title: 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.
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Tetsuya
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authors.lastname: Kubota
authors.forename: Naoto
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authors.lastname: Kubota
authors.forename: Hiroki
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authors.lastname: Kumagai
authors.forename: Shinichi
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authors.forename: Tomoko
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authors.lastname: Kawai
authors.forename: Shinji
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authors.lastname: Hashimoto
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authors.forename: Satoshi
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authors.lastname: Nishimura
authors.forename: Masaki
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authors.lastname: Tsunoda
authors.forename: Tomohiro
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authors.lastname: Ide
authors.forename: Koji
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authors.lastname: Murakami
authors.forename: Tomomi
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authors.lastname: Yamazaki
authors.forename: Osamu
authors.initials: O
authors.lastname: Ezaki
authors.forename: Koichi
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authors.lastname: Kawamura
authors.forename: Hirotake
authors.initials: H
authors.lastname: Masuda
authors.forename: Masao
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authors.lastname: Moroi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Sugi
authors.forename: Yuichi
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authors.lastname: Oike
authors.forename: Hiroaki
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authors.lastname: Shimokawa
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagihara
authors.forename: Masato
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authors.lastname: Tsutsui
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Kazuyuki
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authors.lastname: Tobe
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Katsuo
authors.initials: K
authors.lastname: Kamata
authors.forename: Kenji
authors.initials: K
authors.lastname: Inoue
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000818:Animals; D004041:Dietary Fats; D042783:Endothelial Cells / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D004041:Dietary Fats; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D052250:Nitric Oxide Synthase Type III; D005947:Glucose