Type 2 diabetes mellitus (T2DM) is the most prevalent metabolic disorder characterized by chronic hyperglycemia and an inadequate response to circulatory insulin by peripheral tissues resulting in insulin resistance. Insulin resistance has a complex pathophysiology, and it is contributed to by multiple factors including oxidative stress. Oxidative stress refers to an imbalance between free radical production and the antioxidant system leading to a reduction of peripheral insulin sensitivity and contributing to the development of T2DM via several molecular mechanisms. In this review, we present the molecular mechanisms by which the oxidative milieu contributes to the pathophysiology of insulin resistance and diabetes mellitus.

OBJECTIVE—The presence of insulin resistance and the metabolic syndrome are known risk markers for macrovascular disease in patients with and without type 2 diabetes. This study has examined whether these also were predictors of micro- and macrovascular complications in type 1 diabetic patients participating in the Diabetes Control and Complications Trial (DCCT).RESEARCH DESIGN AND METHODS—International Diabetes Federation (IDF) criteria were used to identify the metabolic syndrome in 1,337 Caucasian DCCT patients at baseline. Insulin resistance was calculated using their estimated glucose disposal rate (eGDR). Insulin dose (units/kg) was also used as a separate marker of insulin resistance.RESULTS—The eGDR (but not insulin dose or metabolic syndrome) at baseline strongly predicted the development of retinopathy, nephropathy, and cardiovascular disease (hazard ratios 0.75, 0.88, and 0.70, respectively, per mg · kg−1 · min−1 change; P < 0.001, P = 0.005, and P = 0.002, respectively). Through mainly weight gain, the prevalence of the metabolic syndrome increased steadily from baseline to year 9 in conventionally treated (from 15.5 to 27.2%) and especially in the intensively treated (from 13.7 to 45.4%) patients.CONCLUSIONS—Higher insulin resistance at baseline in the DCCT (as estimated by eGDR) was associated with increased subsequent risk of both micro- and macrovascular complications. Insulin dose and the presence of IDF-defined metabolic syndrome were poor predictors by comparison. Although intensive treatment was associated with a higher subsequent prevalence of metabolic syndrome, the benefits of improved glycemia appear to outweigh the risks related to development of the metabolic syndrome.

Inflammasomes are large intracellular multi-protein signalling complexes that are formed in the cytosolic compartment as an inflammatory immune response to endogenous danger signals. The formation of the inflammasome enables activation of an inflammatory protease caspase-1, pyroptosis initiation with the subsequent cleaving of the pro-inflammatory cytokines interleukin (IL)-1β and proIL-18 to produce active forms. The inflammasome complex consists of a Nod-like receptor (NLR), the adapter apoptosis-associated speck-like (ASC) protein, and Caspase-1. Dysregulation of NLRP3 inflammasome activation is involved tumor pathogenesis, although its role in cancer development and progression remains controversial due to the inconsistent findings described. In this review, we summarize the current knowledge on the contribution of the NLRP3 inflammasome on potential cancer promotion and therapy.

OBJECTIVE—Debate remains as to whether short- or long-term glycemic instability confers a risk of microvascular complications in addition to that predicted by mean glycemia alone. In this study, we analyzed data from the Diabetes Control and Complications Trial (DCCT) to assess the effect of A1C variability on the risk of retinopathy and nephropathy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS—A1C was collected quarterly during the DCCT in 1,441 individuals. The mean A1C and the SD of A1C variability after stabilization of glycemia (from 6 months onwards) were compared with the risk of retinopathy and nephropathy with adjustments for age, sex, disease duration, treatment group, and baseline A1C. RESULTS—Multivariate Cox regression showed that the variability in A1C added to mean A1C in predicting the risk of development or progression of both retinopathy (hazard ratio 2.26 for every 1% increase in A1C SD [95% CI 1.63–3.14], P < 0.0001) and nephropathy (1.80 [1.37–2.42], P < 0.0001), with the relationship a feature in conventionally treated patients in particular. CONCLUSIONS—This study has shown that variability in A1C adds to the mean value in predicting microvascular complications in type 1 diabetes. Thus, in contrast to analyses of DCCT data investigating the effect of short-term glucose instability on complication risk, longer-term fluctuations in glycemia seem to contribute to the development of retinopathy and nephropathy in type 1 diabetes.

OBJECTIVE—It is not known whether glycemic instability may confer a risk of microvascular complications that is in addition to that predicted by the mean blood glucose (MBG) value alone. This study has analyzed data from the Diabetes Control and Complications Trial (DCCT) to assess the effect of glucose variability on the risk of retinopathy and nephropathy in patients with type 1 diabetes.