The steep rise of type 2 diabetes mellitus (T2DM) and associated complications go along with mounting evidence of clinically important sex and gender differences. T2DM is more frequently diagnosed at lower age and body mass index in men; however, the most prominent risk factor, which is obesity, is more common in women. Generally, large sex-ratio differences across countries are observed. Diversities in biology, culture, lifestyle, environment, and socioeconomic status impact differences between males and females in predisposition, development, and clinical presentation. Genetic effects and epigenetic mechanisms, nutritional factors and sedentary lifestyle affect risk and complications differently in both sexes. Furthermore, sex hormones have a great impact on energy metabolism, body composition, vascular function, and inflammatory responses. Thus, endocrine imbalances relate to unfavorable cardiometabolic traits, observable in women with androgen excess or men with hypogonadism. Both biological and psychosocial factors are responsible for sex and gender differences in diabetes risk and outcome. Overall, psychosocial stress appears to have greater impact on women rather than on men. In addition, women have greater increases of cardiovascular risk, myocardial infarction, and stroke mortality than men, compared with nondiabetic subjects. However, when dialysis therapy is initiated, mortality is comparable in both males and females. Diabetes appears to attenuate the protective effect of the female sex in the development of cardiac diseases and nephropathy. Endocrine and behavioral factors are involved in gender inequalities and affect the outcome. More research regarding sex-dimorphic pathophysiological mechanisms of T2DM and its complications could contribute to more personalized diabetes care in the future and would thus promote more awareness in terms of sex- and gender-specific risk factors.

OBJECTIVE -Available insulin sensitivity (IS) methods based on the oral glucose tolerance test (OGTT) are empirical. We used a glucose-insulin model to derive an OGTT-based IS (oral glucose insulin sensitivity [OGIS]) index, which predicts glucose clearance in a glucose clamp. We validated OGIS against clamp data.RESEARCH DESIGN AND METHODS -OGIS requires glucose and insulin concentrations from a 75-g OGTT at 0, 2, and 3 h (3-h OGTT) or at 0, 1.5, and 2 h (2-h OGTT). The formula includes six constants optimized to match the clamp results. For this purpose, 15 lean nondiabetic subjects (BMI Ͻ 25 kg/m 2 ), 38 obese nondiabetic subjects (BMI Ͼ 25 kg/m 2 ), and 38 subjects with type 2 diabetes randomly underwent an OGTT and a 120 mU ⅐ min Ϫ1 ⅐ m Ϫ2insulin infusion euglycemic clamp. Glucose clearance (Cl CLAMP ), calculated as the ratio of glucose infusion to concentration during the last hour of the clamp, was compared with OGIS. OGIS was also tested on an independent group of 13 subjects with impaired glucose tolerance (IGT).RESULTS -OGIS and Cl CLAMP were correlated in the whole group (R ϭ 0.77, P Ͻ 0.0001), in the subgroups (lean: R ϭ 0.59; obese: R ϭ 0.73; type 2 diabetes: R ϭ 0.49; P Ͻ 0.02), and in the independent IGT group (R ϭ 0.65, P Ͻ 0.02). Reproducibility of OGIS and Cl CLAMP were similar (coefficients of variation: OGIS 7.1%, Cl CLAMP 6.4%). OGIS was as effective as Cl CLAMP in discriminating between groups (for OGIS, lean vs. obese: 440 Ϯ 16 vs. 362 Ϯ 11 ml ⅐ min Ϫ1⅐ m Ϫ2 , P Ͻ 0.001; lean vs. type 2 diabetes: 440 Ϯ 16 vs. 239 Ϯ 7, P Ͻ 0.0001; obese vs. type 2 diabetes: 362 Ϯ 11 vs. 239 Ϯ 7, P Ͻ 0.0001; results were similar for Cl CLAMP ). The relationships between IS and BMI, fasting plasma insulin, and insulin secretion (calculated from the OGTT insulin concentration) were examined. OGIS yielded results similar to Cl CLAMP and fully consistent with established physiological principles. The performance of the index for the 3-h and 2-h OGTT was similar.CONCLUSIONS -OGIS is an index of IS in good agreement with the clamp. Because of its simplicity (only three blood samples required), this method has potential use for clinical investigation including large-scale epidemiological studies. Diabetes Care 24:539 -548, 2001

A consensus meeting was held in Vienna on September 8–9, 2013, to discuss diagnostic and therapeutic challenges surrounding development of diabetes mellitus after transplantation. The International Expert Panel comprised 24 transplant nephrologists, surgeons, diabetologists and clinical scientists, which met with the aim to review previous guidelines in light of emerging clinical data and research. Recommendations from the consensus discussions are provided in this article. Although the meeting was kidney-centric, reflecting the expertise present, these recommendations are likely to be relevant to other solid organ transplant recipients. Our recommendations include: terminology revision from new-onset diabetes after transplantation to posttransplantation diabetes mellitus (PTDM), exclusion of transient posttransplant hyperglycemia from PTDM diagnosis, expansion of screening strategies (incorporating postprandial glucose and HbA1c) and opinion-based guidance regarding pharmacological therapy in light of recent clinical evidence. Future research in the field was discussed with the aim of establishing collaborative working groups to address unresolved questions. These recommendations are opinion-based and intended to serve as a template for planned guidelines update, based on systematic and graded literature review, on the diagnosis and management of PTDM.

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.

No abstract

No abstract

OBJECTIVE -To examine the effects of dipeptidyl peptidase-IV (DPP-4) inhibition on meal-related ␤-cell function and insulin sensitivity over 52 weeks in type 2 diabetes. RESEARCH DESIGN AND METHODS-In a 12-week core study, placebo (n ϭ 51) or vildagliptin (n ϭ 56; 50 mg OD) was added to metformin treatment (1.5-3.0 mg/day). A 40-week extension followed in 71 patients. Meal tests were performed at 0, 12, 24, and 52 weeks; glucose, insulin, and C-peptide were evaluated.RESULTS -In subjects completing 52 weeks with participation in all meal tests (n ϭ 57), HbA 1c (A1C) decreased in the vildagliptin/metformin group (VM group, n ϭ 31) but increased in the placebo/metformin group (PM group, n ϭ 26; between-group difference Ϫ1.0 Ϯ 0.2%; P Ͻ 0.001; baseline of all subjects combined 7.7 Ϯ 0.1%). Also, fasting glucose decreased in the VM group but increased in the PM group (difference Ϫ0.9 Ϯ 0.3 mmol/l, P ϭ 0.016; baseline 9.8 Ϯ 0.3 mmol/l). Insulin secretion (postmeal suprabasal area under the 0-to 30-min C-peptide curve divided by the 30-min increase in glucose) was increased in the VM group but was reduced in the PM group (difference ϩ0.011 Ϯ 0.03 pmol/l 30 min/mmol/l, P ϭ 0.018; baseline 0.036 Ϯ 0.02). Insulin sensitivity during meal ingestion (oral glucose insulin sensitivity) increased in the VM group but was not altered in the PM group (difference ϩ27 Ϯ 4 ml ⅐ min Ϫ1 ⅐ m Ϫ2 , P ϭ 0.036; baseline 246 Ϯ 6). Insulin secretion related to insulin sensitivity (adaptation index) increased in the VM group but decreased in the PM group (difference ϩ3.2 Ϯ 1.0, P ϭ 0.040; baseline 9.1 Ϯ 0.5). The change in adaptation index correlated to the change in A1C (r ϭ Ϫ0.39, P ϭ 0.004).CONCLUSIONS -This study presents evidence that DPP-4 inhibition by vildagliptin when added to metformin in type 2 diabetes over 52 weeks improves ␤-cell function along with improved postmeal insulin sensitivity. Diabetes Care 28:1936 -1940, 2005T he enzyme dipeptidyl peptidase-IV (DPP-4) inactivates glucagon-like peptide-1 (GLP-1) (1). Since GLP-1 has antidiabetic actions (2), prevention of its inactivation by DPP-4 inhibition is currently explored as a novel approach for treatment of type 2 diabetes (3). DPP-4 inhibition thereby shows antidiabetic action both in animal models of diabetes (4 -6) and in patients with type 2 diabetes (7-9).One of the DPP-4 inhibitors in clinical development is vildagliptin (previously called LAF237) (10). Vildagliptin has thus been shown to inhibit plasma DPP-4 activity, increase circulating levels of intact GLP-1, and improve glycemic control in diabetic patients (8,9). Although several mechanisms may contribute to the improved metabolic control by DPP-4 inhibition, in comparison to the actions of GLP-1 (2), previous studies have indicated the importance of increased insulin secretion. Thus, a standardized meal test performed before and after 28 days of treatment with the DPP-4 inhibitors NVPDPP728 and vildagliptin showed sustained insulin levels in the presence of reduced circulating glycemia in drug-naïve patients (7,8...

No abstract