title: Insulin receptor substrate-2 (Irs2) in endothelial cells plays a crucial role in insulin secretion.
abstract: Endothelial cells are considered to be essential for normal pancreatic β-cell function. The current study attempted to demonstrate the role of insulin receptor substrate-2 (Irs2) in endothelial cells with regard to insulin secretion. Endothelial cell-specific Irs2 knockout (ETIrs2KO) mice exhibited impaired glucose-induced, arginine-induced, and glucagon-induced insulin secretion and showed glucose intolerance. In batch incubation and perifusion experiments using isolated islets, glucose-induced insulin secretion was not significantly different between the control and the ETIrs2KO mice. In contrast, in perfusion experiments, glucose-induced insulin secretion was significantly impaired in the ETIrs2KO mice. The islet blood flow was significantly impaired in the ETIrs2KO mice. After the treatment of these knockout mice with enalapril maleate, which improved the islet blood flow, glucose-stimulated insulin secretion was almost completely restored to levels equal to those in the control mice. These data suggest that Irs2 deletion in endothelial cells leads to a decreased islet blood flow, which may cause impaired glucose-induced insulin secretion. Thus, Irs2 in endothelial cells may serve as a novel therapeutic target for preventing and ameliorating type 2 diabetes and metabolic syndrome.
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Hashimoto
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Translational Systems Biology and Medicine Initiative (TSBMI), The University of Tokyo, Tokyo, Japan Clinical Nutrition Program, National Institute of Health and Nutrition, Tokyo, Japan Laboratory for Metabolic Homeostasis, Rikagaku Kenkyusho (RIKEN) Center for Integrative Medical Sciences, Kanagawa, Japan kadowaki-3im@h.u-tokyo.ac.jp nkubota-tky@umin.ac.jp.
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Translational Systems Biology and Medicine Initiative (TSBMI), The University of Tokyo, Tokyo, Japan.
authors.forename: Iseki
authors.initials: I
authors.lastname: Takamoto
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Clinical Nutrition Program, National Institute of Health and Nutrition, Tokyo, Japan Laboratory for Metabolic Homeostasis, Rikagaku Kenkyusho (RIKEN) Center for Integrative Medical Sciences, Kanagawa, Japan Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kubota
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Nakaya
authors.affiliation: Department of Diabetes Research, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Noda
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Translational Systems Biology and Medicine Initiative (TSBMI), The University of Tokyo, Tokyo, Japan.
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Translational Systems Biology and Medicine Initiative (TSBMI), The University of Tokyo, Tokyo, Japan Clinical Nutrition Program, National Institute of Health and Nutrition, Tokyo, Japan kadowaki-3im@h.u-tokyo.ac.jp nkubota-tky@umin.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D004656:Enalapril / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D004656:Enalapril