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The gene transfer of caveolin improves metabolism in diabetic mice

Caveolin的基因转移改善了糖尿病小鼠的新陈代谢

基本信息

批准号：
17590943
负责人：
TOYA Yoshiyuki
金额：
$ 1.98万
依托单位：
Yokohama City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

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.

膜锚定蛋白的小窝蛋白家族在小窝中积累生长受体并抑制它们的功能。因此，已知小窝蛋白的上调减弱细胞增殖和生长。在这里，我们证明了小窝蛋白是一种有效的胰岛素信号增强剂，当在体内肝脏中过表达时，可以改善葡萄糖代谢。腺病毒介导的小窝蛋白-3基因转移到肝脏导致糖尿病小鼠肝糖原合成的显着增加，并伴随着磷酸烯醇丙酮酸羧激酶的mRNA表达的减少和葡萄糖激酶的增加。糖尿病肥胖小鼠的胰岛素敏感性显著增加，如降低的血糖水平和改善的葡萄糖耐量测试表现所例示。当小窝蛋白-3被类似地基因转移时，在KKAy糖尿病小鼠（一种自发性糖尿病小鼠系）中也获得了葡萄糖代谢的改善。这些影响主要归因于胰岛素受体活性增加，磷酸酶活性降低;肥胖小鼠肝脏中PTP 1B的表达显著增加，PTP 1B磷酸酶活性被来自小窝蛋白-3或-1的支架结构域肽有效且直接抑制，但不是来自小窝蛋白-2。小窝蛋白-3过表达增强了培养肝细胞胰岛素受体信号。总之，我们的研究结果表明，小窝蛋白是一个重要的，内源性调节葡萄糖代谢，可以增强胰岛素信号，特别是在病理条件下，磷酸酶活性上调。