Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes. In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance. When insulin resistance is accompanied by dysfunction of pancreatic islet beta-cells - the cells that release insulin - failure to control blood glucose levels results. Abnormalities in beta-cell function are therefore critical in defining the risk and development of type 2 diabetes. This knowledge is fostering exploration of the molecular and genetic basis of the disease and new approaches to its treatment and prevention.

The potential risks and benefits, the profile of adverse events, and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00279045 [ClinicalTrials.gov].).

IL-1β is an important inflammatory mediator of type 2 diabetes (T2D). Here we show that oligomers of islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas during T2D, trigger the Nlrp3 inflammasome and generate mature interleukin (IL)-1β. A T2D therapy, glyburide, suppresses IAPP-mediated IL-1β production in vitro. Processing of IL-1β initiated by IAPP first requires priming, a process that involves glucose metabolism and can be facilitated by minimally oxidized low density lipoprotein. Finally, mice transgenic for human IAPP have increased IL-1β in pancreatic islets, which colocalizes with amyloid and macrophages. Our findings reveal novel mechanisms in the pathogenesis of T2D and treatment of pathology caused by IAPP.

Normal regulation of glucose metabolism is determined by a feedback loop involving the islet β-cell and insulin-sensitive tissues in which tissue sensitivity to insulin determines the magnitude of the β-cell response. When insulin resistance is present, the β-cell maintains normal glucose tolerance by increasing insulin output. It is only when the β-cell is incapable of releasing sufficient insulin in the presence of insulin resistance that glucose levels rise. While β-cell dysfunction has a clear genetic component, environmental changes play a vital role. Modern approaches have also informed regarding the importance of hexoses, amino acids and fatty acids in determining insulin resistance and β-cell dysfunction as well as the potential role of alterations in the microbiome. A number of new treatment approaches have been developed, but more effective therapies that slow the progressive loss of β-cell function are needed. Recent clinical trials have provided important information regarding approaches to prevent and treat type 2 diabetes as well as some of the adverse effects of these interventions. However, additional long-term studies of medications and bariatric surgery are required in order to identify novel approaches to prevention and treatment, thereby reducing the deleterious impact of type 2 diabetes.

BACKGROUND Weight loss is recommended for overweight and obese individuals with type 2 diabetes based on short-term studies, but long-term effects on cardiovascular disease remain unknown. We examined whether intensive lifestyle intervention for weight loss decreased cardiovascular morbidity and mortality in overweight or obese adults with type 2 diabetes. METHODS We randomly assigned 5,145 overweight or obese individuals with type 2 diabetes recruited at 16 US centers to intensive lifestyle intervention (the intervention group), which promoted weight loss through decreased calorie intake and increased physical activity, or diabetes support and education (the control group). The primary outcome was the first post-randomization occurrence of a composite cardiovascular outcome (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalized angina) over a planned maximum follow-up of 13.5 years. RESULTS The trial was stopped early based on a futility analysis when median follow-up was 9.6 years. Weight loss was greater in the intervention group than the control group throughout (8.6% vs. 0.7% at 1 year; 6.0% vs. 3.5% at study end). Intensive lifestyle intervention also produced greater reductions in hemoglobin A1c and greater initial improvements in fitness and all cardiovascular risk factors, except LDL cholesterol. The primary outcome occurred in 403 patients in the intervention group and in 418 in the control group (1.83/100 person-years and 1.92/100 person-years, respectively; hazard ratio 0.95; 95% CI 0.83 to 1.09, p=0.505). CONCLUSION In our study, intensive lifestyle intervention focused on weight loss did not reduce cardiovascular events in overweight or obese adults with type 2 diabetes. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT00017953.)

Progression to diabetes is more common in women with a history of GDM compared with those without GDM history despite equivalent degrees of IGT at baseline. Both intensive lifestyle and metformin are highly effective in delaying or preventing diabetes in women with IGT and a history of GDM.

Insulin resistance is a major feature of NAFLD that, in some patients, can progress to steatohepatitis. Treatments aimed at reducing insulin resistance have had some success, but larger placebo-controlled studies are needed to fully establish the efficacy of these interventions and possibly others in reducing the deleterious effects of fat accumulation in the liver.

Objective-The effectiveness of intentional weight loss in reducing cardiovascular disease (CVD) events in type 2 diabetes is unknown. This report describes one-year changes in CVD risk factors in a trial designed to examine the long-term effects of an intensive lifestyle intervention on the incidence of major CVD events.Research Design and Methods-A multi-centered randomized controlled trial of 5,145 individuals with type 2 diabetes, aged 45-74 years, with body mass index ≥25 kg/m 2 (≥27 kg/m 2 if taking insulin). An Intensive Lifestyle Intervention (ILI) involving group and individual meetings to achieve and maintain weight loss through decreased caloric intake and increased physical activity was compared to a Diabetes Support and Education (DSE) condition.Results-Participants assigned to ILI lost an average 8.6% of their initial weight versus 0.7% in DSE group (p<0.001). Mean fitness increased in ILI by 20.9% versus 5.8% in DSE (p<0.001). A greater proportion of ILI participants had reductions in diabetes, hypertension, and lipid-lowering medicines. Mean HbA 1 c dropped from 7.3% to 6.6% in ILI (p<0.001) versus from 7.3% to 7.2% in DSE. Systolic and diastolic pressure, triglycerides, HDL-cholesterol, and urine albumin/creatinine improved significantly more in ILI than DSE participants (all p<0.01).Conclusions-At 1 year, ILI resulted in clinically significant weight loss in persons with type 2 diabetes. This was associated with improved diabetes control and CVD risk factors and reduced medicine use in ILI versus DSE. Continued intervention and follow-up will determine whether these changes are maintained and will reduce CVD risk.