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Abstracts

Diabetes

ABSTRACTS

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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 < 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 < 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 < 0.05 vs. placebo). After caffeine administration, plasma FFAs increased (P < 0.05) and remained higher than during placebo. Plasma epinephrine increased fivefold (P < 0.0005), and smaller increases were recorded in plasma norepinephrine (P < 0.02) and blood pressure (P < 0.001). Dipyridamole did not alter insulin sensitivity and only increased plasma norepinephrine (P < 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 & 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 (<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<0.0001), waist girth (r=0.37, P<0.0001), and visceral AT accumulation measured by computed tomography at L4 to L5 (r=0.28, P<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<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 <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<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<0.001) and abdominal fat volume (r -0.80, P<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<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<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<0.001; diabetics: 21.28+/-3.18 vs. 19.66+/-3.04 micromoles/kg(ffm)/minute, p<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<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 < 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.

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