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PMID: 17200721 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Glucokinase and IRS-2 are required for compensatory beta cell hyperplasia in response to high-fat diet-induced insulin resistance.

The Journal of clinical investigation ·Vol. 117 ·No. 1 ·2007-01-00 ·Pages 246-57

Terauchi Y, Takamoto I, Kubota N, Matsui J, Suzuki R, Komeda K, Hara A, Toyoda Y, Miwa I, Aizawa S, Tsutsumi S, Tsubamoto Y, Hashimoto S, Eto K, Nakamura A, Noda M, Tobe K, Aburatani H, Nagai R, Kadowaki T

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.

MeSH Terms
Animals Dietary Fats/pharmacology Glucokinase/deficiency,genetics,physiology Humans Hyperplasia Insulin/physiology Insulin Receptor Substrate Proteins Insulin Resistance/physiology Insulin-Secreting Cells/pathology Intracellular Signaling Peptides and Proteins/deficiency,genetics,physiology Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Phosphoproteins/deficiency,genetics,physiology Signal Transduction
Chemicals
Dietary Fats IRS2 protein, human Insulin Insulin Receptor Substrate Proteins Intracellular Signaling Peptides and Proteins Irs2 protein, mouse Phosphoproteins Glucokinase
Authors & Affiliations
20 authors, click to expand affiliations / ORCID
Terauchi Yasuo
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Hongo, Tokyo, Japan.
Takamoto Iseki
Kubota Naoto
Matsui Junji
Suzuki Ryo
Komeda Kajuro
Hara Akemi
Toyoda Yukiyasu
Miwa Ichitomo
Aizawa Shinichi
Tsutsumi Shuichi
Tsubamoto Yoshiharu
Hashimoto Shinji
Eto Kazuhiro
Nakamura Akinobu
Noda Mitsuhiko
Tobe Kazuyuki
Aburatani Hiroyuki
Nagai Ryozo
Kadowaki Takashi
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI17645
Published
2007-01-00
Pages
246-57
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1716196
Subset
IM
Corrections
CommentIn
PMID: 17200709
External Links
PubMed source DOI: 10.1172/JCI17645 PMC Full Text View journal details
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