Suppression of β cell energy metabolism and insulin release by PGC-1α
Suppression of β cell energy metabolism and insulin release by PGC-1α
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DOI：
10.1016/s1534-5807(03)00170-9
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发表时间：
2003-07-01
影响因子：
11.8
通讯作者：
Spiegelman, BM
中科院分区：
文献类型：
--
作者：
Yoon, JC;Xu, G;Spiegelman, BM
β细胞功能障碍是2型糖尿病的一个重要组成部分，但对这种缺陷的分子基础知之甚少。转录辅激活因子PGC-1 α mRNA和蛋白水平在多种糖尿病动物模型的胰岛中显著升高;腺病毒介导的PGC-1 α表达水平与糖尿病啮齿动物中存在的水平相似，可显著抑制培养物和活小鼠胰岛中葡萄糖刺激的胰岛素分泌。这种抑制与P细胞功能受损相关的代谢基因表达变化相一致，包括葡萄糖-8-磷酸酶的诱导和GLUT 2、葡萄糖激酶和甘油-3-磷酸脱氢酶的抑制。这些变化导致葡萄糖诱导的细胞ATP水平升高和负责Ca 2+内流和胰岛素胞吐的膜电活动减弱。这些结果有力地表明，PGC-1 α在β细胞中起着关键的功能作用，并参与糖尿病表型的发病机制。
beta cell dysfunction is an important component of type 2 diabetes, but the molecular basis for this defect is poorly understood. The transcriptional coactivator PGC-1alpha mRNA and protein levels are significantly elevated in islets from multiple animal models of diabetes; adenovirus-mediated expression of PGC-1alpha to levels similar to those present in diabetic rodents produces a marked inhibition of glucose-stimulated insulin secretion from islets in culture and in live mice. This inhibition coincides with changes in metabolic gene expression associated with impaired P cell function, including the induction of glucose-8-phosphatase and suppression of GLUT2, glucokinase, and glycerol-3-phosphate dehydrogenase. These changes result in blunting of the glucose-induced rise in cellular ATP levels and membrane electrical activity responsible for Ca2+ influx and insulin exocytosis. These results strongly suggest that PGC-1alpha plays a key functional role in the beta cell and is involved in the pathogenesis of the diabetic phenotype.