Insulin resistance plays an important role in the pathophysiology of diabetes and is associated with obesity and other cardiovascular risk factors. The "gold standard" glucose clamp and minimal model analysis are two established methods for determining insulin sensitivity in vivo, but neither is easily implemented in large studies. Thus, it is of interest to develop a simple, accurate method for assessing insulin sensitivity that is useful for clinical investigations. We performed both hyperinsulinemic isoglycemic glucose clamp and insulin-modified frequently sampled iv glucose tolerance tests on 28 nonobese, 13 obese, and 15 type 2 diabetic subjects. We obtained correlations between indexes of insulin sensitivity from glucose clamp studies (SI(Clamp)) and minimal model analysis (SI(MM)) that were comparable to previous reports (r = 0.57). We performed a sensitivity analysis on our data and discovered that physiological steady state values [i.e. fasting insulin (I(0)) and glucose (G(0))] contain critical information about insulin sensitivity. We defined a quantitative insulin sensitivity check index (QUICKI = 1/[log(I(0)) + log(G(0))]) that has substantially better correlation with SI(Clamp) (r = 0.78) than the correlation we observed between SI(MM) and SI(Clamp). Moreover, we observed a comparable overall correlation between QUICKI and SI(Clamp) in a totally independent group of 21 obese and 14 nonobese subjects from another institution. We conclude that QUICKI is an index of insulin sensitivity obtained from a fasting blood sample that may be useful for clinical research.

BackgroundThe worldwide epidemic of type 2 diabetes requires effective prevention. We determined the long-term extent of beneficial effects of lifestyle intervention and metformin on diabetes prevention, originally demonstrated during the 3-year Diabetes Prevention Program (DPP), and whether diabetes-associated microvascular complications are reduced.MethodsThe DPP (1996–2001) was a randomized trial comparing an intensive lifestyle intervention or masked metformin with placebo in a cohort selected to be at very high risk to develop diabetes. All participants were offered lifestyle training at DPP-end. 2776 (88%) of the surviving DPP cohort were followed in the DPP Outcome Study (DPPOS 2002–2013) and analyzed by intention-to-treat based on original DPP assignment. During DPPOS, the lifestyle group was offered lifestyle reinforcement semi-annually and the metformin group received unmasked metformin.FindingsDuring 15 years of average follow-up, lifestyle intervention and metformin reduced diabetes incidence rates by 27% (p<0.0001) and 18% (p=0.001), respectively, compared with the placebo group, with declining between group differences over time. At year 15, the cumulative incidences of diabetes were 55, 56 and 62%, respectively. The prevalences at study-end of the aggregate microvascular outcome, composed of nephropathy, neuropathy, and retinopathy, were not significantly different among the treatment groups (11–13%) in the total cohort. However, in women (n=1887) lifestyle intervention was associated with a lower prevalence (8.7%) than in the placebo (11%) and metformin (11.2%) groups, with 21% (p=0.03) and 22% (p=0.02) reductions with lifestyle compared with placebo and metformin, respectively. Compared with participants who progressed to diabetes, those who didn’t progress had a 28% lower prevalence of microvascular complications (p<0.0001).InterpretationLifestyle intervention or metformin significantly reduce diabetes development over 15 years. There were no overall differences in the aggregate microvascular outcome among treatment groups; however, those who did not progress to diabetes had a lower prevalence of microvascular complications than those who progressed.FundingNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Background Our objective was to quantify and predict diabetes risk reduction during the Diabetes Prevention Program Outcomes Study (DPPOS) among those who returned to normal glucose regulation (NGR) at least once during DPP compared to those who were consistently considered to have pre-diabetes. Methods Diabetes cumulative incidence in DPPOS was calculated for subjects with NGR or pre-diabetes status during DPP with and without stratification by prior randomized treatment group. Cox proportional hazards modeling and generalized linear mixed models were used to quantify the impact of previous (DPP) glycemic status on risk of later (DPPOS) diabetes and NGR status, respectively, per standard deviation in change. Included in this analysis are 1990 participants of DPPOS (who had been randomized during DPP: N=736 in intensive lifestyle (ILS), N=647 to metformin (MET), and N=607 to placebo (PLB)). Findings Diabetes risk during DPPOS was 56% lower in NGR vs. pre-diabetes (HR=0.44, 95% CI 0.37-0.55, p<0.0001) and was unaffected by prior group assignment (interaction test for NGR*ILS, p=0.1722; NGR*MET, p=0.3304). Many, but not all, of the variables that increased diabetes risk were inversely associated with the chance of reaching NGR status in DPPOS. Specifically, having had prior NGR (OR=3.18, 95% CI 2.71-3.72, p<0.0001), higher β-cell function (OR=1.28; 95% CI 1.18-1.39, p<0.0001) and insulin sensitivity (OR=1.16, 95% CI 1.08-1.25, p<0.0001) were associated with NGR in DPPOS, whereas the opposite was true for predicting diabetes (HR=0.80, 95% CI 0.71-0.89; HR=0.83, 95% CI 0.74-0.94, respectively, p<0.0001 for both). Surprisingly, among subjects who failed to return to NGR in DPP, those randomized to ILS had a higher diabetes risk (HR=1.31, 95% CI 1.03-1.68, p=0.0304) and lower chance of NGR (OR=0.59, 95% CI 0.42-0.82, p=0.0014) vs. placebo in DPPOS. Interpretation We conclude that pre-diabetes represents a high-risk state for diabetes, especially among those who remain so despite ILS. Reversion to NGR, even if transient, is associated with a significantly lower risk of future diabetes independent of prior treatment group.

Three hours of sitting resulted in a significant impairment in shear rate and SFA FMD. When light activity breaks were introduced hourly during sitting, the decline in FMD was prevented.

Metformin treatment improved both insulin resistance and endothelial function, with a strong statistical link between these variables. This supports the concept of the central role of insulin resistance in the pathogenesis of endothelial dysfunction in type 2 diabetes mellitus. This has important implications for the investigation and treatment of vascular disease in patients with type 2 diabetes mellitus.

OBJECTIVEThis article examines the foundation of β-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment.RESEARCH DESIGN AND METHODSA group of experts participated in a conference on 14–16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations.RESULTSThe writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of β-cell failure, natural history of β-cell failure, and impact of therapeutic interventions.CONCLUSIONSβ-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased β-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to 1) impact the natural history of β-cell failure; 2) identify and characterize genetic loci for T2D; 3) target β-cell signaling, metabolic, and genetic pathways to improve function/mass; 4) develop alternative sources of β-cells for cell-based therapy; 5) focus on metabolic environment to provide indirect benefit to β-cells; 6) improve understanding of the physiology of responses to bypass surgery; and 7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and β-cells.

The metabolic syndrome (MetS) is defined as the concurrence of obesity-associated cardiovascular risk factors including abdominal obesity, impaired glucose tolerance, hypertriglyceridemia, decreased HDL cholesterol, and/or hypertension. Earlier conceptualizations of the MetS focused on insulin resistance as a core feature, and it is clearly coincident with the above list of features. Each component of the MetS is an independent risk factor for cardiovascular disease and the combination of these risk factors elevates rates and severity of cardiovascular disease, related to a spectrum of cardiovascular conditions including microvascular dysfunction, coronary atherosclerosis and calcification, cardiac dysfunction, myocardial infarction, and heart failure. While advances in understanding the etiology and consequences of this complex disorder have been made, the underlying pathophysiologic mechanisms remain incompletely understood, and it is unclear how these concurrent risk factors conspire to produce the variety of obesity-associated adverse cardiovascular diseases. In this review we highlight current knowledge regarding the pathophysiologic consequences of obesity and the MetS on cardiovascular function and disease, including considerations of potential physiologic and molecular mechanisms that may contribute to these adverse outcomes.

Twice-weekly evoked RT to the paralyzed lower extremities resulted in significant skeletal muscle hypertrophy that was associated with reduction in VAT, VAT/subcutaneous adipose tissue ratio, and percent IMF. Significant improvements in insulin profile and lipid metabolism were noted in the RT + diet when compared with diet alone.