| Project/Area Number |
09671084
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
内分泌・代謝学
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| Research Institution | Chiba University |
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Principal Investigator |
YANO hideki Chiba University Graduate school of Medicine, Associate Professor, 大学院・医学研究科, 助教授 (30288576)
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| Co-Investigator(Kenkyū-buntansha) |
JOMORI Takahito Sanwakagaku Kenkyusho co., LTD, 創薬研究部, 課長
YUICHIRO Yamada Kyoto University Graduate school of Medicine, Department of Metabolism and Clinical Nutrition, Associate Professor, 大学院・医学研究科, 助教授 (60283610)
SEINO Susumu Chiba University Graduate school of Medicine, Department of Molecular Medicine, Professor, 大学院・医学研究科, 教授 (80236067)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1999: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1998: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1997: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | GIP receptor deficient mice / GIP modulation / Insulin secretion / Insulin resistance / High fat diet / Diabetes mellitus / ノックアウトマウス / GIP受容体 / ジーンターゲティング |
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| Research Abstract |
Gastric inhibitory polypeptide (GIP) acts as incretin, which promotes insulin secretion from pancreatic β-cells after meal ingestion. It has been shown that the insulinotropic effect of GIP is selectively impaired despite exaggerated GIP secretion in type 2 diabetic patients, suggesting that GIP modulaton of pancreatic β-cells is involved in the pathogenesis of type 2 diabetic mellitus. To analyze the role of GIP as a mediator of singals from the gut to the pancreatic β-cells, we have generated mice with a targeted disruption of the GIP receptor gene (GIPR). GIP stimulated insulin secretion 2.9-fold from the islets of GIPR+/+ mice, while GIP had no insulinotropic effect in GIPR-/- mice, indicating the absence of the GIP receptors in GIPR -/- mice. No significant differences in fasting glucose level and body weight were observed in GIPR-deficient mice. In IPGTT, blood glucose levels were not significantly different between GIPR -/- mice and GIPR +/+ mice. In contrast, GIPR-/- mice showed higher blood gulcose levels accompanied with impaired initial insulin response after oral glucse loading. The high fat diet did not alter blood glucose levels by compensatory higher insulin secretion after meal ingestion in GIPR +/+ mice, but further increased blood glucose levels without enhancement of insulin secretion in GIPR -/- mice. This demonstrates that insulin secretion, especially in the early phase after oral glucose loading, is mediated by GIP, and that GIP plays an important role in the compensatory enhancement of insulin secretion produced by a higher insulin demand. These results indicate that GIP may have critical role in vivo in the development of type 2 diabetes mellitus.
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