Insulin resistance and insulin hypersecretion are established features of obesity. Their prevalence, however, has only been inferred from plasma insulin concentrations. We measured insulin sensitivity (as the whole-body insulin-mediated glucose uptake) and fasting posthepatic insulin delivery rate (IDR) with the use of the euglycemic insulin clamp technique in a large group of obese subjects in the database of the European Group for the Study of Insulin Resistance (1,146 nondiabetic, normotensive Caucasian men and women aged 18-85 yr, with a body mass index (BMI) ranging from 15 to 55 kg·m Ϫ 2 ). Insulin resistance, defined as the lowest decile of insulin sensitivity in the lean subgroup (608 subjects with BMI Յ 25 kg·m Ϫ 2 ), was present in 26% of the obese subgroup (538 subjects with a mean BMI of 29 kg·m Ϫ 2 ). Insulin sensitivity declined linearly with BMI at an age-and sex-adjusted rate of 1.2 mol·min Ϫ 1 ·kg FFM Ϫ 1 per BMI unit (95% confidence intervals ϭ 1.0-1.4). Insulin hypersecretion, defined as the upper decile of IDR, was significantly ( P Ͻ 0.0001) more prevalent (38%) than insulin resistance in the obese group. In the whole dataset, IDR rose as a function of both BMI and insulin resistance in a nonlinear fashion. Neither the waist circumference nor the waistto-hip ratio, indices of body fat distribution, was related to insulin sensitivity after adjustment for age, gender, and BMI; both, however, were positively associated ( P Ͻ 0.001) with insulin hypersecretion, particularly in women.In nondiabetic, normotensive obese subjects, the prevalence of insulin resistance is relatively low, and is exceeded by the prevalence of insulin hypersecretion, particularly in women with central obesity. In the obese with preserved insulin sensitivity, risk for diabetes, cardiovascular risk, and response to treatment may be different than in insulin resistant obesity. ( J. Clin. Invest. 1997. 100:1166-1173.)

This study aims to determine the presence of the components of the metabolic syndrome in primary nonalcoholic steatohepatitis (NASH) and to assess the role of liver disease in the genesis of peripheral hyperinsulinemia. Nineteen patients (18 men and 1 woman; mean age, +/- SD, 38 +/- 10 years; body mass index [BMI], 26 +/- 2 kg/m(2)) with histologic evidence of NASH were enrolled; 19 age- and sex-matched normal subjects were investigated as controls. Plasma glucose, insulin, and C-peptide levels were measured during an oral glucose tolerance test, and a frequently sampled intravenous glucose tolerance test (FSIGT), analyzed by minimal modeling technique, was performed. Compared with controls, the NASH group had lower insulin sensitivity (3.84 +/- 2.44 vs. 7.48 +/- 3.01 10(-4) x min(-1)/microU/mL; P =.0003) and higher total insulin secretion (21 +/- 13 vs. 10 +/- 3 nmol/L in 240 minutes; P =.001). Hepatic insulin extraction was similar in both groups (69.8% +/- 16.1% vs. 70.2% +/- 18.3%; P =.854). According to the results of the oral glucose tolerance test, no patient was classified as diabetic, 5 were classified as glucose intolerant, and 1 was classified as having impaired fasting glycemia. Nine patients (47%) had at least the 2 minimum criteria required to define the metabolic syndrome according to the European Group for the Study of Insulin Resistance (EGIR). In conclusion, hyperinsulinemia and insulin resistance occur frequently in patients with NASH; these conditions do not stem from a reduced hepatic insulin extraction but from an enhanced pancreatic insulin secretion compensatory to reduced insulin sensitivity. The derangement of insulin regulation, often associated with the metabolic syndrome, may play a causal role in the pathogenesis of NASH.

A B S T R A C T Prednisone-induced insulin resistance may depend on either reduced sensitivity (receptor defect) or reduced response to insulin (postreceptor defect). To clarify the mechanism of prednisone-induced insulin resistance, a [3H]glucose infusion (1 ,uCi/ min) was performed for 120 min before and during a euglycemic clamp repeated at 100, -1,000, and -10,000 MU/ml steady state plasma insulin concentration in 10 healthy, normal weight subjects, aged 35±7 yr. Each test was repeated after 7-d administration of placebo or prednisone (15 plus 15 mg/d per subject), in a randomized sequence with an interval of 1 mo between the two tests. Mean fasting blood glucose (89.5±2.1 vs. 83.7± 1.9 mg/dl) and mean fasting plasma insulin values (17.8±1.2 vs. 14.3±0.8 AU/ml) were significantly higher (P < 0.01) after prednisone. The insulin sensitivity index (glucose metabolic clearance rate in ml/kg per min) was significantly lower (P < 0.001) after prednisone at all three steady state plasma insulin levels: 2.8±0.3 vs. 7.4±1.1 at '100 MU/ml; 6.0±0.5 vs. 12.2±1.1 at -1,000 psU/ml; 7.4±0.6 vs. 14.4±0.5 at -10,000 ,uU/ml. Fasting glucose production (in mg/ kg per min) was significantly higher after prednisone: 3.7±0.2 vs. 2.9±0.2, P < 0.001. Suppression of glucose production at steady state plasma insulin level of -100 IAU/ml was less after prednisone (1.01±0.35 vs. 0.14±0.13, NS), and total at -1,000 and -10,000 1uU/ ml after both prednisone and placebo. The metabolic kinetic parameters of insulin after prednisone were not significantly different from those after placebo. In addition, insulin binding and 3-ortho-methyl-glucose transport were studied in vitro on fat cells from 16 normal-weight surgical candidates aged 40±8 yr (10

OBJECTIVE -The aim of this study was to assess in an 11-year survival follow-up of a population-based cohort of type 2 diabetes the predictive role of World Health Organizationdefined metabolic syndrome, independent of conventional cardiovascular risk factors. -up (1991-2001), 1,565 patients were regularly examined with centralized measurements of HbA 1c . The independent role of the metabolic syndrome as a predictor of all-cause and cardiovascular mortality was assessed with multivariate Cox proportional hazards modeling. RESEARCH DESIGN AND METHODS -During the followRESULTS -At baseline, the prevalence of the metabolic syndrome was 75.6% (95% CI 73.6 -77.9). Results are based on 685 deaths (520 with the metabolic syndrome and 165 without it) in 10,890.2 person-years of observations. With respect to subjects without the metabolic syndrome, those with the metabolic syndrome had a similar hazard ratio (HR) of cardiovascular mortality after adjustment for age, sex, smoking, total cholesterol level, and coronary heart disease. In contrast, relative to subjects with diabetes only, the HR of subjects with only one component of the syndrome was 2.92 (1.16 -7.33), independent of other risk factors.CONCLUSIONS -We found that 1) the prevalence of the metabolic syndrome in a population-based cohort of type 2 diabetes is high (75.6%); 2) the metabolic syndrome is not a predictor of 11-year all-cause and cardiovascular mortality; and 3) more than twofold higher cardiovascular risk, independent of conventional risk factors, is evident in diabetic subjects with only one component of the syndrome compared with those with diabetes only. Categorizing type 2 diabetic subjects as having or not having the metabolic syndrome does not provide further prediction compared with the knowledge of its single components.

Abstract. Veglio M, Bruno G, Borra M, Macchia G, Bargero G, D'Errico N, Pagano GF, Cavallo-Perin P (Evangelico Valdese Hospital, Torino; University of Torino, Torino; and S. Spirito Hospital, Casale Monferrato; Italy). Prevalence of increased QT interval duration and dispersion in type 2 diabetic patients and its relationship with coronary heart disease: a population-based cohort. J Intern Med 2002; 251: 317-324.Objective. To evaluate the prevalence of prolonged QT interval and dispersion in a population-based cohort of type 2 diabetic patients and their relationship with clinical and metabolic variables. Design. Cross-sectional population-based cohort. Setting. Diabetes clinics and general practitioners in Casale Monferrato (Northern Italy). Subjects. A total of 1357 patients with known type 2 diabetes (70% of the cohort). Main outcome measures. Albumin excretion rate and coronary heart disease (CHD); a standard supine 12-lead electrocardiogram (ECG) was recorded and coded according to the Minnesota code criteria. QT interval corrected for heart rate (QTc) > 0.44 s and QTc dispersion > 0.080 s were considered abnormally prolonged.Results. Prevalence of increased QTc duration and QTc dispersion were 25.8% (95% CI 23.5-28.3) and 33.1% (95% CI 30.6-35.7), with no sex differences. No metabolic differences were found, apart from fibrinogen and creatinine levels, which were higher in patients with increased QTc dispersion. Patients with CHD had higher mean adjusted values of QTc and QTc dispersion, whereas no association was found with albumin excretion rate (AER) and diabetes treatment. QTc duration and QTc dispersion were significantly correlated (0.17, P < 0.001). In multiple regression analysis, only CHD was independently associated with QTc, after adjustment for age and sex (b ¼ 0.010, P < 0.001, R 2 ¼ 2.5%); as regards QTc dispersion, a similar association with CHD was found (b ¼ 0.20, P < 0.001, R 2 ¼ 4.8%). Conclusions. This population-based study shows a considerably high prevalence of increased QTc and QTc dispersion in type 2 diabetic patients and their association with CHD. These findings have both epidemiological and clinical relevance, as they might be implicated in the excess mortality risk of type 2 diabetic patients.

Aims/hypothesis Mesenchymal stem cells (MSCs) can exert an immunosuppressive effect on any component of the immune system, including dendritic cells (DCs), by direct contact, the release of soluble markers and extracellular vesicles (EVs). We evaluated whether MSCs and MSC-derived EVs have an immunomodulatory effect on monocyte-derived DCs in type 1 diabetes. Methods Bone marrow derived MSCs were characterised and EVs were obtained by ultracentrifugation. DCs were differentiated from CD14 + cells, obtained from nine type 1 diabetic patients at disease onset, pulsed with antigen GAD65 and cultured with MSCs or EVs. Levels of DC maturation and activation markers were evaluated by flow cytometry. GAD65-pulsed DCs and autologous CD14− cell were cocultured and IFN-γ enzyme-linked immunosorbent spot responses were assayed. Secreted cytokine levels were measured and Th17 and regulatory T cells were analysed.Results MSC-and EV-conditioned DCs acquired an immature phenotype with reduced levels of activation markers and increased IL-10 and IL-6 production. Conditioned DC plus T cell co-cultures showed significantly decreased IFN-γ spots and secretion levels. Moreover, higher levels of TGF-β, IL-10 and IL-6 were detected compared with unconditioned DC plus T cell co-cultures. Conditioned DCs decreased Th17 cell numbers and IL-17 levels, and increased FOXP3 + regulatory T cell numbers. EVs were internalised by DCs and EV-conditioned DCs exhibited a similar effect. Conclusions/interpretation In type 1 diabetes, MSCs induce immature IL-10-secreting DCs in vitro, thus potentially intercepting the priming and amplification of autoreactive T cells in tissue inflammation. These DCs can contribute to the inhibition of inflammatory T cell responses to islet antigens and the promotion of the anti-inflammatory, regulatory responses exerted by MSCs.

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A prolonged QT interval is considered an indicator of increased risk of malignant ventricular arrhythmias and/or sudden death. It has been proposed that autonomic neuropathy in diabetes is related to QT interval prolongation and increased mortality rates. Several studies in Type 1 and Type 2 diabetic patients have confirmed the independent relation between prolonged QT interval duration or increased QT interval dispersion and chronic ischemic heart disease. It has been consistently shown that autonomic neuropathy is related to QT interval duration while more controversies exist on the association with QT interval dispersion. In recent years, studies have confirmed the value of QT interval as a predictor of total mortality in both diabetic and non-diabetic subjects. Moreover, several studies have shown a significant relation between QT interval prolongation and cardiovascular disease risk factors. QT interval could be used to stratify the cardiovascular risk in diabetic patients. We still do not know why QT interval is prolonged and how this abnormality leads to death. Nevertheless, QT interval is a simple, low-cost measure, easily obtainable without the need of the patient's compliance and which could help to select patients who need second level diagnostic procedures and strict observation.