Impaired Insulin Signaling in Endothelial Cells Reduces Insulin-Induced Glucose Uptake by Skeletal Muscle

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• 作者：Tetsuya Kubota¹ ; ³ ; ⁵ ; ¹⁸ ; Naoto Kubota¹ ; ³ ; ⁶ ; ¹⁸ ; ^{nkubota-tky@umin.ac.jp} ; Hiroki Kumagai¹ ; ¹⁸ ; Shinichi Yamaguchi¹ ; Hideki Kozono¹ ; Takehiro Takahashi¹ ; Mariko Inoue¹ ; ³ ; Shinsuke Itoh¹ ; Iseki Takamoto¹ ; ⁶ ; Takayoshi Sasako¹ ; Katsuyoshi Kumagai¹ ; ⁶ ; Tomoko Kawai¹ ; ³ ; Shinji Hashimoto¹ ; Tsuneo Kobayashi⁷ ; Maki Sato⁸ ; Kumpei Tokuyama⁸ ; Satoshi Nishimura² ; Masaki Tsunoda⁹ ; Tomohiro Ide⁹ ; Koji Murakami⁹ ; Tomomi Yamazaki⁴ ; Osamu Ezaki⁴ ; Koichi Kawamura¹⁰ ; Hirotake Masuda¹⁰ ; Masao Moroi⁵ ; Kaoru Sugi⁵ ; Yuichi Oike¹¹ ; Hiroaki Shimokawa¹² ; Nobuyuki Yanagihara¹³ ; Masato Tsutsui¹⁴ ; Yasuo Terauchi¹⁵ ; Kazuyuki Tobe¹⁶ ; Ryozo Nagai² ; ⁶ ; Katsuo Kamata⁷ ; Kenji Inoue¹⁷ ; Tatsuhiko Kodama⁶ ; ¹⁷ ; Kohjiro Ueki¹ ; ⁶ ; Takashi Kadowaki¹ ; ³ ; ⁶ ; ^{kadowaki-3im@h.u-tokyo.ac.jp}
• 刊名：Cell Metabolism
• 出版年：2011
• 出版时间：2 March 2011
• 年：2011
• 卷：13
• 期：3
• 页码：294-307
• 全文大小：800 K

文摘

Summary

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.