Defective insulin secretion and increased susceptibility to experimental diabetes are induced by reduced Akt activity in pancreatic islet β cells
Defective insulin secretion and increased susceptibility to experimental diabetes are induced by reduced Akt activity in pancreatic islet β cells
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DOI：
10.1172/jci200420016
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发表时间：
2004-10-01
影响因子：
15.9
通讯作者：
Permutt, MA
中科院分区：
文献类型：
--
作者：
Bernal-Mizrachi, E;Fatrai, S;Permutt, MA
胰岛素和IGF信号通路对于胰腺β细胞质量和功能的发育和维持至关重要。丝氨酸-苏氨酸激酶Akt是由这些途径调节的几种介质之一。我们已经研究了Akt在胰腺β细胞生理学中的作用，通过产生在β细胞中表达这种酶的激酶死亡突变体的转基因小鼠。转基因动物中Akt活性的降低导致由于胰岛素分泌缺陷导致的葡萄糖耐量受损。这些小鼠分泌失调的机制在于胰岛素胞吐水平，而不是葡萄糖信号传导或电压门控Ca 2+通道功能异常的结果。因此，转基因小鼠在脂肪喂养后表现出对葡萄糖耐受不良和糖尿病的易感性增加。这些观察结果表明，Akt在调节分泌途径的远端组分中起着新的重要作用，并且这种酶代表了改善糖尿病β细胞功能的治疗靶点。
The insulin and IGF signaling pathways are critical for development and maintenance of pancreatic beta cell mass and function. The serine-threonine kinase Akt is one of several mediators regulated by these pathways. We have studied the role of Akt in pancreatic beta cell physiology by generating transgenic mice expressing a kinase-dead mutant of this enzyme in beta cells. Reduction of Akt activity in transgenic animals resulted in impaired glucose tolerance due to defective insulin secretion. The mechanisms involved in dysregulation of secretion in these mice lie at the level of insulin exocytosis and are not the result of abnormalities in glucose signaling or function of voltage-gated Ca2+ channels. Therefore, transgenic mice showed increased susceptibility to developing glucose intolerance and diabetes following fat feeding. These observations suggest that Akt plays a novel and important role in the regulation of distal components of the secretory pathway and that this enzyme represents a therapeutic target for improvement of beta cell function in diabetes.