Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Cell Metab. 2011 Mar 2;13(3):294-307. doi: 10.1016/j.cmet.2011.01.018.
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.
在 2 型糖尿病肥胖患者中，胰岛素向骨骼肌的输送以及骨骼肌对胰岛素的依赖型葡萄糖摄取会出现延迟和受损。导致这种延迟和受损的机制尚不清楚。我们证明，内皮细胞中胰岛素信号的延迟和受损，是由于 Irs2 表达减少和胰岛素诱导的 eNOS 磷酸化，导致胰岛素诱导的毛细血管募集和胰岛素输送减弱，进而减少骨骼肌的葡萄糖摄取。此外，在高脂饮食喂养的内皮细胞特异性敲除 Irs2 的组织特异性敲除小鼠中，恢复内皮细胞中胰岛素诱导的 eNOS 磷酸化可完全逆转毛细血管募集和胰岛素输送的减少，从而恢复骨骼肌的葡萄糖摄取。综上所述，我们的结果表明，内皮细胞中的胰岛素信号在调节骨骼肌葡萄糖摄取中起着关键作用。此外，改善内皮细胞的胰岛素信号可能是改善骨骼肌胰岛素抵抗的一种治疗策略。
