Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Cell metabolism (Impact Factor: 16.75). 03/2011; 13(3):294-307. DOI: 10.1016/j.cmet.2011.01.018
Source: PubMed

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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    • "Studies have shown that axon guidance is involved in reinnervation of skeletal muscle (Sanes & Covault 1985; Engle 2010), and its related genes appear to be expressed during muscle nerve formation (Phelan & Hollyday 1990). Significantly altered biological pathway insulin signaling and mannose metabolism are also known to be involved in sepsis and related skeletal muscle dysfunction (Xu et al. 2013), and improving endothelial insulin signaling may serve as a therapeutic strategy for ameliorating skeletal muscle insulin resistance (Kubota et al. 2011). Overall, our study offers insights into the molecular mechanisms of skeletal muscle development. "
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    • "In individuals with insulin resistance , the influence of insulin on microvascular perfusion is markedly impaired (Czernichow et al., 2010; Muris et al., 2012), suggesting that insulin regulates glucose uptake and insulin sensitivity via a feedforward mechanism. Consistent with this notion, capillary recruitment and glucose tolerance are impaired in mice with endothelial deletion of Irs-2 (Kubota et al., 2011). In contrast, mice with endothelial cell-specific insulin receptor knockout do not exhibit glucose intolerance (Vicent et al., 2003). "
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    Cell Reports 05/2014; 7(5). DOI:10.1016/j.celrep.2014.04.046 · 7.21 Impact Factor
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    • "Our findings are also consistent with and expand the conclusions reached in studies of Irs2 EC-specific knockouts (Kubota et al., 2011). These workers proposed that reduced insulininduced eNOS phosphorylation in EC-specific Irs2 −/− mice causes insulin resistance via impaired capillary recruitment in skeletal muscle. "
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