2004 Fiscal Year Final Research Report Summary
Identifying the genes for insulin resistance in Japanese population.
| Project/Area Number |
13204058
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, |
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Principal Investigator |
KASUGA Masato Kobe University Graduate School of Medicine, Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, 大学院医学系研究科糖尿病代謝消化器腎臓内科学, 教授 (50161047)
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| Co-Investigator(Kenkyū-buntansha) |
YASUHIKO Iwamoto Tokyo Women's Medical University School of Medicine, Diabetes Center, Professor, 医学部, 教授 (60143434)
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| Project Period (FY) |
2000 – 2004
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| Keywords | PKCλ / STAT3 / PI 3-kinase / PDK-1 / SREBP-1 / p27^<kip1> / UCP1 |
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| Research Abstract |
1, We have investigated the mechanism of insulin signaling by analyzing knockout mice and cultured cells.
PKClambda is implicated as a downstream effector of PI3K in insulin action. We showed that mice that lack PKClambda specifically in the liver (L-lambdaKO mice) exhibit increased insulin sensitivity as well as a decreased triglyceride content and reduced expression of the SREBP-1c gene in the liver Restoration of PKClambda expression in the liver of L-lambdaKO mice corrected the metabolic abnormalities of these animals. Hepatic PKClambda is thus a determinant of hepatic lipid content and whole-body insulin sensitivity.
We showed that mice with liver-specific deficiency in STAT-3 show insulin resistance associated with increased hepatic expression of gluconeogenic genes. Restoration of hepatic STAT-3 expression in these mice corrected the metabolic abnormalities and the alterations in hepatic expression of gluconeogenic genes. Liver-specific expression of a constitutively active form o
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f STAT-3 markedly reduced blood glucose, plasma insulin concentrations and hepatic gluconeogenic gene expression in diabetic mice. Hepatic STAT-3 signalling is thus essential for normal glucose homeostasis and may provide new therapeutic targets for diabetes.
Moreover we have shown the roles of PI3-kinase, PDK-1, SREBP-1 and p27^<kip1> for insulin signaling and glucose metabolism.
2, We have performed case-control association studies to identify susceptibility genes for type 2 diabetes mellitus. We have shown the-112A > C polymorphism (rs10011540) of the gene for uncoupling protein 1 (UCP1) is associated with type 2 diabetes mellitus in Japanese individuals. Furthermore, we investigated the effects of this polymorphism on clinical characteristics including intramyocellular lipid content (IMCL) and hepatic lipid content (HLC) measured by magnetic resonance spectroscopy. Homeostasis model assessment for insulin resistance (HOMA-IR) and HLC were significantly greater in patients with the -112C allele (risk allele). These results suggest insulin resistance caused by the -112C allele influences the susceptibility to type 2 diabetes. Less
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Research Products
(42 results)
