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

Tetsuya Kubota, Naoto Kubota, Hiroki Kumagai, Shinichi Yamaguchi, Hideki Kozono, Takehiro Takahashi, Mariko Inoue, Shinsuke Itoh, Iseki Takamoto, Takayoshi Sasako, Katsuyoshi Kumagai, Tomoko Kawai, Shinji Hashimoto, Tsuneo Kobayashi, Maki Sato, Kumpei Tokuyama, Satoshi Nishimura, Masaki Tsunoda, Tomohiro Ide, Koji MurakamiTomomi Yamazaki, Osamu Ezaki, Koichi Kawamura, Hirotake Masuda, Masao Moroi, Kaoru Sugi, Yuichi Oike, Hiroaki Shimokawa, Nobuyuki Yanagihara, Masato Tsutsui, Yasuo Terauchi, Kazuyuki Tobe, Ryozo Nagai, Katsuo Kamata, Kenji Inoue, Tatsuhiko Kodama, Kohjiro Ueki, Takashi Kadowaki

Research output: Contribution to journalArticlepeer-review

246 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)294-307
Number of pages14
JournalCell Metabolism
Volume13
Issue number3
DOIs
Publication statusPublished - 2011 Mar 2

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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