Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.

Type 2 Diabetes Mellitus (HEART2D) is a multinational, randomized, controlled trial designed to compare the effects of prandial versus fasting glycemic control on risk for cardiovascular outcomes in patients with type 2 diabetes after acute myocardial infarction (AMI).RESEARCH DESIGN AND METHODS -Patients (type 2 diabetes, aged 30 -75 years) were randomly assigned within 21 days after AMI to the 1) prandial strategy (PRANDIAL) (three premeal doses of insulin lispro targeting 2-h postprandial blood glucose Ͻ7.5 mmol/l) or the 2) basal strategy (BASAL) (NPH twice daily or insulin glargine once daily targeting fasting/premeal blood glucose Ͻ6.7 mmol/l).RESULTS -A total of 1,115 patients were randomly assigned (PRANDIAL n ϭ 557; BASAL n ϭ 558), and the mean patient participation after randomization was 963 days (range 1-1,687 days). The trial was stopped for lack of efficacy. Risks of first combined adjudicated primary cardiovascular events in the PRANDIAL (n ϭ 174, 31.2%) and BASAL (n ϭ 181, 32.4%) groups were similar (hazard ratio 0.98 [95% CI 0.8 -1.21]). Mean A1C did not differ between the PRANDIAL and BASAL groups (7.7 Ϯ 0.1 vs. 7.8 Ϯ 0.1%; P ϭ 0.4) during the study. The PRANDIAL group showed a lower daily mean postprandial blood glucose (7.8 vs. 8.6 mmol/l; P Ͻ 0.01) and 2-h postprandial blood glucose excursion (0.1 vs. 1.3 mmol/l; P Ͻ 0.001) versus the BASAL group. The BASAL group showed lower mean fasting blood glucose (7.0 vs. 8.1 mmol/l; P Ͻ 0.001) and similar daily fasting/premeal blood glucose (7.7 vs. 7.3 mmol/l; P ϭ 0.233) versus the PRANDIAL group.CONCLUSIONS -Treating diabetic survivors of AMI with prandial versus basal strategies achieved differences in fasting blood glucose, less-than-expected differences in postprandial blood glucose, similar levels of A1C, and no difference in risk for future cardiovascular event rates.

In vitro studies revealed that insulin resistance might be associated with the intracellular formation of ceramide, the second messenger in the sphingomyelin signaling pathway. The aim of the present study was to examine the content and composition of fatty acids in ceramide and sphingomyelin in human muscle and to evaluate their relationships with insulin sensitivity. The study was conducted on 27 male subjects with normal glucose tolerance. Euglycemic-hyperinsulinemic clamps and biopsies of vastus lateralis muscle were performed. In 10 subjects, additional biopsies were taken after a 4-h clamp and after a clamp with concurrent Intralipid/ heparin infusion. We identified 13 ceramides and sphingomyelins according to fatty acid residues. Insulin sensitivity was related to total ceramide content (r ‫؍‬ ؊0.49, P ‫؍‬ 0.01) and to ceramide consisting of palmitic (r ‫؍‬ ؊0.48, P ‫؍‬ 0.011), palmitoleic (r ‫؍‬ ؊0.45, P ‫؍‬ 0.019), mirystic (r ‫؍‬ ؊0.42, P ‫؍‬ 0.028), and nervonic acid (r ‫؍‬ ؊0.39, P ‫؍‬ 0.047). Hyperinsulinemia did not affect estimated muscle parameters. Intralipid/heparin infusion resulted in a 24.73% decrease in insulin sensitivity (P ‫؍‬ 0.007) and a 47.81% increase in ceramide content (P ‫؍‬ 0.005). These changes were significantly related to each other (r ‫؍‬ ؊0.64, P ‫؍‬ 0.046). A relationship with the decrease in insulin sensitivity was also observed for ceramides consisting of palmitic (r ‫؍‬ ؊0.68, P ‫؍‬ 0.03) and linoleic (r ‫؍‬ ؊0.66, P ‫؍‬ 0.038) acid. Our data indicate that the sphingomyelin signaling pathway in muscle might be an important factor determining the development of insulin resistance in humans.

Aims/hypothesis Intramyocellular lipids, including ceramide, a second messenger in the sphingomyelin signalling pathway, might contribute to the development of insulin resistance. The aim of our study was to assess parameters of the skeletal muscle sphingomyelin signalling pathway in men at risk of developing type 2 diabetes. Methods We studied 12 lean (BMI<25 kg/m 2 ) men without a family history of diabetes (control group), 12 lean male offspring of type 2 diabetic patients, and 21 men with overweight or obesity comprising 12 with NGT (obese-NGT) and nine with IGT (obese-IGT). A euglycaemic-hyperinsulinaemic clamp and a biopsy of vastus lateralis muscle were performed. Ceramide, sphingomyelin, sphinganine and sphingosine levels and sphingomyelinase and ceramidase activities were measured in muscle. Muscle diacylglycerol and triacylglycerol levels were estimated in a subgroup of 27 men (comprising men from all the above groups). Results Compared with the control group, the lean offspring of diabetic patients and the men with overweight or obesity showed lower insulin sensitivity (all p<0.005) and a greater muscle ceramide level (all p<0.01). The obese-IGT group had lower insulin sensitivity (p=0.0018) and higher muscle ceramide (p=0.0022) than the obese-NGT group. There was lower muscle sphingosine level and alkaline ceramidase activity in offspring of diabetic patients (p=0.038 and p=0.031, respectively) and higher sphinganine level in the obese-NGT (p=0.049) and obese-IGT (p=0.002) groups than in the control group. Muscle sphingomyelin was lower (p=0.0028) and neutral sphingomyelinase activity was higher (p=0.00079) in the obese-IGT than in the obese-NGT group. Muscle ceramide was related to insulin sensitivity independently of other muscle lipid fractions. Conclusions/interpretations Ceramide accumulates in muscle of men at risk of developing type 2 diabetes.

Obesity is associated with the increased risk of cardiovascular disease; however, mechanisms responsible for such an increase are not fully understood. IL-8 is a cytokine that might have atherogenic properties. Recent in vitro studies revealed that IL-8 is produced and secreted by human adipocytes. The aim of the present study was to evaluate plasma IL-8 concentrations in obese subjects and the relationships between circulating IL-8 and anthropometric and biochemical parameters and TNF-alpha system. A total of 75 subjects with normal glucose tolerance, 35 lean and 40 obese, were recruited for this study. Plasma IL-8 levels were measured in fasting state, after an oral glucose tolerance test and after the euglycemic hyperinsulinemic clamp. A significant increase in plasma IL-8 was observed in the obese group. In simple regression analysis, performed for the initial evaluation of relationships, plasma IL-8 was related to body mass index, percentage of body fat, fat mass (FM), and soluble TNF-alpha receptor 2 (sTNFR2) in both groups and with waist-to-hip ratio and sTNFR1 in the obese. In multiple regression analysis, FM, waist-to-hip ratio, gender, sTNFR2, and low density lipoprotein cholesterol were responsible for 44% of IL-8 variability. During oral glucose tolerance testing, mean plasma IL-8 concentrations increased in both groups, whereas clamp resulted in a significant increase in plasma IL-8 only in the obese. We conclude that plasma IL-8 levels are increased in obese subjects, and are related to FM and TNF-alpha system. Increase in circulating IL-8 might be one of the factors linking obesity with greater cardiovascular risk.