| Project/Area Number |
16390263
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | The University of Tokyo |
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Principal Investigator |
YAMAUCHI toshimasa The University of Tokyo, Faculty of Medicine, Visiting Associate Professor, 医学部附属病院, 客員助教授 (40372370)
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| Co-Investigator(Kenkyū-buntansha) |
TERAUCHI Yasuo Yokohama City University, Faculty of Medicine, Professor, 医学部附属病院, 教授 (40359609)
KUBOTA Naoto The University of Tokyo, Faculty of Medicine, Visiting Research Associate, 医学部附属病院, 客員助手 (50396719)
TOBE Kazuyuki The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (30251242)
HARA Kazuo The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (50359600)
KADOWAKI Takashi The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (30185889)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥14,400,000 (Direct Cost: ¥14,400,000)
Fiscal Year 2005: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 2004: ¥8,900,000 (Direct Cost: ¥8,900,000)
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| Keywords | IRS-1 / IRS-2 / pancreatic beta-cells / high-fat diet / glucokinase / Stra13 / adiponectin / exocytosis |
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| Research Abstract |
Glucokinase is known to function as a glucose sensor in insulin secretion, and heterozygous β-cell-type glucokinase-knockout (Gck^<+/->) mice exhibit impaired insulin secretion to glucose and normal β-cell mass on a normal diet. We found that on a high-fat (HF) diet, wild-type mice showed marked β-cell hyperplasia, whereas. Gck^<+/-> mice failed to show such compensatory β-cell hyperplasia in association with decreased β-cell replication, despite the presence of a similar degree of insulin resistance. DNA chip analysis revealed decreased levels of expression of IGF-1-receptor (Igf1r) (2.4-fold) and insulin receptor substrate-2 (Irs2) (25-fold) in the islets of Gck^<+/-> mice on the HF diet, compared with the islets of wild-type mice on the HF diet. Western blot and RT-PCR analyses confirmed up-regulation of Igf1r and Irs2 expression in the islets of the wild-type mice on the HF diet, compared with wild-type mice fed standard chow, and their reduced expression in the islets of Gck^<+/->
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mice on the HF diet, compared with the islets of wild-type mice on the HF diet. Irs2^<+/-> mice on the HF diet failed to show a sufficient increase in β-cell mass. To directly test our hypothesis that reduction in Irs2 explains the impaired β-cell hyperplasia in Gck^<+/-> mice on HF diet, we crossed the Gck^<+/-> mice with β-cell Irs2 transgenic (βIrs2Tg) mice, which expressed a low level of Irs2 (〜2-fold) in β-cells under the control of rat insulin promoter. After 20 weeks on the HF diet, while βIrs2Tg mice had glucose tolerance similar to wild-type mice, βIrs2TgGck^<+/-> mice had slightly, but significantly, better glucose tolerance than Gck^<+/-> mice, indicating that slight up-regulation of Irs2 in β-cells prevents the exacerbation of diabetes in Gck^<+/-> mice. Although β-cell mass was increased in βIrs2TgGck^<+/-> mice compared with Gck^<+/-> mice, β-cell function was unaltered between the two mouse groups. These results suggest that glucokinase and Irs2 are critical requirements for β-cell hyperplasia to occur in response to HF-diet-induced insulin resistance. Less
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