may be secondary to inadequate dietary vitamin C intake or may relate to the varied metabolic roles of the vitamin. To determine whether inadequate dietary intake is a factor we calculated daily vitamin C intakes using both a vitamin C questionnaire and a 4-day food diary in a group of 30 patients with Type 2 diabetes (mean age 68.8 +/- 6.9 yr, 17M/13F) and in 30 community controls (mean age 68.0 +/- 5.5 yr, 12M/18F)). Measures of plasma glucose, serum fructosamine, and plasma ascorbic and dehydroascorbic acid were obtained from 20 subjects in each group. There was no significant difference in daily vitamin C intake between the two groups using both methods: food diary, 61.4 +/- 28.3 (patients) vs 69.5 +/- 33.4 (controls) mg; questionnaire, 54.0 +/- 28.9 (patients) vs 65.0 +/- 30.9 (controls) mg. Vitamin C intake derived from both methods was significantly correlated (p &lt; 0.001). Plasma ascorbate (30.4 +/- 19.1 mumol l-1) and dehydroascorbate (27.6 +/- 6.4 mumol l-1) levels were significantly lower in patients vs in controls (68.8 +/- 36.0 and 31.8 +/- 4.8 mumol l-1, respectively), p &lt; 0.0001 and p &lt; 0.01. Plasma ascorbate levels were significantly correlated with vitamin C intake derived from the food diary (p &lt; 0.01) and questionnaire (p &lt; 0.01) methods in the diabetic group only. Low ascorbate levels in diabetes appears to be a consequence of the disease itself and not due to inadequate dietary intake of vitamin C. A short vitamin C questionnaire is a convenient and reliable estimate of vitamin C intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk factors for developing non-insulin dependent diabetes: a 10 year follow up of men in Uppsala.

Skarfors ET, Selinus KI, Lithell HO. Department of Geriatrics, University of Uppsala, Sweden.

BMJ 1991 Sep 28;303(6805):755-60

OBJECTIVE--To analyse anthropometric and metabolic characteristics as risk factors for development of non-insulin dependent diabetes mellitus in middle aged normoglycaemic men. DESIGN--Prospective population study based on data collected in a health survey and follow up 10 years later.

SETTING--Uppsala, a middle sized city in Sweden.

SUBJECTS--2322 men aged 47-53, of whom 1860 attended the follow up 7-14 years later, at which time they were aged 56-64.

MAIN OUTCOME MEASURES--Incidence of non-insulin dependent diabetes.

RESULTS--In a multivariate logistic regression analysis, variations of 1 SD from the mean of the group that remained euglycaemic were used to calculate odds ratios and 95% confidence intervals. Blood glucose concentration 60 minutes after the start of an intravenous glucose tolerance test (odds ratio = 5.93, 95% confidence interval 3.05 to 11.5), fasting serum insulin concentration (2.12, 1.54 to 2.93), acute insulin increment at an intravenous glucose tolerance test (1.71, 1.21 to 2.43), body mass index (1.41, 1.01 to 1.97), and systolic blood pressure (1.23, 0.97 to 1.56) were independent predictors of diabetes. In addition, the use of antihypertensive drugs at follow up (selective or unselective beta blocking agents, thiazides, or hydralazine) was an independent risk factor (1.70, 1.11 to 2.60).

CONCLUSIONS--Metabolic and anthropometric characteristics associated with or reflecting insulin resistance as well as a poor acute insulin response to glucose challenge were important predictors of future diabetes in middle aged men. Antihypertensive drugs were found to constitute a further, iatrogenic risk factor.

Some Teens Putting Themselves in Danger of Heart Disease 2001

Smith, M.

(http://content.health.msn.com/content/article/1728.89754).

Growth factors regulate expression of osteoblast-associated genes.

Strayhorn CL, Garrett JS, Dunn RL, Benedict JJ, Somerman MJ. Department of Oral Medicine/Pathology and Oncology, University of Michigan, Ann Arbor, MI 48109-1078, USA.

J Periodontol 1999 Nov;70(11):1345-54

BACKGROUND: The goal of periodontal regenerative therapies is to reconstruct periodontal tissues such as bone, cementum, and periodontal ligament cells (PDL). The need to establish predictable treatment modalities is important for reconstruction of these tissues. The aim of this study was to determine the effects of a low molecular extract of bovine bone protein (BP) containing bone morphogenetic proteins (BMPs) 2, 3, 4, 6, 7, 12, and 13, alone or in combination with platelet-derived growth factor (PDGF) and/or insulin-like growth factor (IGF) on osteoblast differentiation in vitro.

METHODS: BP, mixed with a collagen matrix, was added to a poly (DL-lactide-co-glycolide) polymer (PLG) and placed at orthotopic sites in the skullcaps of Sprague-Dawleys rats. At day 28, rats were sacrificed for histological analysis. All sites treated with the polymer/BP produced bone while control sites (without BP) showed no bone formation. Having established the biological activity of BP, in vitro studies were initiated using MC3T3-E1 cells, a mouse osteoprogenitor cell line. The ability of BP and other growth factors to alter cell proliferation was determined by Coulter counter, and differentiation was determined by Northern analysis for specific genes.

RESULTS: When compared with cells treated with 2% serum alone, PDGF enhanced cell numbers at 10 and 20 ng/ml; IGF produced no significant effect at these doses; and BP at 10 and 20 microg/ml decreased cell proliferation. Northern analysis revealed that PDGF blocked gene expression of osteopontin (OPN) and osteocalcin (OCN), while BP and IGF promoted gene expression of bone sialoprotein (BSP) and OPN. The combination of BP and IGF enhanced expression of OPN beyond that of either BP or IGF alone. PDGF was able to block the effects of IGF on gene expression, but not those of BP.

CONCLUSIONS: These results indicate that BP, PDGF, and IGF influence cell activity differently, and thus raise the possibility that combining factors may enhance the biological activity of cells.

Skin tags as markers of diabetes mellitus: an epidemiological study in India.

Thappa DM. Department of Dermatology and STD, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India.

J Dermatol 1995 Oct;22(10):729-31

To ascertain whether skin tags (ST) are associated with a higher risk for diabetes mellitus (DM), 35 patients with ST were screened out of 5000 consecutive patients visiting our dermatology clinic. The study group ranged in age from 35 to 73 years, with a mean of 52.03. Twenty-six of the patients were men, and nine, women. The risk of getting ST was found to increase with age, but this risk decreased after the fifth decade. The neck was invariably involved, followed by the eyelids, axillae and groin. Of the cases, 62.8% (22 patients) had DM. Four new cases of DM were found among this group. All the diabetic patients in this study population had noninsulin dependent DM. The frequency of DM in ST patients was found to increase with age, however, it was statistically insignificant. No correlation was found between localisation, size, color, or number of ST and the presence of DM. The frequency with which ST had been found to co-exist with DM in this population is significant, and ST may serve as a marker for DM.

Is visceral adiposity the "enemy within"?

Tracy RP.

Arterioscler Thromb Vasc Biol 2001 Jun;21(6):881-3

No abstract available.

Type 2 diabetes can be prevented with lifestyle change.

Tuomilehto, J.

Presented at the American Diabetes' Association's 60th Annual Scientific Session, San Antonio, Texas, June 9-13, 2000.

Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance.

Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M; Finnish Diabetes Prevention Study Group. Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland. jaakko.tuomilehto@ktl.fi

N Engl J Med 2001 May 3;344(18):1343-50

BACKGROUND: Type 2 diabetes mellitus is increasingly common, primarily because of increases in the prevalence of a sedentary lifestyle and obesity. Whether type 2 diabetes can be prevented by interventions that affect the lifestyles of subjects at high risk for the disease is not known.

METHODS: We randomly assigned 522 middle-aged, overweight subjects (172 men and 350 women; mean age, 55 years; mean body-mass index [weight in kilograms divided by the square of the height in meters], 31) with impaired glucose tolerance to either the intervention group or the control group. Each subject in the intervention group received individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fat and increasing intake of fiber and physical activity. An oral glucose-tolerance test was performed annually; the diagnosis of diabetes was confirmed by a second test. The mean duration of follow-up was 3.2 years.

RESULTS: The mean (+/-SD) amount of weight lost between base line and the end of year 1 was 4.2+/-5.1 kg in the intervention group and 0.8+/-3.7 kg in the control group; the net loss by the end of year 2 was 3.5+/-5.5 kg in the intervention group and 0.8+/-4.4 kg in the control group (P&lt;0.001 for both comparisons between the groups). The cumulative incidence of diabetes after four years was 11 percent (95 percent confidence interval, 6 to 15 percent) in the intervention group and 23 percent (95 percent confidence interval, 17 to 29 percent) in the control group. During the trial, the risk of diabetes was reduced by 58 percent (P&lt;0.001) in the intervention group. The reduction in the incidence of diabetes was directly associated with changes in lifestyle.

CONCLUSIONS: Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects.

Effects of long-term administration of testosterone enanthate on glucose metabolism in rhesus monkeys.

Tyagi A, Rajalakshmi M, Jeyaraj DA, Sharma RS, Bajaj JS. Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India.

Contraception 1999 May;59(5):333-7

The effects of long term administration of testosterone enanthate (TE) on glucose metabolism including glucose tolerance test (GTT) and fasting serum insulin levels were evaluated in adult rhesus monkeys kept under controlled dietary conditions. Adult male rhesus monkeys (n = 9) were administered 50 mg of TE bimonthly for 32 months, whereas control animals were injected the vehicle only. Glucose concentration reached a maximum 5 min after an intravenous glucose load and thereafter decreased gradually to reach near baseline values within 60 min. Significant changes in GTT or t1/2 of glucose were not seen in animals treated with TE, throughout the treatment period. However, serum insulin levels decreased significantly from months 27-32 of TE treatment and returned to baseline values within 3 months of recovery.

The milieu interieur and the islets of Langerhans.

Unger RH.

Diabetologia 1981;20(1):1-11

No abstract available.

A subcutaneous glucose sensor with improved longevity, dynamic range, and stability of calibration.

Updike SJ, Shults MC, Gilligan BJ, Rhodes RK. Department of Medicine, University of Wisconsin Center for Health Sciences, Madison, WI, USA. sjupdike@facstaff.wisc.edu

Diabetes Care 2000 Feb;23(2):208-14

OBJECTIVE: To evaluate the lifetime, response time, linearity, glucose range, and calibration stability of two different types of continuous glucose sensor implants in a dog model.

RESEARCH DESIGN AND METHODS: Glucose sensors based on the enzyme electrode principle that are coupled to a radio transmitter were evaluated on the bench top, sterilized, and then implanted subcutaneously in nondiabetic mongrel dogs. A multichannel radio receiver and PC data processor were used to record the sensor glucose data. Initial early reliable sensor responsivity was recognized by a vigorous hyperglycemic excursion after an intramuscular injection of glucagon. Periodically the dogs were made temporarily diabetic by blocking pancreatic insulin secretion by subcutaneous injection of a synthetic somatostatin (octreotide). By using exogenous insulin injection followed by intravenous glucose infusion, glucose levels were manipulated through the entire clinical range of interest: 2.2-38.9 mmol/l (40-700 mg/dl). Every 5-10 min, reference blood glucose samples were obtained and run in our hospital clinical laboratory. The glucose sensor data was evaluated by linear least squares optimization and by the error grid method.

RESULTS: Beginning as early as postimplant day 7, the in vivo performances of sensors were evaluated by using glucose infusion studies performed every 1-4 weeks. Bench-top and in vivo 90% response-time sensors were in the range of 4-7 min during sensor lifetime. Best-performing sensors from both types are summarized as follows. The earlier-stage technology was less linear with a dynamic range of no more than 22 mmol/l glucose, had a best-case recalibration interval of 18 days, and had a maximum lifetime of 94 days. The improved later-stage technology sensors, which were constructed with the addition of bioprotective and angiogenic membranes, were linear over the full extended range of clinical interest (2.2-38.9 mmol/l [40-700 mg/dl glucose]), had a best-case recalibration interval of 20 days, and had a maximum lifetime of &gt;160 days.

CONCLUSIONS: Stable clinically useful sensor performance was demonstrated as early as 7 days after implantation and for a sensor lifetime of 3-5 months. This type of subcutaneous glucose sensor appears to be promising as a continuous and painless long-term method for monitoring blood glucose. Specifically sensors with top-layer materials that stimulate angiogenesis at the sensor/tissue interface may have better dynamic measurement range, longer lifetimes, and better calibration stability than our previously reported sensors.

The Finnish Diabetes Prevention Study.

Uusitupa M, Louheranta A, Lindstrom J, Valle T, Sundvall J, Eriksson J, Tuomilehto J. Department of Clinical Nutrition University of Kuopio, Finland. matti.uusitupa@kuh.fi

Br J Nutr 2000 Mar;83 Suppl 1:S137-42

The aim of the Finnish Diabetes Prevention Study is to assess the efficacy of an intensive diet-exercise programme in preventing or delaying type 2 diabetes in individuals with impaired glucose tolerance (IGT) and to evaluate the effect of the programme on the risk factors of atherosclerotic vascular diseases and the incidence of cardiovascular events. In this ongoing study, a total of 523 overweight subjects with IGT based on two oral glucose tolerance tests were randomized to either an intervention group or a control group. The main measure in the intervention group is individual dietary advice aimed at reducing weight and intake of saturated fat and increasing intake of dietary fibre. The intervention subjects are individually guided to increase their level of physical activity. The control group receives general information about the benefits of weight reduction, physical activity and healthy diet in the prevention of diabetes. A pilot study began in 1993, and recruitment ended in 1998. By the end of April 1999 there were 65 new cases of diabetes, 34 drop-outs and one death. The weight reduction was greater (-4.6 kg) at 1 year in the intervention group (n = 152) than in the control group (n = 143, -0.9 kg, P &lt; 0.0001), and this difference was sustained in the second year of follow-up. At 1 year 43.4% and at 2 years 41.8% of the intervention subjects had achieved a weight reduction of at least 5 kg, while the corresponding figures for the control subjects were 14.0 and 12.0% (P &lt; 0.001 between the groups). At 1 year the intervention group showed significantly greater reductions in 2 h glucose, fasting and 2 h insulin, systolic and diastolic blood pressure, and serum triglycerides. Most of the beneficial changes in cardiovascular risk factors were sustained for 2 years. These interim results of the ongoing Finnish Diabetes Prevention Study demonstrate the efficacy and feasibility of the lifestyle intervention programme.

Dietary fat and meat intake in relation to risk of type 2 diabetes in men.

van Dam RM, Willett WC, Rimm EB, Stampfer MJ, Hu FB. Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA. rob.van.dam@rivm.nl

Diabetes Care 2002 Mar;25(3):417-24

OBJECTIVE: To examine dietary fat and meat intake in relation to risk of type 2 diabetes.

RESEARCH DESIGN AND METHODS: We prospectively followed 42,504 male participants of the Health Professionals Follow-Up Study who were aged 40-75 years and free of diagnosed diabetes, cardiovascular disease, and cancer in 1986. Diet was assessed by a validated food frequency questionnaire and updated in 1990 and 1994. During 12 years of follow-up, we ascertained 1,321 incident cases of type 2 diabetes.

RESULTS: Intakes of total fat (multivariate RR for extreme quintiles 1.27, CI 1.04-1.55, P for trend=0.02) and saturated fat (1.34, 1.09-1.66, P for trend=0.01) were associated with a higher risk of type 2 diabetes. However, these associations disappeared after additional adjustment for BMI (total fat RR 0.97, CI 0.79-1.18; saturated fat 0.97, 0.79-1.20). Intakes of oleic acid, trans-fat, long-chain n-3 fat, and alpha-linolenic acid were not associated with diabetes risk after multivariate adjustment. Linoleic acid was associated with a lower risk of type 2 diabetes in men &lt;65 years of age (RR 0.74, CI 0.60-0.92, P for trend=0.01) and in men with a BMI &lt;25 kg/m(2) (0.53, 0.33-0.85, P for trend=0.006) but not in older and obese men. Frequent consumption of processed meat was associated with a higher risk for type 2 diabetes (RR 1.46, CI 1.14-1.86 for &gt; or = 5/week vs. &lt;1/month, P for trend &lt;0.0001).

CONCLUSIONS: Total and saturated fat intake were associated with a higher risk of type 2 diabetes, but these associations were not independent of BMI. Frequent consumption of processed meats may increase risk of type 2 diabetes.

Plasma insulin responses after ingestion of different amino acid or protein mixtures with carbohydrate.

van Loon LJ, Saris WH, Verhagen H, Wagenmakers AJ. Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Department of Human Biology, Maastricht University, Maastricht, The Netherlands. L.vanLoon@hb.unimaas.nl

Am J Clin Nutr 2000 Jul;72(1):96-105

BACKGROUND: Protein induces an increase in insulin concentrations when ingested in combination with carbohydrate. Increases in plasma insulin concentrations have been observed after the infusion of free amino acids. However, the insulinotropic properties of different amino acids or protein (hydrolysates) when co-ingested with carbohydrate have not been investigated.

OBJECTIVE: The aim of this study was to define an amino acid and protein (hydrolysate) mixture with a maximal insulinotropic effect when co-ingested with carbohydrate.

DESIGN: Eight healthy, nonobese male subjects visited our laboratory, after an overnight fast, on 10 occasions on which different beverage compositions were tested for 2 h. During those trials the subjects ingested 0.8 g*kg(-)(1)*h(-)(1) carbohydrate and 0.4 g*kg(-)(1)*h(-)(1) of an amino acid and protein (hydrolysate) mixture.

RESULTS: A strong initial increase in plasma glucose and insulin concentrations was observed in all trials, after which large differences in insulin response between drinks became apparent. After we expressed the insulin response as area under the curve during the second hour, ingestion of the drinks containing free leucine, phenylalanine, and arginine and the drinks with free leucine, phenylalanine, and wheat protein hydrolysate were followed by the largest insulin response (101% and 103% greater, respectively, than with the carbohydrate-only drink; P &lt; 0.05).

CONCLUSIONS: Insulin responses are positively correlated with plasma leucine, phenylalanine, and tyrosine concentrations. A mixture of wheat protein hydrolysate, free leucine, phenylalanine, and carbohydrate can be applied as a nutritional supplement to strongly elevate insulin concentrations.

Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients.

Velussi M, Cernigoi AM, De Monte A, Dapas F, Caffau C, Zilli M. Anti-Diabetes Centre, Monfalcone Hospital, Gorizia, Italy.

J Hepatol 1997 Apr;26(4):871-9

BACKGROUND/AIMS: Several studies have demonstrated that diabetic patients with cirrhosis require insulin treatment because of insulin resistance. As chronic alcoholic liver damage is partly due to the lipoperoxidation of hepatic cell membranes, anti-oxidizing agents may be useful in treating or preventing damage due to free radicals. The aim of this study was to ascertain whether long-term treatment with silymarin is effective in reducing lipoperoxidation and insulin resistance in diabetic patients with cirrhosis.

METHODS: A 12-month open, controlled study was conducted in two well-matched groups of insulin-treated diabetics with alcoholic cirrhosis. One group (n=30) received 600 mg silymarin per day plus standard therapy, while the control group (n=30) received standard therapy alone. The efficacy parameters, measured regularly during the study, included fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria levels, glycosylated hemoglobin (HbA1c) and malondialdehyde levels.

RESULTS: There was a significant decrease (p&lt;0.01) in fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria and HbA1c levels already after 4 months of treatment in the silymarin group. In addition, there was a significant decrease (p&lt;0.01) in fasting insulin levels and mean exogenous insulin requirements in the treated group, while the untreated group showed a significant increase (p&lt;0.05) in fasting insulin levels and a stabilized insulin need. These findings are consistent with the significant decrease (p&lt;0.01) in basal and glucagon-stimulated C-peptide levels in the treated group and the significant increase in both parameters in the control group. Another interesting finding was the significant decrease (p&lt;0.01) in malondialdehyde/levels observed in the treated group.

CONCLUSIONS: These results show that treatment with silymarin may reduce the lipoperoxidation of cell membranes and insulin resistance, significantly decreasing endogenous insulin overproduction and the need for exogenous insulin administration.

Glycogen metabolism and the mechanism of action of cyclic AMP.

Villar-Palasi C, Larner J, Shen LC.

Ann N Y Acad Sci 1971 Dec 30;185:74-84

No abstract available.

Inhibition of aldose reductase in human erythrocytes by vitamin C.

Vincent TE, Mendiratta S, May JM. Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6303, USA.

Diabetes Res Clin Pract 1999 Jan;43(1):1-8

Ascorbic acid, or vitamin C, has been reported to lower erythrocyte sorbitol concentrations, and present studies were performed to determine the mechanism of this effect. Incubation of erythrocytes with increasing concentrations of glucose (5-40 mM) progressively increased erythrocyte sorbitol contents, reflecting increased flux through aldose reductase. At extracellular concentrations of 90 microM, both ascorbic acid and its oxidized form, dehydroascorbate, decreased intracellular sorbitol by 25 and 45%, respectively. This inhibition was not dependent on the extracellular glucose concentration, or on erythrocyte contents of free NADPH or GSH. To test for a direct effect of ascorbate on aldose reductase, erythrocyte hemolysates were prepared and supplemented with 100 microM NADPH. Hemolysates reduced glucose to sorbitol in a dose-dependent manner that was inhibited with a Ki of 120 microM by the aldose reductase inhibitor tetramethylene glutaric acid. Above 100 microM, ascorbic acid also lowered hemolysate sorbitol generation by about 30%. Studies with ascorbic acid derivatives showed that the reducing capacity of ascorbic acid was not required for inhibition of sorbitol production from glucose in erythrocyte hemolysates. These results show that high, but physiologic, concentrations of ascorbic acid can directly inhibit erythrocyte aldose reductase, and provide a rationale for the use of oral vitamin C supplements in diabetes.

The effect of sugar cereal with and without a mixed meal on glycemic response in children with diabetes.

Wang SR, Chase HP, Garg SK, Hoops SL, Harris MA. Barbara Davis Center for Childhood Diabetes, Department of Pediatrics, University of Colorado Health, Sciences Center, Denver, CO 80262.

J Pediatr Gastroenterol Nutr 1991 Aug;13(2):155-60

The effect of sucrose consumption on glycemic control in children with insulin-dependent diabetes mellitus is unclear. Eight young subjects, 7-16 years of age, with a duration of diabetes of 2-8 years participated in this study. All subjects consumed four different breakfasts--oatmeal (OM) alone, oatmeal-sucrose (OMS), oatmeal-protein (OMP), and oatmeal with protein and sucrose (OMPS)--on four different days. Addition of sucrose resulted in a slightly greater area under the tolerance curve in 50% of the subjects; however, in 38% of subjects, the area decreased. The peak glucose level was lowest for OM, but there was no statistical difference in the peak levels of the four test meals. The most significant effect on glucose response was a delay in the peak time when protein was added to the meals. Peak times for OM and OMS (mean of 38 min) when fed alone were significantly (p less than 0.05, ANOVA) shorter when compared to the peak time for OMP and OMPS (mean of 54 min). The average recovery time for OMP was longest. Other indices (tolerance index and change of rise in blood glucose) measured were not significantly different among the test meals. This study demonstrates that adding limited sucrose to OM cereal has little effect on the blood glucose response in children with diabetes. Addition of protein and fat clearly delays the glycemic response.

Waterfall Health and Nutrition Database. Magnesium 2000

(http://www.waterfall2000.com/a-z/magnesium.htm).

Effects of silibinin and antioxidants on high glucose-induced alterations of fibronectin turnover in human mesangial cell cultures.

Wenzel S, Stolte H, Soose M. Institute of Animal Physiology, Justus-Liebig-University, Giessen, Germany.

J Pharmacol Exp Ther 1996 Dec;279(3):1520-6

To elucidate the primary mechanism of high glucose cytotoxicity, the cytoprotective properties of antioxidants against metabolical disorders were assessed in human mesangial cell (HMC) cultures. An 8-day incubation of HMC with high glucose concentration (30 mM) resulted in an extracellular accumulation of the matrixprotein fibronectin (FN), owing to both an expansion of the matrix-associated pericellular FN and a 60% increase of the soluble molecule in the culture medium. The high glucose-induced FN alterations were not due to osmotical effects, as assessed by an iso-osmotic mannitol control. Rather, they are mediated by oxygen-free radicals because the combined treatment of HMC with high glucose and either the antioxidative flavonoid silibinin (given as the water soluble derivative silibinin-C-2,3-dihydrogensuccinate disodium salt) or a radical scavenger cocktail totally prevented the extracellular FN accumulation. This is corroborated further by the determination of malondialdehyde, a product of lipid peroxidation. Incubation of HMC with high glucose resulted in an increase of malondialdehyde in cell homogenates which was completely counteracted by either silibinin or a radical scavenger cocktail. Silibinin alone had no effects on protein synthesis and culture growth. The data presented are compatible with oxidative stress induced by high glucose concentration in HMC cultures. The study further substantiates the proposed role of silibinin in the amelioration of glucose cytotoxicity in renal cells.

The Herbal Drugstore 2000.

White, L. Foster, S.

Emmaus, PA: Rodale.

Diabetes: finally getting the attention it needs.

Whiting, S.E.

Inst. Nutr. Sci. J. 2000 Sep; 5.3.

Gaining and Maintaining Total Health 1989.

Whiting, S.E.

Hilo, HI: The Holistic Health Network.

Understanding Normal and Clinical Nutrition, Fourth Edition 1998.

Whitney, E.N. et al.

Belmont, CA: West/Wadsworth.

Reduced serum dehydroepiandrosterone levels in diabetic patients with hyperinsulinaemia.

Yamaguchi Y, Tanaka S, Yamakawa T, Kimura M, Ukawa K, Yamada Y, Ishihara M, Sekihara H. Third Department of Internal Medicine, Yokohama City University School of Medicine, Kanagawa, Japan.

Clin Endocrinol (Oxf) 1998 Sep;49(3):377-83

OBJECTIVE: To elucidate the interaction between insulin and dehydroepi-androsterone (DHEA) concentrations, we evaluated serum DHEA and DHEA-sulphate (DHEA-S) levels in diabetic patients with hyperinsulinaemia.

PATIENTS AND DESIGN: Twenty-four subjects with non-insulin dependent diabetes mellitus, 12 hyperinsulinaemic subjects (fasting serum insulin concentrations &gt; or = 10 mU/ml (71.8 pmol/l)) and 12 non-hyperinsulinaemic subjects, and 10 normal control subjects were studied. Serum DHEA, DHEA-S, cortisol and ACTH levels were investigated in these subjects. Moreover, their serum DHEA levels were compared during hyperinsulinaemic-euglycaemic clamp and after ACTH stimulation.

MEASUREMENTS: Serum insulin, cortisol, ACTH, DHEA and DHEA-S concentrations were evaluated by RIA. Serum glucose was determined by the glucose oxidase method.

RESULTS: Diabetic patients with hyperinsulinaemia showed significantly lower levels of serum DHEA and DHEA-S than controls. After ACTH stimulation, these patients also showed significantly lower DHEA levels. During the hyperinsulinaemic-euglycaemic clamp, serum DHEA concentrations of diabetic patients with hyperinsulinaemia remained low and did not decline further, although those of control subjects and non-hyperinsulinaemic diabetic patients showed a significant decline of serum DHEA levels. Even after ACTH stimulation during the clamp, serum DHEA in hyperinsulinaemic patients was still significantly lower than in controls.

CONCLUSIONS: In diabetic patients with hyperinsulinaemia, baseline DHEA levels are chronically and maximally suppressed compared to control subjects and non-hyperinsulinaemic diabetic patients, and thus not decreased further by exogenous insulin infusion during hyperinsulinaemic-euglycaemic clamp.

Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.

Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Canadian Cardiovascular Collaboration Project Office, Hamilton General Hospital, McMaster University, ON. hope@ccc.mcmaster.ca

N Engl J Med 2000 Jan 20;342(3):145-53

BACKGROUND: Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction, whether or not they have heart failure. We assessed the role of an angiotensin-converting-enzyme inhibitor, ramipril, in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure.

METHODS: A total of 9297 high-risk patients (55 years of age or older) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were randomly assigned to receive ramipril (10 mg once per day orally) or matching placebo for a mean of five years. The primary outcome was a composite of myocardial infarction, stroke, or death from cardiovascular causes. The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper.

RESULTS: A total of 651 patients who were assigned to receive ramipril (14.0 percent) reached the primary end point, as compared with 826 patients who were assigned to receive placebo (17.8 percent) (relative risk, 0.78; 95 percent confidence interval, 0.70 to 0.86; P&lt;0.001). Treatment with ramipril reduced the rates of death from cardiovascular causes (6.1 percent, as compared with 8.1 percent in the placebo group; relative risk, 0.74; P&lt;0.001), myocardial infarction (9.9 percent vs. 12.3 percent; relative risk, 0.80; P&lt;0.001), stroke (3.4 percent vs. 4.9 percent; relative risk, 0.68; P&lt;0.001), death from any cause (10.4 percent vs. 12.2 percent; relative risk, 0.84; P=0.005), revascularization procedures (16.3 percent vs. 18.8 percent; relative risk, 0.85; P&lt;0.001), cardiac arrest (0.8 percent vs. 1.3 percent; relative risk, 0.62; P=0.02), [corrected] heart failure (9.1 percent vs. 11.6 percent; relative risk, 0.77; P&lt;0.001), and complications related to diabetes (6.4 percent vs. 7.6 percent; relative risk, 0.84; P=0.03).

CONCLUSIONS: Ramipril significantly reduces the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure.

Hyperinsulinaemia, obesity, and syndrome X.

Zavaroni I, Bonini L, Fantuzzi M, Dall'Aglio E, Passeri M, Reaven GM. Institute of General Clinical Medicine, Parma University, Italy.

J Intern Med 1994 Jan;235(1):51-6

OBJECTIVE. The major aim of this study was to compare various aspects of carbohydrate, insulin, and lipoprotein metabolism, serum uric acid concentration, and blood pressure in normal subjects stratified on the basis of both plasma insulin concentration and degree of obesity. The hypothesis to be tested was that hyperinsulinaemia, per se, was associated with relative glucose intolerance, higher triglyceride and uric acid concentrations, lower high-density lipoprotein cholesterol concentration and higher blood pressure, irrespective of degree of obesity.

DESIGN. This represents a case-control study, in which normal volunteers were subdivided into four equal groups based upon degree of obesity and plasma insulin response to a 74 g oral glucose challenge.

SETTING. The study was performed in the out-patient clinic of a university hospital.

SUBJECTS. Sixty-four individuals were recruited for this study, subdivided into four groups based upon their plasma insulin concentration and body mass index. Subjects were classified as hyperinsulinaemic if their plasma insulin concentrations in response to an oral glucose challenge were more than two standard deviations above the mean of 732 volunteers previously studied [1]. Obesity was defined as a body mass index of &gt; 30 kg m-2, and individuals were classified as non-obese if their body mass index was &lt; 27.0 kg m-2. Based upon these criteria, four experimental groups were created: (i) non-obese hyperinsulinaemic (NOB hyper); (ii) obese hyperinsulinaemic (OB hyper); (iii) non-obese normoinsulinaemic (NOB normo); and (iv) obese normoinsulinaemic (OB normo). MAIN

OUTCOME MEASURES. Subject groups were compared on the basis of the integrated plasma glucose response to a 75 g oral glucose challenge, fasting plasma triglyceride, cholesterol, high-density lipoprotein cholesterol, and uric acid concentrations, and blood pressure.

RESULTS. Mean (+/- standard error of the mean) integrated plasma glucose response area for 2 h following a 75 g oral glucose load was significantly higher (13.4 +/- 0.4 vs. 11.0 +/- 0.4 mmol l-1, P &lt; 0.001) in the hyperinsulinaemic group, as were the fasting triglyceride levels (2.4 +/- 0.2 vs. 1.4 +/- 0.1 mmol l-1, P &lt; 0.001) and uric acid (5.3 +/- 0.2 vs. 4.4 +/- 0.2 mmol l-1, P &lt; 0.05) concentrations. In contrast, high-density lipoprotein concentrations were lower in the hyperinsulinaemic group (1.06.0.05 vs. 1.32 +/- 0.05 mmol l-1, P &lt; 0.001). In addition, blood pressure was higher in the hyperinsulinaemic group (136 +/- 5/87 +/- 2 vs. 123 +/- 2/82 +/- 1 mmHg, P &lt; 0.05). Furthermore, when each of the two groups were divided into obese (n = 16) and non-obese (n = 16) groups, all of the differences outlined above persisted. These changes were independent of age, gender distribution, generalized and abdominal obesity, cigarette smoking, and estimated physical activity.

CONCLUSIONS. The cluster of changes subsumed under the heading of syndrome X are closely associated with hyperinsulinaemia (and presumably insulin resistance), and can be discerned irrespective of degree of obesity.

Prevalence of hyperinsulinaemia in patients with high blood pressure.

Zavaroni I, Mazza S, Dall'Aglio E, Gasparini P, Passeri M, Reaven GM. Institute of the General Medical Clinic, Parma University, Italy.

J Intern Med 1992 Mar;231(3):235-40

A total of 41 patients with hypertension were identified in a survey of 732 healthy factory workers. Twenty-three of these individuals were receiving antihypertensive medication, whereas 18 cases were newly discovered. Plasma glucose and insulin responses to oral glucose and fasting plasma triglyceride (TG), cholesterol, and high-density-lipoprotein (HDL) cholesterol concentrations of these 41 individuals were compared with those of 41 other factor workers, with normal blood pressure, matched with the hypertensive group in terms of gender, age, degree of obesity, job in the factory, and leisure-time activity. Patients with hypertension had significantly higher plasma glucose (P less than 0.05) and insulin (P less than 0.05) concentrations in response to oral glucose, as well as a higher plasma TG concentration (P less than 0.05). Similar findings were obtained when the treated and untreated hypertensive groups were analysed separately and compared with their respective control groups. However, there were no differences between the treated and untreated hypertensive groups. Ninety per cent of the normotensive group had a plasma insulin concentration of less than 500 pmol l-1 2 h after the glucose load. Using this value as the criterion for definition of hyperinsulinaemia, 41% of the patients with high blood pressure were hyperinsulinaemic. In addition to meeting this cut-off point, the patients with hypertension and hyperinsulinaemia were also glucose intolerant and dyslipidaemic. In conclusion, approximately 50% of an unselected group of patients with hypertension were hyperinsulinaemic. Insulin levels were comparable in treated and untreated patients with high blood pressure, and hyperinsulinaemic patients also tended to be glucose intolerant and dyslipidaemic.

Biotin administration improves the impaired glucose tolerance of streptozotocin-induced diabetic Wistar rats.

Zhang H, Osada K, Sone H, Furukawa Y. Department of Applied Biological Chemistry, Faculty of Agriculture, Tohoku University, Sendai Japan.

J Nutr Sci Vitaminol (Tokyo) 1997 Jun;43(3):271-80

The effect of biotin administration on the glucose tolerance of streptozotocin (STZ)-induced diabetic Wistar rats was investigated. STZ-induced diabetes was induced by intraperitoneal injection of streptozotocin (45 mg/kg body weight as a single dose). The impaired glucose tolerance in response to an oral glucose load (1.8g per kg body weight) in STZ-induced diabetic rats (STZ-rat) was partially improved by intraperitoneal administration of biotin for 15 days (100 micrograms/rat/day). However, a recovery in the STZ-rat's insulin secretion was not found after biotin administration. To help clarify the mechanism underlying the improvement in glucose tolerance seen with biotin treatment, glucokinase and hexokinase activities were determined in the liver and pancreas. In STZ-rats that had received biotin (STZ-biotin rats), glucokinase activity was higher by 3.4-fold in liver and by 2.4-fold in pancreas than in the STZ-rats. The biotin level of STZ-rats was significantly lower in the liver and pancreas than that of the control rats (no STZ administration); but in STZ-biotin rats, the level in these organs recovered to the control level. These results demonstrate that injected biotin can improve glucose handling without increasing insulin secretion in STZ-rats.

Improvement of oral glucose tolerance in gestational diabetes by pyridoxine.

Bennink HJ, Schreurs WH
Br Med J 1975 Jul 5;3(5974):13-5

Fourteen pregnant women were shown by the oral glucose tolerance test to have gestational diabetes. In 13 an increased urinary xanthurenic-acid excretion after an oral load of L-tryptophan indicated a relative pyridoxine deficiency. All patients were treated with vitamin B6 (pyridoxine) 100 mg/day for 14 days by mouth, after which the pyridoxine deficiency disappeared and the oral glucose tolerance improved considerably. Only two patients then had sufficiently impaired glucose tolerance to justify the diagnosis of gestational diabetes; Our results substantiated our hypothesis that increased xanthurenic-acid synthesis during pregnancy may cause gestational diabetes. Treatment with vitamin B6 makes the production of xanthurenic-acid normal by restoring tryptophan metabolism and improves the oral glucose tolerance in patients with gestational diabetes.

Vitamin B6 status in pregnancy.

Heller S, Salkeld RM, Korner WF
Am J Clin Nutr 1973 Dec;26(12):1339-48

No abstract.

[Study of vitamin B6 metabolism during various stages of experimental diabetes]

Shuvalova TI, Smurnov MI
Probl Endokrinol (Mosk) 1970 Jan-Feb;16(1):79-81

No abstract.

[Studies on vitamin B6 deficiency during pregnacy and in various pathological states using pyridoxine saturation test]

Karlin R, Croizat P, Revol L, Pommatau E, Viala JJ, Dumont M
Pathol Biol 1968 Nov;16(21):917-24

No abstract.

[Studies on carbohydrate metabolism in vitamin B6-deficient albino rat]

Watanabe K
Nippon Naibunpi Gakkai Zasshi 1968 May 20;44(2):154-67

No abstract.

[Contribution to the study of latent B6 avitaminoses in pregnant women]

Karlin R, Dumont M
Gynecol Obstet (Paris) 1967 Jun-Aug;66(3):339-46

No abstract.

[Effect of vitamin B6 on the lecithin-cholesterin ratio and protein fraction of the blood serum of patients with diabetes mellitus]

Shifrin MA
Ter Arkh 1966 Jan;38(1):96-9

No abstract.

[Clinical studies on the relation between endocrine function and vitamin B6 metabolism. II. Vitamin B6 metabolism in patients with pituitary, adrenal diseases and diabetes mellitus]

Azechi S
Naika Hokan 1966 Apr;13(4):205-16

No abstract.

Dehydroepiandrosterone, dehydroepiandrosterone sulfate, obesity, waist-hip ratio, and noninsulin-dependent diabetes in postmenopausal women: the Rancho Bernardo Study.

Barrett-Connor E, Ferrara A
Department of Family and Preventive Medicine, University of California, San Diego, La Jolla 92093, USA.
J Clin Endocrinol Metab 1996 Jan;81(1):59-64

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) levels were determined in morning specimens from 659 fasting postmenopausal women who were not using estrogen therapy or antidiabetic medication. All women had concurrent oral glucose tolerance tests and measurements of body mass index (BMI) and waist-hip ratio (WHR). DHEA levels were weakly and inversely associated with BMI but not with WHR or glucose tolerance status. DHEAS levels were not associated with BMI but were positively associated with WHR, diabetes, and impaired glucose tolerance. In analyses adjusted for or stratified by WHR, the DHEAS association with abnormal carbohydrate tolerance was reduced but still independent of fat distribution. Because this was a cross-sectional study, it was not possible to determine whether DHEAS levels were raised by central obesity or vice versa. At a minimum, these data strongly suggest that the positive association of DHEAS with both central obesity and abnormal glucose tolerance does not support the thesis that DHEAS protect against diabetes or obesity in older women as had been suggested by animal studies.

Differences in substrate metabolism between selperceived 'large-eating' and 'small-eating' women.

Clark DG, Tomas FM, Withers RT, Brinkman M, Berry MN, Oliver JR, Owens PC, Butler RN, Ballard FJ, Nestel PJ
CSIRO, Division of Human Nutrition, Adelaide, Australia.
Int J Obes Relat Metab Disord 1995 Apr;19(4):245-52

OBJECTIVE: To compare different aspects of intermediary metabolism in self perceived 'small-eating' females and selperceived near normal weight 'large-eating' females and relate the data to those reported for Pima Indians who have the world's highest prevalence of non-insulin dependent diabetes mellitus and obesity.

DESIGN: Make repeat measurements of rates of oxygen consumption, carbon dioxide production and blood metabolites in 'large-' and 'small-eating' females at rest, during different activities and after ingestion of a standardised liquid meal.

SUBJECTS: Nine self perceived, 'large-eating' females and nine self perceived 'small-eating' females.

MEASUREMENTS: Resting metabolic rates (RMR), respiratory quotient (RQ) values and plasma insulin, glucagon insulin-like growth factor (IGF-1), dehydroepiandrosterone sulphate (DHEA-SO4) and glucose.

RESULTS: RMR (adjusted for FFM) averaged 3891 +/- 93 J/min in the 'small-eaters' and 3375 +/- 107 J/min in the 'large-eaters' for ten consecutive measurements conducted at 30 min intervals during the control period for the measurement of the thermic effect of food. Over this period the average RQ for the 'small-eating' women (0.81) was significantly greater than that of the 'large-eating' women (0.78). The two groups responded similarly to an oral glucose tolerance test but the concentration of DHEA-SO4 in plasma was 35% higher in the 'small-eaters'.

CONCLUSION: The 'small-eating' women may have a greater risk of weight gain but they counteract this tendency by maintaining high activity levels.

[43 cases of primary empty sella syndrome: a case series]

Bragagni G, Bianconcini G, Mazzali F, Baldini A, Brogna R, Iori I, Sarti G
Divisione di Medicina Generale, USL 30 di Cento.
Ann Ital Med Int 1995 Apr-Jun;10(2):138-42

Primary empty sella syndrome (ESS) is an anatomo-radiological picture characterized by the presence of an arachnoid herniation filled with liquor that compresses the pituitary against the sellar wall. ESS occurs particularly in obese, hypertensive, cephalalgic women. It is often asymptomatic but may be associated with ophthalmologic, neurologic and non-characterizing endocrine disorders. We report here 43 cases of primary ESS observed and assessed in our Departments of Internal Medicine from June 1983 to May 1993. The following endocrinological diagnostic procedures were carried out: hormonal (RIA) basal profile: FT3, FT4, TSH, PRL, ACTH, FSH, LH, 8.00 a.m. and p.m., blood cortisol, aldo, PRA, DHEA-S, FTe, E2, P, PTH, CT, and calcemia and phosphoremia; provocative tests: TRH, GnRH, etc.; inhibition tests: high dose dexamethasone. Clinical, neurologic (skull radiographs, sellar stratigraphy, computed tomography scan and magnetic resonance), and ophthalmologic (fundus, visual fields) assessments were also made. Our findings fit with the data in the literature concerning common symptoms of ESS, associated endocrinopathies and other illness. We found obesity (62.7%), oligo-amenorrhea (16.6%), galactorrhea (14.6%), hyperPRL (11.6%), hypopituitarism (9.3%), hypogonadism (4.6%), diabetes insipidus (2.3%), (micro-)polycystic ovary syndrome (19%), hyperACTH (2.3%). In 9.3% of the cases, endocrinopathy referred to pituitary adenomas. Moreover, we noted a high frequency of psychological disorders, to our knowledge not previously reported in the literature, including anxiety or dysthymic disorders with altered behavior (chiefly oral compulsion). We also make the hypothesis that obesity (occurring in 62.7% of our patients) and hypertension (62.7%) may be related to hypothalamic alterations.

Differential expression of hepatic oestrogen, phenol and dehydroepiandrosterone sulphotransferases in genetically obese diabetic (ob/ob) male and female mice.

Borthwick EB, Burchell A, Coughtrie MW
Department of Biochemical Medicine, University of Dundee, Ninewells Hospital and Medical School, UK.
J Endocrinol 1995 Jan;144(1):31-7

Sulphotransferases (STs) are a family of closely related enzymes playing a key role in regulation of the bioavailability and activity of important endogenous molecules such as steroid hormones. A relationship between the expression of steroid STs and the diabetic state has been demonstrated in various laboratory animal models, and steroid sulphates such as dehydroepiandrosterone sulphate are known to have anti-diabetic properties. In order to further our understanding of the molecular basis for the association of steroid hormone sulphation and diabetes, we have examined the expression of oestrogen, phenol and dehydroepiandrosterone (DHEA) STs in mice carrying the obesity mutation (ob), which in the homozygous state (ob/ob) produces mice which are obese and diabetic. Our data show that, in male mice, ST activities towards oestrone (E1), oestriol (E3), DHEA and the xenobiotic 1-naphthol are elevated in ob/ob mice, whereas in female mice, only the oestrogen ST activities were elevated, with the DHEA and 1-naphthol ST activities reduced. Using antibodies directed against oestrogen ST, it was demonstrated that the induction of E1 and E3 ST activity in ob/ob mice correlated with the expression of an ST isoenzyme not constitutively expressed in control mouse liver.

[Isolated gonadotropin deficiency and secretory discrepancy of cortisol and adrenal androgen by hemochromatosis secondary to congenital dyserythropoietic anemia]

Okano J, Yanase T, Takayanagi R, Mimura K, Nawata H
Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka
Nippon Naibunpi Gakkai Zasshi 1994 Jan 20;70(1):57-64

A 37-yr-old woman was admitted to our hospital for evaluation of diabetes mellitus, liver cirrhosis and primary amenorrhea. Serological and hematological examinations revealed that she suffered from hemochromatosis secondary to congenital dyserythropoietic anemia (CDA), characterized by ineffective hematopoiesis and erythropoietic dysplasia. Iron deposition was suggested by MRI on the pancreas, liver and pituitary gland. Endocrinological examinations demonstrated that she had isolated gonadotropin deficiency and ovarian failure, resulting in hypogonadotropic hypogonadism. In addition, despite normal responses of serum cortisol and plasma aldosterone to ACTH and furosemide-standing tests, respectively, serum dehydroepiandrosterone (DHEA) responded poorly to ACTH test, suggesting selective damage of zona reticularis in adrenocortical steroidogenesis in association with hemochromatosis.

Decreased testosterone and dehydroepiandrosterone sulfate concentrations are associated with increased insulin and glucose concentrations in nondiabetic men.

Haffner SM, Valdez RA, Mykkanen L, Stern MP, Katz MS
Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78284
Metabolism 1994 May;43(5):599-603

Although many studies indicate that increased androgenicity is associated with insulin resistance and hyperinsulinemia in both premenopausal and postmenopausal women, relatively few data are available on this relationship in men. We examined the association of sex hormone-binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-SO4), and estradiol to glucose and insulin concentrations before and during an oral glucose tolerance test in 178 men from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Total and free testosterone and DHEA-SO4 were significantly inversely associated with insulin concentrations. Free testosterone and DHEA-SO4 were also significantly inversely correlated with glucose concentrations. SHBG was weakly positively associated with glucose concentrations. Estradiol was not related to glucose or insulin concentrations. After adjustment for age, obesity, and body fat distribution, insulin concentrations remained significantly inversely correlated with free testosterone (r = -.23), total testosterone (r = -.21), and DHEA-SO4 (r = -.21; all P < .01). In conclusion, we observed that increased testosterone and DHEA-SO4 are associated with lower insulin concentrations in men. This is in striking contrast to women, where increased androgenicity is associated with insulin resistance and hyperinsulinemia.

Enhanced adrenocortical activity as a contributing factor to diabetes in hyperandrogenic women.

Buffington CK, Givens JR, Kitabchi AE
Department of Medicine, University of Tennessee, Memphis.
Metabolism 1994 May;43(5):584-90

The high incidence of non-insulin-dependent diabetes mellitus (NIDDM) in women with polycystic ovarian syndrome (PCO) is believed to occur secondary to the insulin resistance associated with their androgenicity. In the present study, we have examined the interrelationships between glucose tolerance, androgenicity, and various in vivo and in vitro parameters of insulin sensitivity in 11 obese PCO patients with NIDDM, 14 PCO patients without diabetes, and 14 weight-matched controls. Both groups of PCO patients were hypertestosteronemic, hyperinsulinemic, and insulin-resistant when compared with a group of weight-matched controls. However, PCO patients with NIDDM differed from those without diabetes in that they had elevated basal and corticotropin-stimulated adrenal steroids (cortisol, dehydroepiandrosterone [DHEA], dehydroepiandrosterone sulfate [DHEAS]). The hyperglycemia of our diabetic patients was not related to their elevated testosterone levels or to their degree of insulin resistance, but was significantly and positively correlated with adrenal hypersecretion, which in turn was associated with postreceptor defects in insulin action. These findings would suggest that enhanced adrenocortical activity may be an important factor underlying the development of NIDDM in women with PCO.

Obesity, body fat distribution and sex hormones in men.

Haffner SM, Valdez RA, Stern MP, Katz MS
Department of Medicine, University of Texas Health Science Center at San Antonio 78284-7873.
Int J Obes Relat Metab Disord 1993 Nov;17(11):643-9

An unfavourable body fat distribution may cause metabolic abnormalities including diabetes and dyslipidemia. These effects may be mediated by alterations in sex hormones. In women the available data suggest that upper body adiposity is related to increased androgenicity (especially as indicated by low concentrations of sex hormone binding globulin). Few data, however, are available on these relationships in men. We therefore examined the association of total testosterone, free testosterone, oestradiol, dehydroepiandrosterone sulphate (DHEA-SO4) and sex hormone binding globulin (SHBG) to waist-to-hip ratio (WHR) and conicity index in 178 men from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. The conicity index is equal to the abdominal circumference divided by 0.109 x the square root of (weight/height). The conicity index and WHR were significantly inversely related to DHEA-SO4 and free testosterone. SHBG was only weakly associated with body mass index (r = -0.18, P < 0.05). After adjustment for age and body mass index, DHEA-SO4 remained inversely correlated with WHR (r = -0.22, P < 0.01) and conicity index (r = -0.31, P < 0.001) and free testosterone remained inversely associated with conicity index (r = -0.21, P < 0.01). Thus, in men, the association between unfavourable body fat distribution and increased androgenicity is inverse in contrast to the situation in women.

Relationship of sex hormones to lipids and lipoproteins in nondiabetic men.

Haffner SM, Mykkanen L, Valdez RA, Katz MS
Department of Medicine, University of Texas Health Science Center, San Antonio.
J Clin Endocrinol Metab 1993 Dec;77(6):1610-5

Although many studies show that increased androgenicity is associated with increased triglyceride (TG) and decreased high density lipoprotein cholesterol in both pre- and postmenopausal women, relatively few data are available on the association of sex hormones to lipids and lipoproteins in men. We examined the association of sex hormone-binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-SO4), and estradiol with lipids and lipoproteins in 178 nondiabetic men from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. The TG concentration was significantly inversely related to SHBG (r = -0.22), free testosterone (r = -0.15), total testosterone (r = -0.22), and DHEA-SO4 (r = -0.16). High density lipoprotein (HDL) cholesterol was significantly positively correlated to SHBG (r = 0.21), free testosterone (r = 0.15), total testosterone (r = 0.17), and DHEA-SO4 (r = 0.16). Total testosterone was significantly related to total cholesterol (r = -0.17) and low density lipoprotein cholesterol (r = -0.15). After adjustment for age, body mass index, waist to hip ratio, and glucose and insulin concentrations, TG concentrations remained significantly related to SHBG (r = -0.20), free testosterone (r = -0.15), and DHEA-SO4 (r = -0.18), and HDL cholesterol remained significantly associated with SHBG (r = 0.17), free testosterone (r = 0.15), total testosterone (r = 0.14), and DHEA-SO4 (r = 0.16). In conclusion, we observed a less atherogenic lipid and lipoprotein profile with increased testosterone concentrations. This was not explained by differences in glucose or insulin concentrations. However, sex hormones explained only a small percentage of the variation in total TG and HDL cholesterol concentrations. These findings are in striking contrast to data from women, in whom increased androgenicity is strongly associated with increased TG and decreased HDL cholesterol levels.

Adrenal steroid and adrenocorticotropin responses to human corticotropin-releasing hormone stimulation test in adolescents with type I diabetes mellitus.

Ghizzoni L, Vanelli M, Virdis R, Alberini A, Volta C, Bernasconi S
Department of Pediatrics, University of Parma, Italy.
Metabolism 1993 Sep;42(9):1141-5

To determine whether abnormalities of hypothalamic-pituitary-adrenal axis function occur in type I diabetes mellitus, corticotropin, cortisol, 17-hydroxyprogesterone (17-OHP), androstenedione (D4-A), dehydroepiandroste rone (DHEA), and DHEA sulfate (DS) levels were measured after an intravenous (IV) injection of 1 microgram/kg human corticotropin-releasing hormone (CRH) in diabetic adolescents and normal age-matched subjects. CRH produced a consistent increase in corticotropin blood levels that was comparable in the two groups. In contrast, both baseline and stimulated cortisol concentrations were greater in diabetic patients. Levels of 17-OHP increased after CRH administration, and the magnitude of increase was similar in all subjects. Stimulation with CRH determined an attenuated integrated DS response in diabetics compared with normal subjects with a different pattern of the hormone secretion, whereas no differences in D4-A concentrations were detected between the two groups. DHEA serum levels of subjects from both groups underwent similar changes following administration of CRH. In conclusion, patients with type I diabetes have a discrete response of adrenal steroids to CRH stimulation that appears to be independent of corticotropin secretion. This phenomenon might be related to a direct effect of insulin on enzyme systems involved in the biosynthetic pathway of adrenal steroids or, alternatively, to an intra-adrenal CRH/corticotropin mechanism acting on the adrenal cortex in a paracrine manner.

Excess androgenicity only partially explains the relationship between obesity and bone density in premenopausal women.

Haffner SM, Bauer RL
Department of Medicine, University of Texas Health Science Center, San Antonio.
Int J Obes Relat Metab Disord 1992 Nov;16(11):869-74

Obese subjects have increased bone density relative to non-obese subjects yet this relationship is not fully understood. We examined whether alterations in sex hormones or binding proteins might explain the effect of obesity on osteoporosis in 83 premenopausal women from the San Antonio Heart Study, a population-based study of diabetes. We measured total testosterone, oestradiol, oestrone, sex hormone binding globulin (SHBG), and serum dehydroepiandrosterone sulphate (DHEA-SO4). Bone density was assessed by a Hologic dual photon absorptometer. Lumbar spine and femoral neck density were positively correlated with body mass index (BMI). In addition, femoral neck density was positively correlated with DHEA-SO4. BMI was negatively correlated with SHBG. After adjustment for sex hormones by multiple linear regression a positive association between bone density and obesity still exists suggesting that the association between obesity and bone density is at least partially independent of sex steroids in premenopausal women.

Lower endogenous androgen levels and dyslipidemia in men with non-insulin-dependent diabetes mellitus

Barrett-Connor E
Department of Community and Family Medicine, University of California, San Diego, La Jolla 92093-0607.
Ann Intern Med 1992 Nov 15;117(10):807-11

OBJECTIVE: To compare plasma androgen levels in diabetic and nondiabetic men and to determine their relation to diabetic dyslipidemia.

DESIGN: A population-based, case-control study.

SETTING: Community.

PARTICIPANTS: Men 53 to 88 years of age from the Rancho Bernardo, California, cohort who were screened for diabetes using an oral glucose tolerance test.

MEASUREMENTS: Plasma androgen levels were compared in 44 men with untreated non-insulin-dependent diabetes mellitus and 88 age-matched men who had a normal glucose tolerance test. The relation of lipid and lipoprotein levels to androgen level and diabetic status was assessed before and after adjusting for covariates.

RESULTS: Men with diabetes had significantly lower plasma levels of free (4.96 nmol/L compared with 5.58 nmol/L) and total testosterone (14.7 nmol/L compared with 17.4 nmol/L), dihydrotestosterone (428 pg/mL compared with 533 pg/mL), and dehydroepiandrosterone sulfate (DHEA-S) (1.92 mumol/L compared with 2.42 mumol/L) than nondiabetic men. They also had significantly lower high-density lipoprotein (HDL) cholesterol and significantly higher triglyceride levels. Differences were not explained by obesity, alcohol use, or cigarette habit. Overall, the total testosterone level, but not the free testosterone level, was positively correlated with the HDL cholesterol level (P = 0.009) and negatively correlated with the triglyceride level (P = 0.0001). Similar associations were seen in analyses restricted to the men without diabetes.

CONCLUSIONS: Lower levels of endogenous androgens are seen in older diabetic men, and low androgen levels are associated with diabetic dyslipidemia.

Increased testosterone in type I diabetic subjects with severe retinopathy.

Haffner SM, Klein R, Dunn JF, Moss SE, Klein BE
Department of Medicine, University of Texas Health Science Center, San Antonio.
Ophthalmology 1990 Oct;97(10):1270-4

Diabetic retinopathy rarely occurs before puberty, suggesting that changes in sex hormones may influence the development of this condition. The authors measured serum testosterone, estradiol, DHEA-S, and sex hormone binding globulin levels in 26 men and 22 women with type I diabetes from the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), a population-based study of diabetic complications. The mean age was 23 years and the mean duration of diabetes was 14 years. Subjects with proliferative or preproliferative retinopathy (greater than or equal to retinopathy level 51-80) were matched by duration of diabetes (+/- 2 years) and sex to subjects with minimal or no retinopathy (less than or equal to retinopathy level 21). Seven stereoscopic retinal photographs of each eye were obtained and photographs were read by the University of Wisconsin Reading Center. Serum testosterone concentrations were significantly higher in male diabetic subjects with proliferative retinopathy (648 +/- 36 ng/dl) than in male diabetic subjects with minimal or no retinopathy (512 +/- 43 ng/dl) (P = 0.017). No other statistically significant differences in sex hormones between subjects with and without proliferative retinopathy were observed. Although these results should be regarded as preliminary because of the small number of subjects, they support the hypothesis that testosterone concentrations may be associated with the development of retinopathy in type I diabetic patients.

Increase in plasma 5 alpha-androstane-3 alpha,17 beta-diol glucuronide as a marker of peripheral androgen action in hirsutism: a side-effect induced by cyclosporine A.

Vexiau P, Fiet J, Boudou P, Villette JM, Feutren G, Hardy N, Julien R, Dreux C, Bach JF, Cathelineau G
Diabetology and Endocrinology Department, Hopital Saint-Louis, Paris, France.
J Steroid Biochem 1990 Jan;35(1):133-7

Dose-dependent hypertrichosis is a common dermatological side-effect affecting the majority of patients treated with cyclosporine A (CSA). Previous studies have not demonstrated the influence of CSA on specific sex hormone levels. The aim of this study is to investigate whether CSA increases the activity of 5 alpha-reductase, an enzyme which transforms androgens into dihydrotestosterone in peripheral tissues. The metabolite which best reflects this activity is 5 alpha-androstane-3 alpha,17 beta-diol glucuronide (Adiol G). The study was carried out on 49 insulin-dependent diabetes patients participating in the double-blind "Cyclosporine-Diabete-France" clinical trial, of which 28 were treated with CSA (16 males and 12 females), and 21 received only placebo (10 males and 11 females). All patients underwent extensive clinical and laboratory evaluations prior to and during the present study. In addition to Adiol G, testosterone (T), dehydroepiandrosterone sulfate (DHEA S) and sex hormone-binding globulin (SHBG) were assayed. Levels of Adiol G increased significantly in CSA-treated groups: males, 11.86 +/- 2.58 vs 7.83 +/- 2.30 nmol/l; females, 4.48 +/- 2.70 vs 2.10 +/- 1.22 nmol/l; P less than 0.02 (comparison of means). There were no significant differences in this parameter before and during treatment in either the male or female placebo groups (paired t-test). During the treatment period, T, DHEA S, SHBG and the T/SHBG ratio did not significantly change with respect to their baseline values in any of the groups studied (comparison of means). Comparison (using paired t-test) showed a significant increase of DHEA S in CSA-treated groups: males, delta = 3.08 +/- 3.33 nmol/l, P less than 0.01; females, delta = 0.98 +/- 1.13 nmol/l, P less than 0.05. In conclusion, it is possible that CSA induces hypertrichosis or hirsutism by increasing 5 alpha-reductase activity in peripheral tissues. Nevertheless the role of increased DHEA S as a possible Adiol G precursor cannot be excluded.

[Dehydroepiandrosterone. Renaissance after 13 years]

Sonka J
Cas Lek Cesk 1989 Sep 8;128(37):1157-60

DHEA, a steroid precursor of androgens and estrogens has also an inhibitory effect on several enzymes, namely on 11 beta-hydroxylase, NADH oxidase and glucose 6-phosphate dehydrogenase. The latter is the rate limiting enzyme of the pentose phosphate cycle. This metabolic pathway provides the cells with extramitochondrial NADPH and pentose phosphates. NADPH is used for the synthesis of fatty acids and steroids. Together with ribose 5-phosphate, NADPH (as coenzyme of folate reductases) is required for the synthesis of nucleic acids. A deficient production of DHEA has been found to be responsible for several diseases obesity, diabetes type 2, hypertension, arteriosclerosis and hyperuricemia as well as malignant growth (low DHEA syndrome). DHEA administration favourably modified several of these metabolic disorders. These studies were started in our laboratory in 1962 and stopped in 1976 because we were short of DHEA. At that time the response to our results was rather theoretical, but the last years a new wave of interest in DHEA called for two consecutive symposia, where important findings were presented (Paris in January and Jena in April 1989). It is a damage that this new trend, started in our laboratory, could not be pursued up to now without interruption.

[Effect of androgen on the onset of diabetes in the KK mice treated with monosodium aspartate]

Higuchi N, Sasaki M, Arai T, Oki Y
Department of Veterinary Biochemistry, Nippon Veterinary and Zootechnical College, Tokyo, Japan.
Jikken Dobutsu 1989 Jan;38(1):25-9

Obese diabetes was induced by monosodium aspartate (MSA) administration in KK male mice and the diabetic KK mice were divided into two groups, younger (12-week-old) and older (35-week-old). The diabetic KK mice were castrated and administered with androgen and effect of androgen on glycosuria appearance was investigated. Androgen dependent tear proteins (Mtp-M) were detected by the method of polyacrylamide gel electrophoresis. Blood androgen level was estimated by observation of change of the pattern of Mtp-M. In the younger mice group, glycosuria disappeared temporarily after castration and then appeared naturally again. The Mtp-M declined with castration, but did not disappear in this experimental period. In the older mice group, glycosuria and Mtp-M disappeared completely and blood glucose level decreased considerably after castration. However, in the castrated older mice, the glycosuria and the Mtp-M appeared again after the administration of dehydroepiandrosterone (DHEA), and the increasing of blood glucose level was observed. These results strongly suggested that androgen had an important role in the onset of diabetes in the KK mice treated with MSA.

The influence of genetic background on the expression of mutations at the diabetes locus in the mouse. V. Interaction between the db gene and hepatic sex steroid sulfotransferases correlates with gender-dependent susceptibility to hyperglycemia.

Leiter EH, Chapman HD, Coleman DL
Jackson Laboratory, Bar Harbor, Maine 04609.
Endocrinology 1989 Feb;124(2):912-22

Steroid sulfurylation represents a potential mechanism for controlling the level of active steroids within a tissue. We have elucidated an inbred strain background-dependent interaction between the diabetes (db) mutation and steroid sulfotransferase (ST) enzymes, potentially modulating the level of active steroid hormones or their precursors in the liver. Gonadectomized mutants were analyzed to correlate how strain- and gender-dependent variation in ST activities interacted with db to achieve diabetogenesis. Both sexes on the C57BL/KsChp (BKs) background developed severe early-onset hyperglycemia, and gonadectomy failed to prevent diabetes. In contrast, C3HeB/FeChp (C3HeB)-db/db males, but not females, were diabetes susceptible, and the male susceptibility was completely dependent upon endogenous testes-derived testosterone. The female resistance, in turn, was dependent upon ovarian sex steroids. The differential requirements of BKs- and C3HeB-db/db males and females for gonadal sex steroids could be explained on the basis of the differential strength of the interaction between the db mutation and hepatic ST activities. Hepatic ST from normal adult females sulfurylated dehydroepiandrosterone (DHEA), whereas this activity disappeared in cytosols of normal adult males by 8 weeks of age. This sexually dimorphic inability to sulfurylate (pre)androgens was controlled by testosterone. Diabetogenic susceptibility in BKs mutant mice of both sexes was associated with marked depression of preandrogen/androgen sulfurylation [female mutants exhibiting at least a 5-fold reduced DHEA sulfurylation at a near-physiological concentration (0.2 microM)]. This reduced preandrogen/androgen sulfurylation occurred concomitant with a 10-fold acceleration of estrone (E1) sulfurylation at a limiting (0.2 microM) concentration, essentially producing a hyperandrogenized hepatic tissue state. These extreme shifts in ST substrate preferences were not observed in the diabetes-resistant C3HeB-db/db females. Kinetic analysis of semipurified hepatic ST from BKs-db/db females showed a 10-fold decrease in Km for E1 (apparent Km = 0.9 microM in mutants vs. 9.0 microM in normals). Whereas the Km for DHEA did not differ from the control value, hepatic ST from BKs-db/db females showed a 10-fold decreased maximal velocity for DHEA sulfurylation (1230 vs. 12750 pmol/mg.h in control preparations). The antihyperglycemic effects of dietary E1 therapy were associated with enhanced androgen sulfurylation in BKs-db/db females and restoration of androgen sulfurylation in BKs-db/db males.

Therapeutic effects of dehydroepiandrosterone (DHEA) and its metabolites in obese-hyperglycemic mutant mice.

Coleman DL
Jackson Laboratory, Bar Harbor, ME 04609.
Prog Clin Biol Res 1988;265:161-75

Dehydroepiandrosterone (DHEA) fed at 0.4%, and its metabolites, 3 alpha-hydroxyetiocholanolone (alpha-ET) and 3 beta-hydroxyetiocholanolone (beta-ET), fed at 0.1%, had marked anti-hyperglycemic and anti-obesity properties in mutant mice with single gene obesity mutations (diabetes, db; obese, ob; viable yellow, Avy). The therapeutic effects differed depending on the mutation as well as the inbred background on which the mutation was maintained. These steroids prevented onset of hyperglycemia and reduced the rate of weight gain in C57BL/6J-db/db and ob/ob mice, whereas in C57BL/KsJ-db/db mice, only hyperglycemia was prevented. The viable yellow (Avy) mutant, exhibiting a more slowly developing obesity condition, responded to all steroids with a marked decrease in rate of weight gain associated with decreased plasma insulin concentrations. Steroid treatment of most mouse mutants was associated with normal or increased food intake, a feature that suggests a decrease in metabolic efficiency. In order to assess any potential energy wastage by steroid stimulation of futile cycles we looked at the rates of lipogenesis, gluconeogenesis and oxygen consumption in steroid-treated normal and mutant mice. With the possible exception of the rate of gluconeogenesis that in obesity mutants was consistently reduced to normal by treatment, no metabolic changes were of sufficient magnitude to account for the marked decrease in metabolic efficiency. All treatments potentiated the action of insulin. This potentiation may change the hormonal balance such that minor changes in the rates of many metabolic pathways may interact to produce a large decrease in metabolic efficiency.

Hormonal intervention: "buffer hormones" or "state dependency". The role of dehydroepiandrosterone (DHEA), thyroid hormone, estrogen and hypophysectomy in aging.

Regelson W, Loria R, Kalimi M
Department of Medicine, Medical College of Virginia, Richmond 23298.
Ann N Y Acad Sci 1988;521:260-73

No abstract.

Modulation of growth, differentiation and carcinogenesis by dehydroepiandrosterone.

Gordon GB, Shantz LM, Talalay P
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Adv Enzyme Regul 1987;26:355-82

Dehydroepiandrosterone (3 beta-hydroxy-5-androsten-17-one; DHEA) and its conjugates are abundant circulating steroids that originate largely from the adrenal cortex. Their levels decline profoundly with age in human beings of both sexes, as the incidence of most cancers rises. Low levels of these steroids have been associated with the presence and risk ofdevelopment of cancer. Administration of DHEA to rodents produces protection against spontaneous tumors and chemical carcinogenesis, suppresses weight gain without significantly affecting food intake, ameliorates the severity of diabetes in genetically diabetic mice, and restrains autoimmune processes. DHEA and related steroids also depress the mitogenic effects of carcinogens, tumor promoters and plant lectins, and block viral and carcinogen-induced cell transformations. DHEA and certain congeners are also potent and quite specific inhibitors of mammalianglucose-6-phosphate dehydrogenases. We have observed that the conversion of 3T3-L1 and 3T3-F442A preadipocyte clones to the adipocyte phenotype, in response to appropriate differentiation stimuli (fetal calf serum, insulin, dexamethasone, and 1-methyl-3-isobutylxanthine), is blocked by DHEA and other steroidal inhibitors of glucose-6-phosphate dehydrogenase. The structural requirements for blocking adipocyte differentiation and for inhibiting glucose-6-phosphate dehydrogenase are closely correlated. Evidence is reviewed suggesting that the inhibition of glucose-6-phosphatedehydrogenase is central to the anticarcinogenic and differentiation-blocking actions of DHEA and related steroids. The 3T3 preadipocyte clones provide a valuable system for the analysis of the mechanisms of the effects of DHEA on growth, differentiation and carcinogenesis. (94 Refs.)

Androgenic and estrogenic metabolites in serum of mice fed dehydroepiandrosterone: relationship to antihyperglycemic effects.

Leiter EH, Beamer WG, Coleman DL, Longcope C
Metabolism 1987 Sep;36(9):863-9

The steroid prehormone, dehydroepiandrosterone (DHEA) has potentanti hyperglycemic effects when fed in the diet of genetically diabetic C57BL/KsJ-db/db mice. The purpose of this investigation was to analyze changes in sex steroid levels in serum of mice fed DHEA, and to compare the antihyperglycemic potencies of the various metabolites in order to clarify the mechanism of DHEA action. Steroid radioimmunoassays showed that dietary DHEA entered the blood in high concentrations and was actively metabolized to both androgens (testosterone, T; dihydrotestosterone, DHT) and estrogens (estrone, E1; 17 beta-estradiol, E2). This metabolism did not require intact adrenal glands or gonads. In C57BL/KsJ normal (+/+) males, conversion of DHEA to androgens was the prominent feature; in db/db males, DHEA feeding not only increased serum T and DHT, but also serum E1 and E2 levels. The db/db mice had increased amounts of adipose tissue that sequestered more intravenously injected 3H-E2; this additional body fat could account for increased aromatization of DHEA-derived estrogen precursors. Comparisons of the relative antihyperglycemic potencies of androgenic and estrogenic steroid metabolites of DHEA in db/db mice showed that the estrogens and metabolites with estrogenic properties (androstenediol) or those convertible to estrogens (DHEA sulfate) were the most potent. Although 17 beta-E2 was effective by injection or per os, DHEA was effective only when administered per os, implicating alimentary tract conversion of DHEA to more biologically active reactants. Based on the pivotal position of DHEA as a prehormone for androgens, estrogens, andetiocholanolones, an explanation of the seemingly paradoxical effects exerted by this compound in blocking autoimmune disease, hyperglycemia, obesity, and neoplasia was proposed.

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Peculiarities of the endocrine time structure in noninsulin-dependent adult-onset (type II) diabetes mellitus.

Sackett-Lundeen L, Nicolau GY, Lakatua DJ, Bogdan C, Petrescu E, Jachimowicz A, Haus E
Prog Clin Biol Res 1987;227A:467-82

Twenty noninsulin-dependent elderly diabetic patients, ten of whom were treated by oral hypoglycemic agents and ten of whom were regulated by diet alone, and 20 clinically healthy subjects matched for age, sex, height, and weight were examined with six blood and six urine samples at 4-hr intervals over a 24-hr span. Plasma ACTH, cortisol, aldosterone, and dehydroepiandrosterone-sulfate (DHEA-S) were determined by radioimmunoassay (RIA); epinephrine, norepinephrine, and dopamine in urine were determined by high-pressure liquid chromatography (HPLC); and magnesium in urine was determined colorimetrically on a DuPont ACA. There were a number of changes in some of these functions in type II diabetic patients with and without oral hypoglycemic agents that appear to be of interest. The circadian mean in plasma ACTH concentration in diabetic patients with and without oral hypoglycemic agents is significantly higher than in matched nondiabetic controls. The plasma aldosterone concentration is similar in type II diabetics treated by diet only and in matched controls but is statistically significantly elevated in patients on oral hypoglycemic agents. Correspondingly, the urinary excretion of sodium in type II diabetic patients on oral hypoglycemic agents is lower than in matched controls. The plasma cortisol concentration is unchanged in type II diabetic patients treated by diet alone but shows a slight increase in patients on oral hypoglycemic agents. The circadian means of plasma DHEA-S concentration is slightly higher in diabetic patients with and without oral hypoglycemic agents than in matched controls. This elevation, however, does not quite reach the 95% level of statistical significance. Urinary norepinephrine excretion in type II diabetic patients is similar to that in matched controls. The urinary epinephrine excretion in diabetics with and without oral hypoglycemic agents, however, was lower than in controls, and the urinary excretion of dopamine was higher in the diabetics. The urinary magnesium excretion in type II diabetic patients was lower than in matched controls.

Antiobesity effects of etiocholanolones in diabetes (db), viable yellow (Avy), and normal mice.

Coleman DL
Endocrinology 1985 Dec;117(6):2279-83

Two metabolites of the adrenal steroid dehydroepiandrosterone (DHEA), 3alpha-hydroxyetiocholanolone and 3 beta-hydroxyetiocholanolone, were found to have antiobesity properties with respect to both prevention of the development of obesity as well as weight reduction after obesity was established. All of the obesity types studied responded to metabolite therapy to a greater or lesser extent. The more natural obesity seen in certain strains of mice with aging responded most rapidly to the feeding of either metabolite. The effective dosage (0.1%) fed in the diet was only one quarter the dosage required for DHEA to produce the same effect in preventing diabetes symptoms in C57BL/Ks diabetic (db) mutant mice. Unlike DHEA, neither metabolite produced any undesirable estrogenic or androgenic side-effects. 3 alpha-hydroxyethiocholanolone and 3 beta-hydroxyetiocholanolone, formerly considered only as inert end products of steroid metabolism, have beneficial actions in mice with various diabetes-obesity conditions and may be metabolic effectors in their own right.

Circadian time structure of endocrine and biochemical parameters in adult onset (type II) diabetic patients.

Nicolau GY, Haus E, Lakatua D, Bogdan C, Petrescu E, Robu E, Sackett-Lundeen L, Swoyer J, Adderley J
Endocrinologie 1984 Oct-Dec;22(4):227-43

Forty-one endocrine and biochemical serum parameters were studied over a 24-hour span with 6 samples at 4-hour intervals in 20 non-insulin dependent (Type II) diabetics and in 20 non-diabetic subjects matched for sex, age, height and weight. Circadian rhythms were verified by cosinor analysis. Group-synchronized circadian rhythms were detected in diabetic and non-diabetic subjects with no statistically significant difference in any of the rhythm parameters (rhythm adjusted mean, amplitude and acrophase) in: Aldosterone, cortisol, insulin, 17-OH progesterone, prolactin, testosterone, TSH, and in serum albumin, creatine phosphokinase (CPK), serum iron, inorganic phosphate and total protein. Statistically significant (p less than .05) circadian rhythms in both groups with a difference in some parameters between the diabetic and the non-diabetic subjects, which were verified by the Bingham Test (p less than .05) were found with a difference in the mesor in cholesterol, glucose, urea nitrogen (BUN), in the amplitude in C-peptide and in the acrophase in triglycerides, globulin and reverse T3 (rT3). Statistically significant circadian rhythms were detected as a group phenomenon for the diabetics only in progesterone, free and total T4, chloride, calcium, bilirubin and LDH and in the non-diabetic subjects only in ACTH, LH, total T3, alkaline phosphatase, uric acid and potassium. In the remainder of the functions studied, acircadian rhythm was detectable with statistical significance by cosinor analysis as a group phenomenon neither in the diabetics nor in the matched non-diabetic controls (DHEA-S, estradiol, FSH, GH, glucagon, free T3, sodium, GOT and gamma GT). In the absence of a detectable circadian rhythmas group phenomenon, the circadian mean was different between the diabetics and the non-diabetic subjects in sodium, chloride and calcium which were higher in the diabetic patients and serum LDH which was lower. In a comparison of endocrine determinations in the two groups, the circadian mean or mesor in T3 was lower in the diabetics and ACTH higher, without corresponding changes in TSH or in corticosteroids. The circadian time structure of Type II diabetic patients thus seems to be very similar to that seen in non-diabetic subjects of the same sex, age, weight and height.The minor differences found in some rhythm parameters will have to be confirmed or excluded in larger numbers of subjects. The higher circadian mean ACTH concentrations without change in steroid rhythm parameters observed in this group is interesting but will also require confirmation. (ABSTRACT TRUNCATED AT 400 WORDS)

Effect of genetic background on the therapeutic effects of dehydroepiandrosterone (DHEA) in diabetes-obesity mutants and in aged normal mice.

Coleman DL, Schwizer RW, Leiter EH
Diabetes 1984 Jan;33(1):26-32

Dehydroepiandrosterone (DHEA) was fed at 0.1-0.4% in the diet to genetically diabetic (db/db) or obese (ob/ob) C57BL/KsJ (BL/Ks) or C57BL/6J (BL/6) mice. Treatment of BL/Ks-db/db or ob/ob mice with 0.4% DHEA prevented hyperglycemia, islet atrophy, and severe diabetes associated with this inbred background, but did not affect weight gain and food consumption. Homozygous obese (ob) or diabetes (db) mice on the BL/6 background were more sensitive to DHEA, and the mild, transient hyperglycemia associated with ob or db gene expression on the BL/6 inbred background could be prevented by 0.1% DHEA. Both body weight and food consumption were decreased in BL/6 mutants maintained on 0.1% DHEA whereas this effect was not seen in BL/Ks mutants fed up to 0.4% DHEA. Early therapy with 0.4% DHEA, initiated at 2 wk of age, prevented the developmentof most diabetes symptoms and decreased the rate of weight gain in pups of all genotypes. In addition to therapeutic effects on both obese mutants, DHEA effected significant changes in an aging study using normal BL/6 female mice. Four weeks of DHEA treatment initiated at 2 yr of age improved glucose tolerance and at the same time reduced plasma insulin to a "younger" level. This suggests that DHEA may act in insulin-resistant mutant mice and in aging normal mice to increase the sensitivity to insulin.

Amniotic fluid beta-endorphin and beta-lipotropin concentrations during the second and third trimesters.

Petrucha RA, Goebelsmann U, Hung TT, Haase HR, Lobo RA
Am J Obstet Gynecol 1983 Jul 15;146(6):644-51

Amniotic fluid beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) were measured by radioimmunoassay after silicic acid extraction and gelchromatographic separation of the two peptides in uncomplicatedsecond-trimester and term pregnancies, in diabetic patients at term, and inpregnancies complicated by Rh-isoimmunization, premature labor, and intrauterine growth retardation. Furthermore, the lecithin/sphingomyelin (L/S) ratios as well as the dehydroepiandrosterone sulfate (DHEA-S) and cortisol levels were determined in most of the amniotic fluid specimens. Both the mean (+/- SE) beta-EP (65.3 +/- 9.1 fmol/ml) and beta-LPH (150 +/-15.8 fmol/ml) concentrations were significantly higher in the 20 patients with normal pregnancies of 16 to 21 weeks' duration than those found in 21 patients with uncomplicated term pregnancies of 38 weeks' gestation, averaging 42.6 +/- 6.0 and 80.1 +/- 10.7 fmol/ml, respectively. The mean amniotic fluid beta-EP and beta-LPH concentrations measured in the latter subjects were similar to those observed in 23 diabetic patients with otherwise uncomplicated term pregnancies. The mean amniotic fluid beta-EP and beta-LPH levels found in the limited number of patients with Rh-isoimmunization (N = 9), premature labor (n = 8), and intrauterine growth retardation (n = 5) with pregnancies of 24 to 36, 24 to 36, and 34 to 38 weeks' gestation, respectively, were not significantly different from the mean amniotic fluid beta-EP and beta-LPH concentrations of uncomplicated term pregnancies. In all patients but those with Rh-isoimmunization, beta-EP concentrations exhibited a positive correlation with beta-LPH levels. However, the molar beta-LPH:beta-EP ratio was significantly lower at term than during the early second trimester. Neither beta-EP nor beta-LPH correlated with the amniotic fluid L/S ratio and only beta-LPH exhibited a significant inverse correlation with amniotic fluid DHEA-S. The latter was significantly higher in uncomplicated term than second-trimester pregnancies. These results confirm that immunoassayable beta-EP is present in amniotic fluid and declines toward term. These data demonstrate that immunoassayable beta-LPH is present in amniotic fluid and show a more pronounced decrease toward the end of pregnancy than beta-EP. Neither peptide, at least on account of the amniotic fluid levels, appears to be associated with fetal maturation. The physiologic significance of amniotic fluid beta-EP and beta-LPH and their possible role as markers of fetal response to stress remain to be elucidated.

Therapeutic effects of dehydroepiandrosterone (DHEA) in diabetic mice.

Coleman DL, Leiter EH, Schwizer RW
Diabetes 1982 Sep;31(9):830-3

Dehydroepiandrosterone (DHEA), a major adrenal secretory steroid in humans, was therapeutic when fed in a concentration of 0.4% to C57BL/KsJ mice with either non-insulin-dependent or insulin-dependent diabetes. Genetically diabetic (db/db) mice of both sexes develop obesity and aglucose intolerance and hyperglycemia associated with insulin resistance by 2 mo of age, and exhibit beta-cell necrosis and islet atrophy by 4 mo. In contrast, DHEA feeding initiated between 1 and 4 mo of age, while only moderately effective in preventing obesity, did prevent the other pathogenic changes and effected a rapid remission of hyperglycemia, a preservation of beta-cell structure and function, and an increased insulin sensitivity as measured by glucose tolerance tests. DHEA feeding was also therapeutic to normal C57BL/KsJ male mice made diabetic by multiple low doses of streptozotocin (SZ). While DHEA treatments did not block either the direct cytotoxic action of SZ on beta-cells or the development of insulitis, the steroid significantly moderated the severity of the ensuing diabetes (reduced hyperglycemia and water consumption, and increased plasma insulin and numbers of residual, granulated beta-cells.

Plasma androgen concentrations in diabetic women.

Szpunar WE, Blair AJ Jr, McCann DS
Diabetes 1977 Dec;26(12):1125-9

Plasma androgen levels were determined in women assigned to the following groups: idiopathically hirsute, diabetic, both idiopathically hirsute and diabetic, and normal. The androgens examined were androstenedione (AD), dihydrotestosterone (DHT), testosterone (T), and dehydroepiandrosterone (DHEA). We find statistical differences between young (less than 38 years) and older (larger than or equal to 38 years) controls at confidence levels of p less than or equal to 0.01 for AD, DHT, and T and of p less than or equal to 0.05 for DHEA. The results indicate that peak circulating androgen levels occur prior to age 30-35 years for women. There are no significant differences between the young controls and young idiopathically hirsute subjects, but a statistical difference exists between older hirsute and older controls for all four androgens (p less than or equal to 0.05). When a comparison is made among the diabetic, hirsute diabetic, and older control groups (all groups larger than or equal to 38 years), the diabetic group is significantly higher than the control in plasma AD (p less than or equal to 0.01) and DHEA (p less than or equal to 0.05). These same two steroids are also higher in the diabetic group than in the hirsute diabetic group (p less than or equal to 0.05), while the latter differs from controls only in testosterone levels (p less than or equal to 0.05). DHT levels are similar for all three groups.

Conversion of DHEA-sulfate to estrogens as a test of placental function.

Lauritzen C
Horm Metab Res 1969 Mar;1(2):96

No abstract.

[Evaluation of placenta function using DHEA-S tolerance test; comparison with cardiotocography and placental histology]

Crabben H van der, Hammacher K, Werner C, Kaiser E
Geburtshilfe Frauenheilkd 1970 Jan;30(1):71-84

No abstract.

Interaction of alpha-lipoic acid enantiomers and homologues with the enzyme components of the mammalian pyruvate dehydrogenase complex.

Loffelhardt S, Bonaventura C, Locher M, Borbe HO, Bisswanger H
Physiologisch-Chemisches Institut, University of Tubingen, Germany.
Biochem Pharmacol 1995 Aug 25;50(5):637-46

Lipoic acid (alpha-lipoic acid, thioctic acid) is applied as a therapeutic agent in various diseases accompanied by polyneuropathia such as diabetes mellitus. The stereoselectivity and specificity of lipoic acid for the pyruvate dehydrogenase complex and its component enzymes from different sources has been studied. The dihydrolipoamide dehydrogenase component from pig heart has a clear preference for R-lipoic acid, a substrate which reacts 24 times faster than the S-enantiomer. Selectivity is more at the stage of the catalytic reaction than of binding. The Michaelis constants of both enantiomers are comparable (Km = 3.7 and 5.5 mMfor R- and S-lipoic acid, respectively) and the S-enantiomer inhibits the R-lipoic acid dependent reaction with an inhibition constant similar to its Michaelis constant. When three lipoic acid homologues were tested, RS-1,2-dithiolane-3-caproic acid was one carbon atom longer than lipoic acid, while RS-bisnorlipoic acid and RS-tetranorlipoic acid were two and four carbon atoms shorter, respectively. All are poor substrates but bind to and inhibit the enzyme with an affinity similar to that of S-lipoic acid. No essential differences with respect to its reaction with lipoicacid enantiomers and homologues exist between free and complex-bound dihydrolipoamide dehydrogenase. Dihydrolipoamide dehydrogenase from human renal carcinoma has a higher Michaelis constant for R-lipoic acid (Km = 18mM) and does not accept the S-enantiomer as a substrate. Both enantiomers of lipoic acid are inhibitors of the overall reaction of the bovine pyruvate dehydrogenase complex, but stimulate the respective enzyme complexes from rat as well as from Escherichia coli. The S-enantiomer is the stronger inhibitor, the R-enantiomer the better activator. The two enantiomers have no influence on the partial reaction of the bovine pyruvate dehydrogenase component, but do inhibit this enzyme component from rat kidney. The implications of these results are discussed.

alpha-Lipoic acid as a biological antioxidant.

Packer L; Witt EH; Tritschler HJ
Department of Molecular & Cell Biology, University of California, Berkeley, CA 94720 USA
Free Radic Biol Med 1995 Aug;19(2):227-50

alpha-Lipoic acid, which plays an essential role in mitochondrial dehydrogenase reactions, has recently gained considerable attention as an antioxidant. Lipoate, or its reduced form, dihydrolipoate, reacts with reactive oxygen species such as superoxide radicals, hydroxyl radicals, hypochlorous acid, peroxyl radicals, and singlet oxygen. It also protects membranes by interacting with vitamin C and glutathione, which may in turn recycle vitamin E. In addition to its antioxidant activities, dihydrolipoate may exert prooxidant actions through reduction of iron. alpha-Lipoic acid administration has been shown to be beneficial in a number of oxidative stress models such as ischemia-reperfusion injury, diabetes (both alpha-lipoic acid and dihydrolipoic acid exhibit hydrophobic binding to proteins such as albumin, which can prevent glycation reactions), cataract formation, HIV activation, neurodegeneration, and radiation injury. Furthermore, lipoate can function as a redox regulator of proteins such as myoglobin, prolactin, thioredoxin and NF-kappa B transcription factor. We review the properties of lipoate in terms of

(1) reactions with reactive oxygen species;
(2) interactions with other antioxidants;
(3) beneficial effects in oxidative stress models or clinical conditions. (153 Refs.)

[Diabetes mellitus--a free radical-associated disease. Results of adjuvant antioxidant supplementation]

Kahler W, Kuklinski B, Ruhlmann C, Plotz C
Klinik fur Innere Medizin, Klinikums Rostock-Sudstadt.
Z Gesamte Inn Med 1993 May;48(5):223-32

Our investigations carried out in patients with diabetes mellitus revealed oxidative stress loads. The study presented here was to clarify whether a therapy with antioxidants can contribute to an improvement of prognosis. 80 patients affected with a long term diabetic late syndrome were randomised and arranged to 4 groups of n = 20 each. In contrast to a control group these patients received 600 mg of alpha lipoic acid or 100 micrograms of selenium (sodium selenite) daily or 1200 IE of D-alpha-tocopherol respectively for a time of 3 months. In comparison with the control group all groups treated in an antioxidative way showed significantly diminished serum concentrations of thiobarbituric acid reactive substances and of urinary albumin excretion rates. The symptoms of distal symmetric neuropathy measured according to the thermo- and vibration sensitivity also improved in a highly significant manner. The results prove that oxidative stress plays a promoting role in developing of long term diabetic late complications and that a therapy with adjuvant antioxidants may lead to a regression of diabetic late complications.

Lipoate prevents glucose-induced protein modifications.

Suzuki YJ, Tsuchiya M, Packer L
Department of Molecular & Cell Biology, University of California, Berkeley 94720.
Free Radic Res Commun 1992;17(3):211-7

Nonenzymatic glycation has been found to increase in a variety of proteins in diabetic patients. The present study examined a possibility of preventing glycation and subsequent structural modifications of proteins by alpha-lipoic acid (thioctic acid) as lipoate, a substance which has gained attention as a potential therapeutic agent for diabetes-induced complications. Incubation of bovine serum albumin (BSA) at 2 mg/ml with glucose (500 mM) in a sterile condition at 37 degrees C for seven days caused glycation and structural modifications of BSA observed by SDS-PAGE, near UV absorption, tryptophan and nontryptophan fluorescence, and fluorescence of an extrinsic probe, TNS (6-(p-toluidinyl) naphthalene-2-sulfonate). When BSA and glucose were incubated in the presence of lipoate (20mM), glycation and structural modifications of BSA were significantly prevented. Glycation and inactivation of lysozyme were also prevented by lipoate. These results suggest a potential for the therapeutic use of lipoic acid against diabetes-induced complications.

Effect of DL-alpha-lipoic acid on the citrate concentration and phosphofructokinase activity of perfused hearts from normal and diabetic rats.

Singh HP, Bowman RH
Biochem Biophys Res Commun 1970 Nov 9;41(3):555-61

No abstract.

Increased anti-Gal activity in diabetic patients transplanted with fetal porcine islet cell clusters.

Galili U, Tibell A, Samuelsson B, Rydberg L, Groth CG
Department of Microbiology and Immunology, Medical College of Pennsylvania, Philadelphia, Pennsylvania 19129, USA.
Transplantation 1995 Jun 15;59(11):1549-56

The natural anti-Gal antibody seems to create a major obstacle for discordant xenotransplantation in humans. Anti-Gal, which is produced in large amounts in humans (1% of circulating IgG), interacts specifically with the carbohydrate structure Gal alpha 1-3Gal beta 1-4Glc-NAc-R (termedthe alpha-galactosyl epitope). This epitope is present in large amounts on porcine cells, as well as on cells of other nonprimate mammals (1 x 10(6)to 35 x 10(6) epitopes/cell). The interaction of anti-Gal with alpha-galactosyl epitopes on the xenograft was found to mediate the immune destruction of discordant xenografts. In the present study, the human immune response to alpha-galactosyl epitopes on xenografts was assessed by measuring changes in anti-Gal titers and affinity in sera of diabetic patients transplanted with fetal porcine islet cell clusters. The activityof this antibody was assessed by a hemagglutination assay with RBC, byELISA with mouse laminin as a solid-phase antigen, and by equilibrium dialysis with the radiolabeled free haptenic form of the alpha-galactosylepitope, i.e. [3H]Gal alpha 1-3Gal beta 1-4GlcNAc. All assays revealed a marked increase in anti-Gal activity after transplantation. The increase in anti-Gal titers ranged between 8- and 64-fold. A similar increase was observed in the binding of free alpha-galactosyl epitopes to anti-Gal, as assayed in equilibrium dialysis. Immunoglobulin concentration did not increase after transplantation, suggesting that the observed increase in anti-Gal activity is the result of a specific immune response against alpha-galactosyl epitopes on the xenograft. The elevation in anti-Gal activity was observed in all three immunoglobulin classes and the highest activity was found within the IgG class. Analysis of IgG binding to fixed porcine endothelial cells suggested that most of the observed increased activity against these cells in transplanted patients may be attributed to the elevation in anti-Gal activity.

Intracellular glutathione influences collagen generation by mesangial cells.

Shan Z, Tan D, Satriano J, Silbiger S, Schlondorff D
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York.
Kidney Int 1994 Aug;46(2):388-95

The cellular redox state is altered in a number of pathological conditions, including various forms of glomerular injury and diabetes. For example, glucose, via the pentose phosphate pathway generates NADPH, which maintains glutathione (GSH) (part of a major intracellular reducing system) in its reduced state. GSH in turn influences the activity of transcription factors on gene expression. We therefore examined whether changes in cellular GSH influence total collagen synthesis and mRNA levels for collagen I, collagen IV and TGF-beta in SV-40 transformed mouse mesangial cells (MC) maintained in either 5 or 25 mM glucose media. Total intracellular GSH was increased by N-acetylcysteine (NAC; 10 mM) or decreased with the GSH synthesis inhibitor buthionine sulfoximine (BSO; 0.2mM) in MC. NAC increased 3H-proline incorporation into collagenase-sensitive protein while BSO decreased it under both glucose conditions. The presence of BSO did not reverse the increased collagen synthesis seen in the NAC stimulated cells. Northern blot analysis showed increased mRNA levels for collagen I, collagen IV and TGF-beta in cells grown in high glucose (25 mM). NAC increased the mRNA for all three compounds while BSO alone had no effect on these mRNA levels. However, BSO reversed the increased mRNA levels for collagen I, IV and TGF-beta seen in the presence of NAC. These findings suggest that the cellular redox state may influence gene transcription in MC, and may have implications in explaining injury-associated alterations of mesangial matrix generation.

[Cholestyramine in the treatment of severe diarrhea and diarrhea of the diabetic patient].

Laudanna AA, Germ:an JC, Gama Rodriques JJ, Mekler M, Gama AH, Bertarello A
Rev Fac Cien Med Univ Nac Cordoba 1985;43(2):3-6
Published erratum appears in Rev Fac Cien Med Univ Nac Cordoba 1986;44(2):preceding 3

No abstract.

Neural dysfunction and metabolic imbalances in diabetic rats. Prevention by acetyl-L-carnitine.

Ido Y, McHowat J, Chang KC, Arrigoni-Martelli E, Orfalian Z, Kilo C, Corr PB, Williamson JR
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110.
Diabetes 1994 Dec;43(12):1469-77

The rationale for these experiments is that administration of L-carnitine and/or short-chain acylcarnitines attenuates myocardial dysfunction

1) in hearts from diabetic animals (in which L-carnitine levels are decreased);
2) induced by ischemia-reperfusion in hearts from nondiabetic animals; and
3) in nondiabetic humans with ischemic heart disease.

The objective of these studies was to investigate whether imbalances in carnitine metabolism play a role in the pathogenesis of diabetic peripheral neuropathy. The major findings in rats with streptozotocin-induced diabetes of 4-6 weeks duration were that 24-h urinary carnitine excretion was increased approximately twofold and L-carnitine levels were decreased in plasma (46%) and sciatic nerve endoneurium (31%). These changes in carnitine levels/excretion were associated with decreased caudal nerve conduction velocity (10-15%) and sciatic nerve changes in Na(+)-K(+)-ATPase activity (decreased 50%), Mg(2+)-ATPase (decreased 65%), 1,2-diacyl-sn-glycerol (DAG) (decreased 40%), vascular albumin permeation (increased 60%), and blood flow (increased 65%). Treatment with acetyl-L-carnitine normalized plasma and endoneurial L-carnitine levels and prevented all of these metabolic and functional changes except the increased blood flow, which was unaffected, and the reduction in DAG, which decreased another 40%. In conclusion, these observations

1) demonstrate a link between imbalances in carnitine metabolism and several metabolic and functional abnormalities associated with diabetic polyneuropathy and
2) indicate that decreased sciatic nerve endoneurial ATPase activity (ouabain-sensitive and insensitive) in this model of diabetes is associated with decreased DAG.

Serum and urine levels of levocarnitine family components in genetically diabetic rats.

Morabito E, Corsico N, Marzo A, Arrigoni Martelli E
Department of Pharmacology, Sigma-Tau S.p.A., Pomezia, Roma, Italy.
Arzneimittelforschung 1994 Aug;44(8):965-8

Serum concentration and urinary excretion of levocarnitine (L-carnitine, CAS 541-15-1) family components were evaluated in a Wistar derived strain of genetically diabetic rats BB/BB, in comparison with normal Wistar rats, and their control rats BB/WB of both sexes. BB/BB diabetic animals have lower serum concentration of total-L-carnitine (TC), L-carnitine (LC), acetyl-L-carnitine (ALC), and short chain L-carnitine esters (SCLCE) than both the strains of non-diabetic rats, as previously observed in streptozotocin diabetic rats. No or marginal variations between control and diabetic rats were detected in cumulative urinary excretion of L-carnitine family components. A strain difference was observed between Wistar and BB/WB non-diabetic rats, BB/WB showing higher serum concentration and lower cumulative urinary excretion of LC and TC than Wistar animals. Renal clearance of L-carnitine components proved to be markedly higher in BB/BB diabetic rats, as previously shown in streptozotocin rats. The reduction of serum concentration of the carnitines endogenous pool may explain this finding. The lack of an increased urinary excretion of L-carnitine components in diabetic animals despite the high increase of diuresis suggests that the saturable tubular reabsorption of L-carnitine family components also in diabetes is the primary mechanism to preserve the homeostatic equilibria of the L-carnitine family, the variation in serum concentration being attributable to the complex systemic metabolicalterations typical of diabetes. In agreement with previous investigations,male animals of all the strains showed higher serum concentration andurinary excretion of L-carnitine components as compared to females.

Acetyl-L-carnitine corrects electroretinographic deficits in experimental diabetes.

Lowitt S, Malone JI, Salem A, Kozak WM, Orfalian Z
Department of Pediatrics, University of South Florida, Tampa.
Diabetes 1993 Aug;42(8):1115-8

Acetyl-L-carnitine reduces the latencies of electroretinogram oscillatory potentials in healthy humans. The effect of acetyl-L-carnitine (50mg.kg-1.day-1) on the increased electroretinogram latencies found in rats with STZ-induced hyperglycemia of 3-wk duration was evaluated. The aldosereductase inhibitor sorbinil, which has been shown to normalize abnormal electroretinogram tracings associated with STZ-induced diabetes, was used as a positive control. Aldose reductase inhibitors are thought to lower tissue sorbitol while increasing myo-inositol. The electroretinograms of the STZ-induced diabetic rats in this study were abnormal; treatment withacetyl-L-carnitine as well as sorbinil significantly improved electroretinogram b-wave amplitude and decreased the latencies of oscillatory potentials 2 and 3. Acetyl-L-carnitine treatment of STZ-induced diabetic rats did not affect hyperglycemia or erythrocyte polyol pathway activity as reflected by erythrocyte sorbitol levels. In contrast, sorbinil did reduce elevated erythrocyte sorbitol levels. This suggests that the impaired electroretinograms associated with STZ-induced diabetes may not be caused solely by increased polyol pathway activity.

Acetyl-L-carnitine effect on nerve conduction velocity in streptozotocin-diabetic rats.

Morabito E, Serafini S, Corsico N, Martelli EA
Department of Pharmacology, Sigma-Tau S.p.A. Pomezia, Rome, Italy.
Arzneimittelforschung 1993 Mar;43(3):343-6

Measurement of nerve conduction velocity (NCV) is a useful and sensitive tool for evaluating diabetes related neurological dysfunctions. The method used allows to monitor the parameter at different times in the same group of rats, so that it is possible to observe simultaneously the development of the damage in time, and to evaluate the improvement related to the treatment. The repeated oral treatment with acetyl-L-carnitine (ALC, CAS 5080-50-2) 250 mg/kg caused an improvement in NCV of the diabetic rats; the effect was higher when the treatment started early with respect to the diabetes induction. The improvement in NCV was constant in time and comparable from 2 to 6 weeks of the treatment. In conclusion, oral treatment with ALC was able to normalize the impairment of NCV in streptozotocin rats, the effect being constant in time from 2 to 6 weeks of treatment and up to 8 weeks after induction when administration started in early stage of diabetes (2-3 weeks after induction); however, at this time the NCV is already significantly decreased.

Effect of acetyl-L-carnitine treatment on the levels of levocarnitine and its derivatives in streptozotocin-diabetic rats.

Marzo A, Corsico N, Cardace G, Morabito E
Department of Drug Metabolism and Pharmacokinetics, Sigma-Tau S.p.A., Pomezia, Rome, Italy.
Arzneimittelforschung 1993 Mar;43(3):339-42

The effect of diabetes induced by streptozotocin and that of acetyl-L-carnitine (ALC) hydrochloride (CAS 5080-50-2) treatment on the homeostasis of the levocarnitine (L-carnitine) moiety was investigated in Sprague-Dawley rats. The diabetic status was ascertained by measuring blood glucose. L-carnitine (LC), total acid soluble L-carnitine (TC) and ALC were measured in serum, tissues and urine by radioenzymatic methods. Short-chain L-carnitine esters (SCLCE) were obtained by subtracting LC from TC. Serum concentration of L-carnitine moiety was decreased in diabetic when compared to normal rats; whereas ALC oral treatment (50 and 150 mg/kg p.o. for 4 weeks) in diabetic rats increased, dose-dependently, all the components of L-carnitine moiety, SCLCE and ALC being completely restored. In the liverof diabetic rats all the analytes proved to be higher than in normal rats, mainly LC and TC. A similar trend was observed in skeletal muscle, at least with LC and TC, whereas SCLCE and ALC were not affected. The treatment with ALC increased the liver concentration of all the analytes in a dose-related way whereas in skeletal muscle only LC and TC showed an increase with the highest dose of ALC. Myocardium and kidneys showed a decrease of all the analytes in diabetes; the treatment with ALC normalized the situation in kidneys, in a dose-related way, but not in the myocardium. Urinary excretion and renal clearance of L-carnitine moiety increased in diabetes; an additional dose-related increase was observed with the ALC treatment.

Acetyl-L-carnitine prevents substance P loss in the sciatic nerve and lumbar spinal cord of diabetic animals.

Di Giulio AM, Gorio A, Bertelli A, Mantegazza P, Ferraris L, Ramacci MT
Department of Medical Pharmacology, University of Milan, Italy.
Int J Clin Pharmacol Res 1992;12(5-6):243-6

Diabetic neuropathy is a disease of peripheral nerves, characterized by axonal atrophy and degeneration that might be preceded by a marked impairment of axonal transport and by a reduced conduction velocity. Sensory nerves are particularly susceptible to diabetes. In the present report it is shown that experimental diabetes in rats causes a significant reduction of the content of the pain-related neuropeptide substance P insciatic nerve and lumbar spinal cord. Such a loss of substance P is fully prevented by acetyl-L-carnitine treatment. The neuroprotective pharmacological effect is selective and takes place without significant changes of hyperglycaemia and without modifications of the reduced rate of body growth typical of diabetic animals.

Altered neuroexcitability in experimental diabetic neuropathy: effect of acetyl-L-carnitine.

Malone JI, Lowitt S, Corsico N, Orfalian Z
University of South Florida, Tampa.
Int J Clin Pharmacol Res 1992;12(5-6):237-41

Sciatic nerve conduction velocity (NCV) is reduced in rats made hyperglycaemic with streptozotocin (STZ). This neurophysiologicaldys function has been associated with increased nerve sorbitol and reduced nerve inositol. Treatment of STZ diabetic rats with aldose reductase inhibitors (ARIs) which reduce sorbitol and increase inositol in the nerve results in normalization of NCVs. Male Wistar rats were made diabetic with 50 mg/kg of streptozotocin given intraperitoneally. Those animals with blood glucose > 300 mg/dl two weeks later were included in this study. The STZ-diabetic rats were treated with either the ARI sorbinil (40 mg/kg per day), or acetyl-L-carnitine (ALC) (300 mg/kg per day) or sterile 0.15% aqueous NaCl for 16 weeks after 4 or 8 weeks of untreated hyperglycaemia. A control group of non-diabetic rats received no treatment during the interval. Sciatic-nerve sorbitol was elevated (1.08 +/- 0.13 nanomol/mg wet weight vs. 0.19 +/- 0.03 nm/mg wet weight) and inositol was reduced (1.21+/- 0.12 nm/mg ww vs. 2.02 +/- 0.08 nm/mg ww) in the STZ diabetic rats, which were untreated for 4 weeks. Treatment with sorbinil was associated with normalization of the tissue sorbitol (0.10 +/- 0.05 nm/mg ww), while ALC treatment also significantly reduced the nerve sorbitol but only to a level (0.34 +/- 0.08 nm/mg ww) more elevated than the normal level. The nerves of STZ animals treated with sorbinil or ALC had inositol levels no different from untreated diabetic rats. Thus, hyperglycaemic animals treated with either ALC or sorbinil had similar improvements in NCVs as the diabetic, even though the effect on nerve sorbitol was different and nerve inositol was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

[The action of carnitine-series preparations in experimental alloxan diabetes mellitus]

Kim EK, Trevisani C, Trevisani M
Eksp Klin Farmakol 1992 Jul-Aug;55(4):35-6

The study was undertaken to examine the effects of l-carnitine and acetyl-l-carnitine in rats and mice with experimental alloxan diabetes. The findings suggest that acetyl-l-carnitine is more effective against diabetes in increasing glucose tolerance, restoring the impaired response of glucagon to glucose, showing glycogen-sparing action than is l-carnitine.

Aminoguanidine and diabetic neuropathy

Monnier VM
Institute of Pathology, Case Western Reserve University, Cleveland, OH, USA.
Eur J Endocrinol 1996 Apr;134(4):398-400

No abstract.

Evaluation of the mechanism of endothelial dysfunction in the genetically-diabetic BB rat.

Pieper GM, Moore-Hilton G, Roza AM
Department of Transplant Surgery, Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital, Milwaukee, 53226 USA.
Life Sci 1996;58(9):PL147-52

Endothelial dysfunction is known to occur in chemically-induced animal models of diabetes. The BB diabetic rat is a genetic diabetes-prone model which more closely resembles Type I diabetes mellitus. In this study, we examined the role of superoxide anion radical and cyclooxygenase activity on endothelial dysfunction in aorta of the spontaneous diabetic BB rat.Vascular endothelial function was studied in vitro in aortic rings from 8-wk diabetic rats and age-matched nondiabetic littermates. There was no alteration in reactivity to norepinephrine as a result of diabetes. Relaxation to acetylcholine (but not nitroglycerin) was impaired in diabetic rings. Relaxation to acetylcholine was abolished by 100 micro ML-nitroarginine but unaltered by an equimolar concentration of aminoguanidine (an inducible nitric oxide synthase inhibitor) in both control and diabetic rings. Incubation with 10 microM indomethacin did not alter relaxation to acetylcholine in either control or diabetic rings. In contrast, addition of 20 U/ml superoxide dismutase enhanced relaxation to acetylcholine in diabetic rings but had no effect on relaxation to acetylcholine in control rings. Thus, nitric oxide-mediated, endothelium-dependent relaxation is diminished in aortic rings of the genetic diabetic BB rat. Furthermore, superoxide anion radicals but not cyclooxygenase products play an important role in endothelial dysfunction in this genetic diabetic model.

Effect of aminoguanidine on the frequency of neuroaxonal dystrophy in the superior mesenteric sympathetic autonomic ganglia of rats with streptozocin-induced diabetes.

Schmidt RE, Dorsey DA, Beaudet LN, Reiser KM, Williamson JR, Tilton RG
Department of Pathology, Washington University of Medicine, St. Louis, Missouri 63110, USA.
Diabetes 1996 Mar;45(3):284-90

Aminoguanidine, which prevents formation of advanced glycation end products and is a relatively selective potent inhibitor of the inducible (versus constitutive) isoform(s) of nitric oxide synthase, has been reported to ameliorate structural and functional abnormalities in peripheral somatic nerves in rats with streptozocin (STZ)-induced diabetes. In the present studies, the effects of aminoguanidine treatment on ultrastructural changes in the autonomic nervous system of rats with STZ-induced diabetes were examined. The frequency of neuroaxonal dystrophy, the neuropathological hallmark of sympathetic autonomic neuropathy in diabetic rats, increased 9- to 11-fold in the superior mesenteric ganglia of 7- and 10-month STZ-diabetic rats compared with that in age-matched controls. Administration of aminoguanidine continuously from the time of induction of diabetes at a dose equal to or in excess of that providing a salutary effect in the diabetic somatic peripheral nervous system did not alter the severity of diabetes as assessed by plasma glucose level, 24-hurine volume, and levels of glycated hemoglobin. Chronic aminoguanidine therapy did not diminish the frequency or affect the ultrastructural appearance of neuroaxonal dystrophy in diabetic or age-matched control rat sympathetic ganglia after 7 or 10 months of continuous administration. Our findings (under these experimental conditions) do not support a role for aminoguanidine-sensitive processes in the development of sympathetic neuroaxonal dystrophy in diabetic rats. Glycation-linked aminoguanidine-insensitive processes, however, such as the formation of early glucose adducts (Schiff bases and Amadori products) withintra cellular and/or extracellular proteins and amine-containing lipids, superoxide anion generation during subsequent autoxidation of these glucoseadducts, and non-glycative processes, remain potential pathogenetic mechanisms for diabetic autonomic neuropathy.

[The relation between the changes of width and anionic sites of glomerular basement membrane and transferrinuria in rats]

Chen Y, Qian Y
Department of Endocrine, First Hospital, Beijing Medical University.
Chung Hua I Hsueh Tsa Chih 1995 Sep;75(9):537-9, 574

The changes of width and anionic sites of glomerular basement membrane (GBM) are considered early changes of diabetic nephropathy. Recent work suggests that the normal barrier to the penetration of renal glomerular basement membrane by anionic plasma proteins may depend in part on the existence of negatively charged sites within the membrane. We evaluated the relationship between the change of width, anionic sites of GBM and transferrinuria in diabetic rats and normal controls in 1, 3, 6 months after administration by STZ. Diabetic rats revealed a thicken GBM(0.40-0.44 microns) and reduced anionic sites (16-12/1000nm GBM length) compared with control rats (0.22 microns, 20-22/1000 nm GBM lenth). Transferrinuria was also significantly greater in diabetic rats than normals (P < 0.01). The changes in anionic sites and transferrinuria represented defect of GBM charge barrier in early phase of diabetic nephropathy. Aminoguanidine attenuated the rise in transferrinuria and prevented GBM thickness and loss of anionie sites.

Increased endocytosis in retinal vascular endothelial cells grown in high glucose medium is modulated by inhibitors of nonenzymatic glycosylation.

Stitt AW, Chakravarthy U, Archer DB, Gardiner TA
Department of Ophthalmology, Queen's University of Belfast, Northern Ireland.
Diabetologia 1995 Nov;38(11):1271-5

We sought to determine if hyperglycaemia is responsible for increased retinal vascular endothelial-cell (RVEC) endocytosis in diabetes and to assess the role of nonenzymatic glycosylation in mediation of this novel endothelial-cell pathology. RVECs were propagated in media containing either 5 or 25 mmol/l glucose for up to 10 days after which they were exposed to the protein tracer horseradish peroxidase for 30 min. The level of RVEC endocytosis was quantified in intact cell monolayers by electron microscopic stereology, and in cell lysates by a simple spectrophotometric method. The effect of the nonenzymatic glycosylation inhibitors, aminoguanidine and D-lysine, on high-glucose medium induced changes in RVEC endocytosis was tested by inclusion of these agents in the culture medium. RVECs exposed to 25 mmol/l glucose showed a stepwise increase in endocytosis of horseradish peroxidase culminating in a two- to threefold increase after 10 days. Endocytosis returned to normal levels after afurther 10 days in 5 mmol/l glucose medium. The increase in RVEC endocytosis was markedly reduced, but not completely normalised, by aminoguanidine and D-lysine. Exposure of cultured RVECs to 25 mmol/l glucose causes an increase in endocytosis of similar magnitude to that experienced by RVEC in early diabetes, and implicates hyperglycaemia in the latter situation. A significant component of the increase in RVEC endocytosis appears to be mediated by nonenzymatic glycosylation.

In vitro advanced glycation end product formation in rat tail tendon fibers: influence of aminoguanidine.

Troncoso IA, Esteban MM, Ruiz MA, Florez L, Barneo L
Functional Biology Department, University of Oviedo, Spain.
Transplant Proc 1995 Dec;27(6):3345-6

No abstract.

Yorek MA, Conner CE, Spanheimer RG
Department of Internal Medicine, Veterans Affairs Medical Center, Iowa City, IA 52246, USA.
J Cell Physiol 1995 Dec;165(3):658-66

L-fucose is a monosaccharide which is present in low concentrations in normal serum but is increased in diabetes, cancer, and inflammatory diseases. The contribution that abnormal L-fucose levels make to the progression of these disorders is unknown. In a previous study we showed that increased L-fucose concentration reduced proliferation and proteoglycan production by cultured cerebral microvessel endothelial cells. In the present study we show that exposing cerebral microvessel endothelial cells for 2 weeks to medium containing an increased concentration of L-fucose causes a significant decrease in collagen and to a lesser extent noncollagen protein production. The effect of L-fucose on collagen and noncollagen protein production is concentration-dependent: 1 mM L-fucose causes a significant decrease in collagen production but has no effect on noncollagen protein production; a 5 mM L-fucose concentration causes a maximum decrease in both collagen and noncollagen protein production. This defect is unrelated to the reduction in myo-inositol uptake caused by L-fucose and is not prevented by aminoguanidine. Collagen production can be improved by restoring L-fucose-conditioned cells to normal medium. Culturing cells for 2 weeks in medium containing 10 mM L-fucose resulted in a 50% decrease in collagen production, which was restored to 75% of control after cells were transferred to normal medium for 7 days. In contrast, noncollagen protein production was totally restored after 3 days in normal medium. Increasing levels of L-fucose in serum of rats also resulted in a decrease in collagen production. Collagenase digestible in corporation of L-[2,3,4,5-3H]proline into protein of the articular cartilage from rats fed a diet containing 20% L-fucose for 3 weeks was reduced by about 40%compared to rats fed a normal diet. The decrease in collagen production in L-fucose fed rats was less than the reduction that occurred in streptozotocin-induced diabetic rats. These data suggest that changes in L-fucose concentration itself may be a factor in the regulation of collagen production.

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The relative roles of advanced glycation, oxidation and aldose reductase inhibition in the development of experimental diabetic nephropathy in the Sprague-Dawley rat.

Soulis-Liparota T, Cooper ME, Dunlop M, Jerums G
Department of Medicine, University of Melbourne, Austin Hospital, Victoria, Australia.
Diabetologia (Germany) Apr 1995, 38 (4) p387-94

Advanced glycation is an important pathogenic mechanism in the development of diabetic complications. However, other biochemical processes, such as the polyol pathway or lipid and protein oxidation which can interact with advanced glycation can also yield tissue fluorescence and may also be implicated in the genesis of diabetic microangiopathy. Aminoguanidine is an inhibitor of advanced glycation, but it is not known if all of its effects are mediated by this mechanism. The present study explores the relative contributions of aldose reductase, oxidative stress and advanced glycation on the development of aortic and renal fluorescence and urinary albumin excretion in streptozotocin diabetic rats. The study groups included non-diabetic (control), streptozotocin diabetic rats and diabetic rats receiving aminoguanidine, the anti-oxidants butylated hydroxytoluene and probucol and the aldose reductase inhibitor, ponalrestat. Serial measurements of glycaemic control and urinary albumin excretion were performed every 8 weeks. At 32 weeks, animals were killed, tissues removed and collagen extracted for measurement of fluorescence. Diabetic rats had increased fluorescence in aorta, glomeruli and renal tubules. Aminoguanidine prevented an increase in fluorescence at all three sites suggesting that diabetes-related tissue fluorescence is predominantly due to advanced glycation. Ponalrestat retarded fluorescence in aorta only and butylated hydroxytoluene attenuated fluorescence at the renal sites but not in the aorta. Diabetic rats had increased renal cortical sorbitol levels. Ponalrestat normalized renal cortical sorbitol levels but aminoguanidine did not affect this parameter. The only agent to decrease plasma thiobarbituric acid reactive substances was butylatedhydroxytoluene. Diabetic rats developed albuminuria over the 32-week period.

Cloning and expression of cytokine-inducible nitric oxide synthase cDNA from rat islets of Langerhans.

Karlsen AE, Andersen HU, Vissing H, Larsen PM, Fey SJ, Cuartero BG, Madsen OD, Petersen JS, Mortensen SB, Mandrup-Poulsen T, et al
Steno Diabetes Center, Gentofte, Denmark.
Diabetes 1995 Jul;44(7):753-8

An inducible nitric oxide (NO) synthase isoform (iNOS) is specifically induced in the beta-cells of interleukin (IL)-1 beta-exposed rat islets, suggesting a role for NO in the pathogenesis of type I diabetes. The aim of this study was to clone and characterize iNOS cDNA from cytokine-exposed islets. Neither NO production nor iNOS transcription could be detected in rat islets or in rat insulinoma RIN-5AH beta-cells cultured in the absence of cytokines. Addition of IL-1 beta alone or in combination with tumor necrosis factor-alpha induced a concentration- and time-dependent expression of the iNOS gene and associated NO production (measured asnitrite) from both islets and RIN cells. iNOS transcripts were cloned by reverse transcriptase-polymerase chain reaction from the cytokine-exposed rat islets and RIN cells, and DNA sequence analysis revealed a near 100% identity to the recently published iNOS cDNA cloned from cytokine-exposed rat hepatocytes and smooth muscle cells. Recombinant rat islet iNOS was transiently and stably expressed in human kidney 293 fibroblasts, and the high enzymatic activity was inhibited by addition of the L-arginine analogs, N omega-nitro-L-arginine methyl ester and aminoguanidine. Two-dimensional gel electrophoresis revealed the recombinant iNOS as aseries of spots with the expected molecular mass of 131 kDa and pI values in the range of 6.8 to 7.0. In conclusion, the IL-1 beta-induced iNOS cloned and expressed from rat islets and RIN cells is encoded by the same transcript as the iNOS induced in other cell types.

Aminoguanidine does not inhibit the initial phase of experimental diabetic retinopathy in rats.

Hammes HP, Ali SS, Uhlmann M, Weiss A, Federlin K, Geisen K, Brownlee M
Third Medical Department, Justus-Liebig-University of Giessen, Germany.
Diabetologia (Germany) Mar 1995, 38 (3) p269-73

We have previously shown that long-term administration of aminoguanidine, an inhibitor of advanced glycosylation product formation, reduces the extent of experimental diabetic retinopathy in the rat by 85%. In order to determine whether the residual retinopathy that developed despite aminoguanidine was attributable to advanced glycation endproduct formation, a time-course study was performed in three different groups of male Wistar rats: non-diabetic controls (NC), streptozotocin-diabetic controls (DC) and streptozotocin-diabetic rats treated with aminoguanidine HCL, 50 mg/100 ml drinking water (D-AG). Eyes were obtained at 24, 32, 44 and 56 weeks of diabetes/treatment duration and morphologic evaluation was done on retinal digest preparations. At 56 weeks, retinal basement membrane thickness was additionally measured. After 24 weeks of diabetes, the number of acellular capillaries was significantly elevated in DC (44.6 +/- 5.7/mm2 of retinal area, NC 19.6 +/- 4.9; p < 0.001) and increased continuously over time (DC56 weeks 87.4 +/- 15.1; p < 0.001 vs DC24 weeks). In contrast, acellular capillaries in D-AG increased over the first 24 weeks and then remained constant for the rest of the study (D-AG 24 weeks 35.7 +/- 5.18; p < 0.01 vs NC 24 weeks and NS vs DC 24 weeks; D-AG 56 weeks 42.0 +/- 6.20; p NS vsD-AG 24 weeks). (ABSTRACT TRUNCATED AT 250 WORDS)

Neurotoxicity of advanced glycation endproducts during focal stroke and neuroprotective effects of aminoguanidine.

Zimmerman GA, Meistrell M 3rd, Bloom O, Cockroft KM, Bianchi M, Risucci D, Broome J, Farmer P, Cerami A, Vlassara H, et al
Department of Surgery, North Shore University Hospital, Manhasset, NY 11030, USA.
Proc Natl Acad Sci U S A (United States) Apr 25 1995, 92 (9) p3744-8

Cerebral infarction (stroke) is a potentially disastrous complication of diabetes mellitus, principally because the extent of cortical loss is greater in diabetic patients than in nondiabetic patients. The etiology of this enhanced neurotoxicity is poorly understood. We hypothesized that advanced glycation endproducts (AGEs), which have previously been implicated in the development of other diabetic complications, might contribute to neurotoxicity and brain damage during ischemic stroke. Using a rat model of focal cerebral ischemia, we show that systemically administered AGE-modified bovine serum albumin (AGE-BSA) significantly increased cerebral infarct size. The neurotoxic effects of AGE-BSA administration were dose- and time-related and associated with a paradoxical increase in cerebral blood flow. Aminoguanidine, an inhibitor of AGE cross-linking, attenuated infarct volume in AGE-treated animals. We conclude that AGEs may contribute to the increased severity of stroke associated with diabetes and other conditions characterized by AGE accumulation.

Agmatine and spermidine reduce collagen accumulation in kidneys of diabetic db/db mice.

Marx M, Trittenwein G, Aufricht C, Hoeger H, Lubec B
Department of Pediatrics, University of Vienna, Austria.
Nephron (Switzerland) 1995, 69 (2) p155-8

In the present study, we tested the hypothesis whether agmatine and spermidine, metabolites of arginine metabolism, share the pharmacological activities of arginine reducing collagen accumulation in the diabetic kidney. Eleven db/db mice were administered agmatine and 12 db/db mice spermidine (50 mg/kg body weight). Ten db/db mice received no treatment as negative controls and 10 db/db mice were treated with aminoguanidine (50mg/kg body weight) as positive controls. Mean kidney OH-proline content reflecting kidney collagen content and mean CML concentration were significantly higher but acid solubility of collagen significantly lower in the untreated group than in the treated groups. Agmatine, although missing the alpha-amino group and the carboxyl group, and spermidine, although missing the guanidino group, thus still revealed the arginine activity. We hypothesize that the strongly nucleophilic structure of polyamines common to all active compounds is able to block reactive carbonyls.

Mechanism of autoxidative glycosylation: identification of glyoxal and arabinose as intermediates in the autoxidative modification of proteins by glucose.

Wells-Knecht KJ, Zyzak DV, Litchfield JE, Thorpe SR, Baynes JW
Department of Chemistry and Biochemistry, University of South Carolina, Columbia 29208.
Biochemistry (United States) Mar 21 1995, 34 (11) p3702-9

Glycation and oxidation reactions contribute to protein modification in aging and diabetes. Formation of dicarbonyl sugars during autoxidation of glucose is the hypothetical first step in the autoxidative glycosylation and subsequent browning of proteins by glucose [Wolff, S. P., & Dean, R. T. (1987) Biochem. J. 245, 243-250]. In order to identify the dicarbonyl sugar(s) formed during autoxidation of glucose under physiological conditions, glucose was incubated in phosphate buffer (pH 7.4) at 37 degrees C under air (oxidative conditions) or nitrogen with transition metal chelators (antioxidative conditions). Dicarbonyl compounds were analyzed spectrophotometrically and by HPLC after reaction with Girard-T reagent. Carbohydrates were analyzed by gas chromatography-mass spectrometry. Both dicarbonyl sugar and arabinose concentrations increased with time and glucose concentration in incubations conducted under oxidative conditions; only trace amounts of these products were detected in glucose incubated under antioxidative conditions. HPLC analysis of adducts formed with Girard-T reagent indicated that glyoxal was the only alpha-dicarbonyl sugar formed on autoxidation of glucose. Glyoxal and arabinose accounted for > or = 50% of the glucose lost during a 21 day incubation. Neither glucosone nor its degradation product, ribulose, was detectable