| Project/Area Number |
20790645
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Metabolomics
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| Research Institution | Kyoto University |
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Principal Investigator |
TOMITA Tsutomu Kyoto University, 医学研究科, 医員 (50402897)
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| Project Period (FY) |
2008 – 2009
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| Project Status |
Completed (Fiscal Year 2009)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2009: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2008: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | GPR40 / G蛋白共役型受容体 / インスリン分泌 / 糖尿病 / 肥満 / 創薬 / 遊離脂肪酸 / 脂肪毒性 / コレツキーラット |
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| Research Abstract |
To elucidate the regulation and pathophysiological implication of GPR40 in diabetes, we investigated GPR40 gene expression in pancreatic islets in Koletsky rats (fa^k/fa^k), a genetically obese model with a homozygous nonsense mutation in the ObR gene, as reported by us, and compared with lean littermates (+/+). In 14-week-old fa^k/fa^k with established glucose intolerance, GPR40 gene expression in pancreatic islets markedly (~1/3) decreased. Augmentation of insulin secretion in response to oleic acids was markedly attenuated in isolated islets from fa^k/fa^k. Tissue triglyceride levels were ~3-folds increased in pancreatic islets of fa^k/fa^k. Notably, mRNA expression of Pdx1, for which a putative binding domain is reported in the GPR40 promoter, was markedly (~1/2) decreased in pancreatic islets of fa^k/fa^k. Our results suggest a link between decreased GPR40 expression and dysregulated insulin secretion in pancreatic beta cells with lipid accumulation, where decreased Pdx1 gene expression may play a pivotal role in the regulation of GPR40 expression. The data also provide evidence for Koletsky rats as a suitable model for investigation of lipid accumulation and dysfunction in pancreatic beta cells.
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