Glucokinase and IRS-2 Are Required for Compensatory Beta Cell Hyperplasia in Response to High-fat Diet-induced Insulin Resistance

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2007 Jan 4

PMID 17200721

Citations 160

Authors

Yasuo Terauchi

Iseki Takamoto

Naoto Kubota

Junji Matsui

Ryo Suzuki

Kajuro Komeda

Akemi Hara

Yukiyasu Toyoda

Ichitomo Miwa

Shinichi Aizawa

Shuichi Tsutsumi

Yoshiharu Tsubamoto

Shinji Hashimoto

Kazuhiro Eto

Akinobu Nakamura

Mitsuhiko Noda

Kazuyuki Tobe

Hiroyuki Aburatani

Ryozo Nagai

Takashi Kadowaki

Affiliations

Soon will be listed here.

Abstract

Glucokinase (Gck) functions as a glucose sensor for insulin secretion, and in mice fed standard chow, haploinsufficiency of beta cell-specific Gck (Gck(+/-)) causes impaired insulin secretion to glucose, although the animals have a normal beta cell mass. When fed a high-fat (HF) diet, wild-type mice showed marked beta cell hyperplasia, whereas Gck(+/-) mice demonstrated decreased beta cell replication and insufficient beta cell hyperplasia despite showing a similar degree of insulin resistance. DNA chip analysis revealed decreased insulin receptor substrate 2 (Irs2) expression in HF diet-fed Gck(+/-) mouse islets compared with wild-type islets. Western blot analyses confirmed upregulated Irs2 expression in the islets of HF diet-fed wild-type mice compared with those fed standard chow and reduced expression in HF diet-fed Gck(+/-) mice compared with those of HF diet-fed wild-type mice. HF diet-fed Irs2(+/-) mice failed to show a sufficient increase in beta cell mass, and overexpression of Irs2 in beta cells of HF diet-fed Gck(+/-) mice partially prevented diabetes by increasing beta cell mass. These results suggest that Gck and Irs2 are critical requirements for beta cell hyperplasia to occur in response to HF diet-induced insulin resistance.

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