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.
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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