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

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

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

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

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

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

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

No abstract available.

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

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

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

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

Daily magnesium supplements improve glucose handling in elderly subjects.

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

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

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

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

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

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

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

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

Pariza, M.

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

Family Guide to Prescription Drugs 1999.

PDR.

New York: Three Rivers Press.

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

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

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

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

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

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

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

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

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

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

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

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

Nutrition: An Integrated Approach 1984.

Pike, R. et al.

New York: MacMillan

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

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

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

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

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

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

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

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

Advanced glycation end products: a Nephrologist's perspective.

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

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

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

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

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

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

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

The influence of zinc supplementation on glucose homeostasis in NIDDM.

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

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

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

Syndrome X 2000.

Reaven, G.M.

New York: Simon & Schuster.

Gum Disease Linked to Diabetes 2001

Reuters Health.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Enter the Zone 1995.

Sears, B.

New York: Regan Books.

The Anti-Aging Zone 1999.

Sears, B.

New York: Regan Books.

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

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

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

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

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

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

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

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

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

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

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

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

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

Some Teens Putting Themselves in Danger of Heart Disease 2001

Smith, M.

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

Growth factors regulate expression of osteoblast-associated genes.

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

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

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

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

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

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

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

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

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

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

Is visceral adiposity the "enemy within"?

Tracy RP.

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

No abstract available.

Type 2 diabetes can be prevented with lifestyle change.

Tuomilehto, J.

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

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

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

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

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

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

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

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

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

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

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

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

The milieu interieur and the islets of Langerhans.

Unger RH.

Diabetologia 1981;20(1):1-11

No abstract available.

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

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

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

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

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

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

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

The Finnish Diabetes Prevention Study.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Glycogen metabolism and the mechanism of action of cyclic AMP.

Villar-Palasi C, Larner J, Shen LC.

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

No abstract available.

Inhibition of aldose reductase in human erythrocytes by vitamin C.

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

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

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

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

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

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

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

Waterfall Health and Nutrition Database. Magnesium 2000

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

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

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

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

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

The Herbal Drugstore 2000.

White, L. Foster, S.

Emmaus, PA: Rodale.

Diabetes: finally getting the attention it needs.

Whiting, S.E.

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

Gaining and Maintaining Total Health 1989.

Whiting, S.E.

Hilo, HI: The Holistic Health Network.

Understanding Normal and Clinical Nutrition, Fourth Edition 1998.

Whitney, E.N. et al.

Belmont, CA: West/Wadsworth.

Reduced serum dehydroepiandrosterone levels in diabetic patients with hyperinsulinaemia.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Hyperinsulinaemia, obesity, and syndrome X.

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

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

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

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

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

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

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

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

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

Prevalence of hyperinsulinaemia in patients with high blood pressure.

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

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

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

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

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

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

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