Caveolin gene transfer improves glucose metabolism in diabetic mice
Caveolin gene transfer improves glucose metabolism in diabetic mice
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DOI：
10.1152/ajpcell.00077.2009
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发表时间：
2010-03-01
影响因子：
5.5
通讯作者：
Ishikawa, Yoshihiro
中科院分区：
文献类型：
--
作者：
Otsu, Koji;Toya, Yoshiyuki;Ishikawa, Yoshihiro
大津K，Toya Y，Oshikawa J，Kurotani R，Yazawa T，Sato M，Yokyama U，Memura S，南泽S，大村S，石川Y.Cavelin基因转移改善糖尿病小鼠的葡萄糖代谢。Am J Physiol Cell Physiol 298：C450-C456,2010。2009年11月18日首次出版；doi：10.1152/ajpcell.00077.2009。小窝蛋白是膜锚定蛋白家族中的一员，它在小窝中积聚各种生长受体并抑制其功能。小窝蛋白上调可抑制细胞的增殖和生长。然而，小窝蛋白在调节胰岛素信号中的作用仍然存在争议。在这里，我们证明了当在活体肝脏中过表达时，小窝蛋白有效地增强了胰岛素受体(IR)信号。腺病毒介导的基因转移被用来在糖尿病肥胖小鼠的肝脏中特异性地过度表达小凹蛋白，这些小鼠是由高脂饮食产生的。IR、Akt等参与IR信号转导的分子在基因转移后表达无明显变化。而肝糖原合成明显增加，磷酸烯醇式丙酮酸羧基激酶蛋白表达降低。通过注射胰岛素后血糖水平的降低和空腹血糖水平的测定，小窝蛋白基因转移后胰岛素敏感性增加。糖耐量试验成绩也有所提高。在KKAy遗传性糖尿病小鼠中也获得了类似的改善。腺病毒介导的小窝蛋白-3在肝细胞中的过表达也增强了IR信号，表现为胰岛素刺激后IR的磷酸化增加和基线时更高的糖原合成。这些作用主要归因于胰岛素受体活性的增加和小窝蛋白介导的直接抑制蛋白酪氨酸磷酸酶1B，后者在肥胖小鼠肝脏中增加。综上所述，我们的结果表明，小窝蛋白是一种重要的糖代谢调节剂，可以增强胰岛素信号。
Otsu K, Toya Y, Oshikawa J, Kurotani R, Yazawa T, Sato M, Yokoyama U, Umemura S, Minamisawa S, Okumura S, Ishikawa Y. Caveolin gene transfer improves glucose metabolism in diabetic mice. Am J Physiol Cell Physiol 298: C450-C456, 2010. First published November 18, 2009; doi: 10.1152/ajpcell.00077.2009. Caveolin, a member of the membrane-anchoring protein family, accumulates various growth receptors in caveolae and inhibits their function. Upregulation of caveolin attenuates cellular proliferation and growth. However, the role of caveolin in regulating insulin signals remains controversial. Here, we demonstrate that caveolin potently enhances insulin receptor (IR) signaling when overexpressed in the liver in vivo. Adenovirus-mediated gene transfer was used to overexpress caveolin specifically in the liver of diabetic obese mice, which were generated with a high-fat diet. Expression of molecules involved in IR signaling, such as IR or Akt, remained unchanged after gene transfer. However, hepatic glycogen synthesis was markedly increased with a decrease in phosphoenolpyruvate carboxykinase protein expression. Insulin sensitivity was increased after caveolin gene transfer as determined by decreased blood glucose levels in response to insulin injection and fasting blood glucose levels. Glucose tolerant test performance was also improved. Similar improvements were obtained in KKAy genetically diabetic mice. Adenovirus-mediated overexpression of caveolin-3 in hepatic cells also enhanced IR signaling, as shown by increased phosphorylation of IR in response to insulin stimulation and higher glycogen synthesis at baseline. These effects were attributed mostly to increased insulin receptor activity and caveolin-mediated, direct inhibition of protein tyrosine phosphatase 1B, which was increased in obese mouse livers. In conclusion, our results suggest that caveolin is an important regulator of glucose metabolism that can enhance insulin signals.