Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824, USA.
Biochem J. 2010 Jan 15;425(3):541-51. doi: 10.1042/BJ20090429.
Chronic hyperglycaemia is detrimental to pancreatic beta-cells by causing impaired insulin secretion and diminished beta-cell function through glucotoxicity. Understanding the mechanisms underlying beta-cell survival is crucial for the prevention of beta-cell failure associated with glucotoxicity. Autophagy is a dynamic lysosomal degradation process that protects organisms against metabolic stress. To date, little is known about the physiological function of autophagy in the pathogenesis of diabetes. In the present study, we explored the roles of autophagy in the survival of pancreatic beta-cells exposed to high glucose using pharmacological and genetic manipulation of autophagy. We demonstrated that chronic high glucose increases autophagy in rat INS-1 (832/13) cells and pancreatic islets, and that this increase is enhanced by inhibition of 5'-AMP-activated protein kinase. Our results also indicate that stimulation of autophagy rescues pancreatic beta-cells from high-glucose-induced cell death and inhibition of autophagy augments caspase-3 activation, suggesting that autophagy plays a protective role in the survival of pancreatic beta-cells. Greater knowledge of the molecular mechanisms linking autophagy and beta-cell survival may unveil novel therapeutic targets needed to preserve beta-cell function.
慢性高血糖通过糖毒性导致胰岛素分泌受损和β细胞功能下降，对胰岛β细胞有害。了解β细胞存活的机制对于预防与糖毒性相关的β细胞衰竭至关重要。自噬是一种动态的溶酶体降解过程，可保护机体免受代谢应激。迄今为止，关于自噬在糖尿病发病机制中的生理功能知之甚少。在本研究中，我们通过自噬的药理学和遗传学操作，探讨了自噬在高糖暴露的胰岛β细胞存活中的作用。我们证明慢性高葡萄糖增加了大鼠 INS-1（832/13）细胞和胰岛中的自噬，并且这种增加可被 5'-AMP 激活蛋白激酶的抑制所增强。我们的结果还表明，自噬的刺激可挽救胰岛β细胞免受高葡萄糖诱导的细胞死亡，而自噬的抑制则增强半胱天冬酶-3 的激活，提示自噬在胰岛β细胞的存活中发挥保护作用。对自噬与β细胞存活之间的分子机制有更深入的了解，可能揭示出保护β细胞功能所需的新的治疗靶点。
