Terauchi Yasuo, 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
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Hongo, Tokyo, Japan.
J Clin Invest. 2007 Jan;117(1):246-57. doi: 10.1172/JCI17645.
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.
葡萄糖激酶（Gck）作为胰岛素分泌的葡萄糖传感器，在喂食标准饲料的小鼠中，β细胞特异性Gck单倍不足（Gck(+/-)）会导致对葡萄糖的胰岛素分泌受损，尽管这些动物的β细胞量正常。当喂食高脂肪（HF）饮食时，野生型小鼠表现出明显的β细胞增生，而Gck(+/-)小鼠尽管表现出相似程度的胰岛素抵抗，但β细胞复制减少且β细胞增生不足。DNA芯片分析显示，与野生型胰岛相比，喂食HF饮食的Gck(+/-)小鼠胰岛中胰岛素受体底物2（Irs2）的表达降低。蛋白质印迹分析证实，与喂食标准饲料的野生型小鼠相比，喂食HF饮食的野生型小鼠胰岛中Irs2表达上调，而与喂食HF饮食的野生型小鼠相比，喂食HF饮食的Gck(+/-)小鼠中Irs2表达降低。喂食HF饮食的Irs2(+/-)小鼠未能显示出β细胞量的充分增加，并且在喂食HF饮食的Gck(+/-)小鼠的β细胞中过表达Irs2可通过增加β细胞量部分预防糖尿病。这些结果表明，Gck和Irs2是响应HF饮食诱导的胰岛素抵抗而发生β细胞增生的关键条件。
