The gene transfer of caveolin improves metabolism in diabetic mice

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其功能。因此，已知小窝蛋白的上调会减弱细胞的增殖和生长。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，当在体内肝脏中过度表达时，它可以改善葡萄糖代谢。腺病毒介导的caveolin-3基因转移到肝脏后，糖尿病小鼠肝糖原合成明显增加，并伴有磷酸丙酮酸羧激酶mRNA表达减少和葡萄糖激酶mRNA表达增加。糖尿病肥胖小鼠的胰岛素敏感性显著增加，血糖水平降低，葡萄糖耐量测试表现改善。当caveolin-3基因同样被转移时，KKAy糖尿病小鼠（一种自发性糖尿病小鼠系）的葡萄糖代谢也得到了改善。这些影响主要归因于胰岛素受体活性增加而磷酸酶活性降低；肥胖小鼠肝脏中PTP1B的表达显著增加，并且PTP1B磷酸酶活性被caveolin-3或1衍生的支架结构域肽直接有效地抑制，而不是caveolin-2。在培养的肝细胞中，过表达caveolin-3可增强胰岛素受体信号。综上所述，我们的研究结果表明，小窝蛋白是一种重要的内源性葡萄糖代谢调节剂，可以增强胰岛素信号，特别是在磷酸酶活性上调的病理条件下。

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.