2004 Fiscal Year Final Research Report Summary
Analysis of molecular mechanisms for impaired insulin secretion and beta-cell hyperplasia caused by lipotoxicity
| Project/Area Number |
15390285
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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 |
TERAUCHI Yasuo The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (40359609)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAUCHI Toshimasa The University of Tokyo, Faculty of Medicine, Visiting Assistant Professor, 医学部附属病院, 寄附講座教員(客員助教授) (40372370)
ETO Kazuhiro The University of Tokyo, Faculty of Medicine, Medical Staff, 医学部附属病院, 医員
KUBOTA Naoto The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 寄附講座教員(助手相当)
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) |
2003 – 2004
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| Keywords | PPARγ / islet triglyceride content / insulin secretion / SREBP-1c / AMP kinase / high-fat diet / glucokinase / IRS-2 |
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| Research Abstract |
On a high-fat diet, glucose-induced insulin secretion in PPARγ^<+/-> mice was impaired. The tissue triglyceride content of the white adipose tissue, skeletal muscle, and liver was decreased in PPARγ^<+/-> mice, but it was increased in the islets. Administration pioglitazone reduced the islet triglyceride content in PPARγ^<+/-> mice on a high-fat diet and ameliorated the impaired insulin secretion.
Despite reduced body weight, serum leptin level was significantly higher in PPARγ^<+/-> mice on the high-fat diet than in wild-type mice. To determine the impact of a lack of leptin action on PPARγ^<+/-> mice, we generated PPARγ^<+/-> mice on the ob/ob genetic background. At 16 weeks, PPARγ^<+/-> ob/ob mice showed worse glucose tolerance than ob/ob mice. Insulin secretion from islets was markedly impaired in PPARγ^<+/-> ob/ob mice as compared with ob/ob mice. Thus, leptin plays a role in the protection from high-fat diet-induced glucose intolerance in PPARγ^<+/-> mice.
We overexpressed a consti
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tutively active form of SREBP-1c in INS-1 cells with an adenoviral vector. This treatment activated transcription of the genes involved in fatty acid biosynthesis, increased cellular triglyceride content, and blunted glucose-stimulated insulin secretion. Exposure of AICAR increased free fatty acid oxidation, partially reversed the triglyceride accumulation, phosphorylated AMPK and acetyl-coenzyme A carboxylase, and improved the impaired glucose-stimulated insulin secretion. Mice overexpressing SREBP-1c in. β-cells developed diabetes with decreased insulin secretion.
On a high-fat 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 (2.4-fold) and Irs2 (25-fold) in the islets of Gck^<+/-> mice on the high-fat diet, compared with the islets of wild-type mice on the high-fat diet. Western blot and RT-PCR analyses confirmed up-regulation of IGF-1-receptor and Irs2 expression in the islets of the wild-type mice on the high-fat diet, compared with wild-type mice fed standard chow, and their reduced expression in the islets of Gck^<+/-> mice on the high-fat diet, compared with the islets of wild-type mice on the high-fat diet. Moreover, Irs2^<+/-> mice on the high-fat diet failed to show a sufficient increase in β-cell mass. Less
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Research Products
(4 results)
