Glucokinase and IRS-2 are required for compensatory β cell hyperplasia in response to high-fat diet–induced insulin resistance
Yasuo Terauchi, … , Ryozo Nagai, Takashi Kadowaki
Yasuo Terauchi, … , Ryozo Nagai, Takashi Kadowaki
Published January 2, 2007
Citation Information: J Clin Invest. 2007;117(1):246-257. https://doi.org/10.1172/JCI17645.
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Category: Research Article

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

Abstract

Glucokinase (Gck) functions as a glucose sensor for insulin secretion, and in mice fed standard chow, haploinsufficiency of β cell–specific Gck (Gck+/–) causes impaired insulin secretion to glucose, although the animals have a normal β cell mass. When fed a high-fat (HF) diet, wild-type mice showed marked β cell hyperplasia, whereas Gck+/– mice demonstrated decreased β cell replication and insufficient β 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 β cell mass, and overexpression of Irs2 in β cells of HF diet–fed Gck+/– mice partially prevented diabetes by increasing β cell mass. These results suggest that Gck and Irs2 are critical requirements for β cell hyperplasia to occur in response to HF diet–induced insulin resistance.

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

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Figure 2

Failure of compensatory β cell hyperplasia in HF diet–fed Gck+/– mice caused by decreased β cell replication rate.

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Failure of compensatory β cell hyperplasia in HF diet–fed Gck+/– mice ca...
(A) Histologic analysis of pancreatic islets of wild-type and Gck+/– mice after 20 weeks on standard chow or HF diet. Sections were double stained with anti-insulin antibody and a cocktail of anti-glucagon, anti-somatostatin, and anti-pancreatic polypeptide antibodies. Representative islets are shown. Red stain, β cells; brown stain, non–β cells. Scale bars: 100 μm. (B) Quantitation of β cell and non–β cell mass in wild-type and Gck+/– mice after 20 weeks on standard chow or HF diet. Areas of β or non–β cells (α, δ, and pancreatic polypeptide cells) are shown relative to total pancreas area (n = 4). (C) Changes in β cell mass on HF diet. Shown is β cell area relative to pancreas area (n = 4) after 4, 20, and 40 weeks on HF diet. (D) Number of cells in wild-type and Gck+/– mouse islets after 20 weeks on standard chow or HF diet (n = 6). (E and F) Replication rate of β cells, assayed (E) on the basis of BrdU incorporation after 20 weeks on standard chow or HF diet or (F) by PCNA staining after 20 weeks on HF diet. Results are shown as ratios of double-positive cells to insulin-positive cells (n = 4). Values represent mean ± SEM. *P < 0.05; **P < 0.01.