2006 Fiscal Year Final Research Report Summary
The gene transfer of caveolin improves metabolism in diabetic mice
| Project/Area Number |
17590943
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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 | Yokohama City University |
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Principal Investigator |
TOYA Yoshiyuki Yokohama City University, Hospital, Associate Professor, 附属病院, 準教授 (30237143)
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| Project Period (FY) |
2005 – 2006
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| Keywords | insulin / insulin receptor / insulin resistance / caveolin / glycogen / type 2 diabetes / gene transfer / phosphatase |
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| Research Abstract |
The caveolin family of the membrane anchoring proteins accumulates grouth receptors in caveolae and inhibits their function. Upregulation of caveolin is thus known to attenuate cellular proliferation and growth. Here, we demonstrate that caveolin is a potent enhancer of insulin signal that improves glucose metabolism when overexpressed in the liver in vivo. Adenovirus-mediated caveolin-3 gene transfer to the liver led to a marked increase in hepatic glycogen synthesis on diabetic mice, and was accompanied by a decrease in mRNA expression of phosphoenlopyruvate carboxykinase and an increase in that of glucokinase. There was a marked increase in insulin sensitivity in diabetic obese mice as exemplified by decreased blood glucose levels and improved glucose tolerant test performance. Improvement of glucose metabolisms was obtained also in KKAy diabetic mice, a spontaneously diabetic mouse line, when caveolin-3 was gene similarly transferred. These effects were attributed mostly to increased insulin receptor activity with decreased phosphatase activity ; the expression of PTP1B was significantly increased in obese mouse livers, and PTP1B phosphatase activity was potently and directly inhibited by scaffolding domain peptides derived from either caveolin-3 or-1, but not from caveolin-2. Overexpression of caveolin-3 enhanced the insulin receptor signal in cultured hepatic cells. Putting together, our results suggest that caveolin is an important, endogenous regulator of glucose metabolism that can enhance insulin signal, in particular, under pathological conditions where phosphatase activity is upregulated.
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