Yoon J Cliff, Xu Gang, Deeney Jude T, Yang Shao-Nian, Rhee James, Puigserver Pere, Levens Adah R, Yang Ruojing, Zhang Chen-Yu, Lowell Bradford B, Berggren Per-Olof, Newgard Christopher B, Bonner-Weir Susan, Weir Gordon, Spiegelman Bruce M
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
Dev Cell. 2003 Jul;5(1):73-83. doi: 10.1016/s1534-5807(03)00170-9.
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 beta cell function, including the induction of glucose-6-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 Ca(2+) 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.
β细胞功能障碍是2型糖尿病的一个重要组成部分，但这种缺陷的分子基础尚不清楚。在多种糖尿病动物模型的胰岛中，转录共激活因子PGC-1α的mRNA和蛋白水平显著升高；腺病毒介导的PGC-1α表达至与糖尿病啮齿动物相似的水平，可显著抑制培养的胰岛和活体小鼠中葡萄糖刺激的胰岛素分泌。这种抑制与β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-6-磷酸酶的诱导以及GLUT2、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+)内流及胰岛素胞吐作用的膜电活动减弱。这些结果强烈表明，PGC-1α在β细胞中起关键功能作用，并参与糖尿病表型的发病机制。
