Activation of autophagy through modulation of 5'-AMP-activated protein kinase protects pancreatic beta-cells from high glucose.
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.
Han
Diana
D
Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824, USA.
Yang
Byungho
B
Olson
L Karl
LK
Greenstein
Alexander
A
Baek
Seung-Hoon
SH
Claycombe
Kate J
KJ
Goudreau
John L
JL
Yu
Seong-Woon
SW
Kim
Eun-Kyoung
EK
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D005947:Glucose / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D051336:Mitochondrial Membranes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D055372:AMP-Activated Protein Kinases; D053148:Caspase 3; D005947:Glucose