Activation of autophagy through modulation of 5'-AMP-activated protein kinase protects pancreatic beta-cells from high glucose

• Published in: Biochemical journal Vol. 425; no. 3; p. 541
• Main Authors: Han, Diana, Yang, Byungho, Olson, L Karl, Greenstein, Alexander, Baek, Seung-Hoon, Claycombe, Kate J, Goudreau, John L, Yu, Seong-Woon, Kim, Eun-Kyoung
• Format: Journal Article
• Language: English
• Published: England 01.02.2010
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; Apoptosis; Autophagy; Caspase 3 - metabolism; Cell Proliferation; Cell Survival; Glucose - metabolism; Insulin-Secreting Cells - metabolism; Lysosomes - metabolism; Male; Membrane Potentials; Mitochondrial Membranes - metabolism; Rats; Rats, Sprague-Dawley
• ISSN: 1470-8728
• 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.