Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle.
ABSTRACT In obese patients with type 2 diabetes, insulin delivery to and insulin-dependent glucose uptake by skeletal muscle are delayed and impaired. The mechanisms underlying the delay and impairment are unclear. We demonstrate that impaired insulin signaling in endothelial cells, due to reduced Irs2 expression and insulin-induced eNOS phosphorylation, causes attenuation of insulin-induced capillary recruitment and insulin delivery, which in turn reduces glucose uptake by skeletal muscle. Moreover, restoration of insulin-induced eNOS phosphorylation in endothelial cells completely reverses the reduction in capillary recruitment and insulin delivery in tissue-specific knockout mice lacking Irs2 in endothelial cells and fed a high-fat diet. As a result, glucose uptake by skeletal muscle is restored in these mice. Taken together, our results show that insulin signaling in endothelial cells plays a pivotal role in the regulation of glucose uptake by skeletal muscle. Furthermore, improving endothelial insulin signaling may serve as a therapeutic strategy for ameliorating skeletal muscle insulin resistance.
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ABSTRACT: We previously reported that insulin resistance was induced by the impairment of insulin signaling in the skeletal muscle from heart failure (HF) via NAD(P)H oxidase-dependent oxidative stress. (Pro)renin receptor ((P)RR) is involved in the activation of local renin-angiotensin system and subsequent oxidative stress. We thus examined whether (P)RR inhibitor, handle-region peptide (HRP), could ameliorate insulin resistance in HF after myocardial infarction (MI) by improving oxidative stress and insulin signaling in the skeletal muscle. C57BL6J mice were divided into 4 groups; sham-operated (Sham, n=10), Sham treated with HRP (Sham+HRP, 0.1mg/kg/day, n=10), MI-operated (MI, n=10), and MI treated with HRP (MI+HRP, 0.1 mg/kg/day, n=10). After 4 weeks, MI mice showed left ventricular dysfunction, which was not affected by HRP. (P)RR was upregulated in the skeletal muscle after MI (149% of sham, p<0.05). The decrease in plasma glucose after insulin load was smaller in MI than Sham (21±2 vs. 44±3%, p<0.05), and was greater in MI+HRP (38±2%, p<0.05) than MI. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter-4 translocation were decreased in the skeletal muscle from MI by 48 and 49% of Sham, both of which were ameliorated in MI+HRP. Superoxide production and NAD(P)H oxidase activities were increased in MI, which was inhibited in MI+HRP. HRP ameliorated insulin resistance associated with HF by improving insulin signaling via the inhibition of NAD(P)H oxidase-induced superoxide production in the skeletal muscle. (P)RR pathway is involved in the development of insulin resistance, at least in part, via the impairment of insulin signaling in the skeletal muscle from HF.AJP Endocrinology and Metabolism 07/2014; · 4.09 Impact Factor
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ABSTRACT: Obesity is a risk factor for developing type 2 diabetes and cardiovascular disease and has quickly become a world-wide pandemic with few tangible and safe treatment options. While it is generally accepted that the primary cause of obesity is energy imbalance, i.e., the calories consumed are greater than are utilized, understanding how caloric balance is regulated has proven a challenge. Many "distal" causes of obesity, such as the structural environment, occupation, and social influences, are exceedingly difficult to change or manipulate. Hence, molecular processes and pathways more proximal to the origins of obesity-those that directly regulate energy metabolism or caloric intake-appear to be more feasible targets for therapy. In particular, nitric oxide (NO) is emerging as a central regulator of energy metabolism and body composition. NO bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin resistant patients, and increasing NO output has remarkable effects on obesity and insulin resistance. This review discusses the role of NO in regulating adiposity and insulin sensitivity and places its modes of action into context with the known causes and consequences of metabolic disease.Free radical biology & medicine. 05/2014;
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ABSTRACT: Figure optionsDownload full-size imageDownload high-quality image (364 K)Download as PowerPoint slideFree Radical Biology and Medicine. 01/2014;