Life Extension Final Clerance Sale





Controlled Diabetics Have New Reason to Smile 2002.

AAP. Chicago, IL: American Academy of Peridontology ( or

First Human Studies Promising for Popular Nutritional Supplement 2000.

ACS. Washington, D.C.: American Chemical Society (

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.

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 (

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 (

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.

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.


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) (

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.


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.

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.

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.

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.


Vitamin E Shows Promise in Treating Diabetes 2001 Jun 5.

Devaraj, S.

Washington, D.C.: Hearst Newspapers (

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


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.

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.

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.

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.


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.

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


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.

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.

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.


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.

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.

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