TRB3:: A tribbles homolog that inhibits Akt/PKB activation by insulin in liver
TRB3:: A tribbles homolog that inhibits Akt/PKB activation by insulin in liver
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DOI：
10.1126/science.1079817
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发表时间：
2003-06-06
期刊：
影响因子：
56.9
通讯作者：
Montminy, M
中科院分区：
文献类型：
--
作者：
Du, KY;Herzig, S;Montminy, M
胰岛素抵抗是II型糖尿病发展的主要标志，其特征在于胰岛素不能促进肌肉中的葡萄糖摄取和抑制肝脏中的葡萄糖产生。丝氨酸-苏氨酸激酶Akt（PKB）是胰岛素信号传导的主要靶点，其在葡萄糖可从食物获得时抑制肝脏葡萄糖输出。在这里，我们表明，TRB 3，果蝇tribbles的哺乳动物同源物，作为一个负调节Akt的功能。TRB 3表达在禁食条件下在肝脏中被诱导，并且TRB 3通过直接结合Akt并阻断激酶的活化来破坏胰岛素信号传导。与野生型小鼠相比，db/db糖尿病小鼠肝脏中TRB 3 RNA和蛋白质的量增加。与db/db小鼠中的TRB 3的量相当的TRB 3的肝脏过表达促进高血糖症和葡萄糖耐受不良。我们的研究结果表明，通过干扰Akt激活，TRB 3有助于对II型糖尿病易感的个体的胰岛素抵抗。
Insulin resistance is a major hallmark in the development of type II diabetes, which is characterized by the failure of insulin to promote glucose uptake in muscle and to suppress glucose production in liver. The serine-threonine kinase Akt (PKB) is a principal target of insulin signaling that inhibits hepatic glucose output when glucose is available from food. Here we show that TRB3, a mammalian homolog of Drosophila tribbles, functions as a negative modulator of Akt. TRB3 expression is induced in liver under fasting conditions, and TRB3 disrupts insulin signaling by binding directly to Akt and blocking activation of the kinase. Amounts of TRB3 RNA and protein were increased in livers of db/db diabetic mice compared with those in wild-type mice. Hepatic overexpression of TRB3 in amounts comparable to those in db/db mice promoted hyperglycemia and glucose intolerance. Our results suggest that, by interfering with Akt activation, TRB3 contributes to insulin resistance in individuals with susceptibility to type II diabetes.