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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

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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 6

Transgenic rescue by crossing Gck+/– mice with βIrs2Tg mice.

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Transgenic rescue by crossing Gck+/– mice with βIrs2Tg mice.
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(A and B) Glucose tolerance in wild-type, Gck+/–, βIrs2Tg, and βIrs2TgGck+/– mice after 20 weeks on HF diet. (A) Plasma glucose levels. (B) Serum insulin levels. n = 31 (wild-type), 20 (βIrs2Tg), 35 (Gck+/–), 16 (βIrs2TgGck+/–). *P < 0.05, Gck+/– versus βIrs2TgGck+/–. (C) Histologic analysis of wild-type, Gck+/–, βIrs2Tg, and βIrs2TgGck+/– mouse islets after 20 weeks on HF diet. Representative pancreatic islets are shown. Top panels show insulin staining; bottom panels show BrdU staining. Scale bars: 100 μm. Original magnification, ×100 (top panels); ×400 (bottom panels). (D) Area of β cells in each islet after 20 weeks on HF diet. We examined 100–150 islets from 3 animals per group. (E) Replication rate of β cells, assayed on the basis of BrdU incorporation after 20 weeks on HF diet. Results are shown as ratios of insulin and BrdU double-positive cells to insulin-positive cells (n = 4). (F) Static incubation study of islets after 20 weeks on the HF diet. Static incubation of 10 islets/tube was performed at 37°C for 1 hour with various glucose concentrations after preincubation with a 2.8-mM glucose concentration for 20 minutes. Results are shown as pg insulin/cell/h (n = 4). Values represent mean ± SEM. *P < 0.05; **P < 0.01.
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