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Islet Studies

Insulin Receptor Substrate-2 (Irs2) in Endothelial Cells Plays a Crucial Role in Insulin Secretion

  1. Shinji Hashimoto1,
  2. Naoto Kubota1,2,3,4,
  3. Hiroyuki Sato1,
  4. Motohiro Sasaki1,
  5. Iseki Takamoto1,2,
  6. Tetsuya Kubota1,3,4,5,
  7. Keizo Nakaya1,
  8. Mitsuhiko Noda6,
  9. Kohjiro Ueki1,2 and
  10. Takashi Kadowaki1,2,3⇑
  1. 1Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  2. 2Translational Systems Biology and Medicine Initiative (TSBMI), The University of Tokyo, Tokyo, Japan
  3. 3Clinical Nutrition Program, National Institute of Health and Nutrition, Tokyo, Japan
  4. 4Laboratory for Metabolic Homeostasis, Rikagaku Kenkyusho (RIKEN) Center for Integrative Medical Sciences, Kanagawa, Japan
  5. 5Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo, Japan
  6. 6Department of Diabetes Research, National Center for Global Health and Medicine, Tokyo, Japan
  1. Corresponding authors: Takashi Kadowaki, kadowaki-3im{at}h.u-tokyo.ac.jp, and Naoto Kubota, nkubota-tky{at}umin.ac.jp.
  1. S.H. and N.K. contributed equally to this work.

Diabetes 2015 Mar; 64(3): 876-886. https://doi.org/10.2337/db14-0432
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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.

  • Received March 16, 2014.
  • Accepted September 11, 2014.
  • © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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Insulin Receptor Substrate-2 (Irs2) in Endothelial Cells Plays a Crucial Role in Insulin Secretion
Shinji Hashimoto, Naoto Kubota, Hiroyuki Sato, Motohiro Sasaki, Iseki Takamoto, Tetsuya Kubota, Keizo Nakaya, Mitsuhiko Noda, Kohjiro Ueki, Takashi Kadowaki
Diabetes Mar 2015, 64 (3) 876-886; DOI: 10.2337/db14-0432

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Insulin Receptor Substrate-2 (Irs2) in Endothelial Cells Plays a Crucial Role in Insulin Secretion
Shinji Hashimoto, Naoto Kubota, Hiroyuki Sato, Motohiro Sasaki, Iseki Takamoto, Tetsuya Kubota, Keizo Nakaya, Mitsuhiko Noda, Kohjiro Ueki, Takashi Kadowaki
Diabetes Mar 2015, 64 (3) 876-886; DOI: 10.2337/db14-0432
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