BackgroundType 2 diabetes mellitus (T2DM) is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure.Methods and FindingsWe combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein (TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated to total body measures of glucose uptake. Forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that the gene product is also a regulator of glucose uptake. TXNIP expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM.ConclusionsTXNIP regulates both insulin-dependent and insulin-independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic β-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM.
Background: Myocyte contractile dysfunction occurs in pathological remodeling in association with abnormalities in calcium regulation. Mice with cardiac myocyte-specific overexpression of G␣q develop progressive left ventricular failure associated with myocyte contractile dysfunction and calcium dysregulation. Objective:We tested the hypothesis that myocyte contractile dysfunction in the G␣q mouse heart is mediated by reactive oxygen species, and in particular, oxidative posttranslational modifications, which impair the function of sarcoplasmic reticulum Ca
Background-P wave indices of maximum P wave duration and P wave dispersion have been examined in a broad array of cardiovascular and non-cardiovascular disease states. The P wave indices literature has been highly heterogeneous in the measurement methodologies and the described quality control metrics and the distribution of values.
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