| Project/Area Number |
10671062
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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 |
Metabolomics
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| Research Institution | Shiga University Of Medical Science |
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Principal Investigator |
MAEGAWA Hiroshi Shiga University Of Medical Science, Faculty Of Medicine, Rasearch Associates, 医学部, 助手 (00209363)
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2000: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1998: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Keywords | Protein-Tyrosine Phosphatase / SHP-2 / Transgenic Mice / Insulin Resistance / Protein phosphatase |
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| Research Abstract |
To elucidate roles of SHP-2, we generated transgenic (Tg) mice expressing a dominant negative mutant lacking PTPase domain (DPTP). On examining 2 lines of Tg mice identified by Southern blot, the transgene product was expressed in skeletal muscle liver and adipose tissues and insulin-induced association of insulin receptor substrate (IRS) 1 with endogenous SHP-2 was inhibited, confirming that DPTP has a dominant negative property. The intraperitoneal glucose loading test demonstrated an increase in blood glucose levels in Tg mice. Plasma insulin levels in Tg mice after 4 h fasting were 3 times greater with comparable blood glucose levels. To estimate insulin sensitivity by a constant glucose, insulin and somatostatin infusion, steady state blood glucose levels were higher, suggesting the presence of insulin resistance. Furthermore we observed the impairment of insulin-stimulated glucose uptake in muscle and adipocytes in the presence of physiological concentrations of insulin. Moreover, tyrosine-phosphorylation of IRS-1 and stimulation of phosphatidylinositol 3-kinase and Akt kinase activities by insulin were attenuated in muscle and liver. These results indicate that the inhibition of endogenous SHP-2 function by the overexpression of a dominant negative mutant may lead to impaired insulin sensitivity of glucose metabolism and thus SHP-2 may function to modulate insulin signaling in target tissues and these Tg mice are a unique model to investigate molecular mechanism for insulin resistance.
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