Advanced glycation end products inhibit glucose-stimulated insulin secretion through nitric oxide-dependent inhibition of cytochrome c oxidase and adenosine triphosphate synthesis.
Advanced glycation end products (AGEs) are implicated in diabetic complications. However, their role in beta-cell dysfunction is less clear. In this study we examined the effects of AGEs on islet function in mice and in isolated islets. AGE-BSA or BSA was administered ip to normal mice twice a day for 2 wk. We showed that AGE-BSA-treated mice exhibited significantly higher glucose levels and lower insulin levels in response to glucose challenge than did BSA-treated mice, although there were no significant differences in insulin sensitivity and islet morphology between two groups. Glucose-stimulated insulin secretion by islets of the AGE-BSA-treated mice or AGE-BSA-treated normal islets was significantly lower than that by islets isolated from the BSA-treated mice or BSA-treated normal islets. Furthermore, AGE treatment of islet beta-cells inhibited ATP production, and glimepiride, a sulfonylurea derivative, restored glucose-stimulated insulin secretion. Further investigation indicated that AGEs inhibited cytochrome c oxidase activity by inducing the expression of inducible nitric oxide synthase (iNOS). Blocking the formation of nitric oxide with an iNOS selective inhibitor aminoguanidine reversed the inhibitory effects of AGEs on ATP production and insulin secretion. We conclude that AGEs inhibit cytochrome c oxidase and ATP production, leading to the impairment of glucose-stimulated insulin secretion through iNOS-dependent nitric oxide production.
Zhao
Zhengshan
Z
Department of Geriatrics and Adult Development, Division of Experimental Diabetes and Aging, Mount Sinai School of Medicine, New York, New York 10029, USA.
Zhao
Chunying
C
Zhang
Xu Hannah
XH
Zheng
Feng
F
Cai
Weijing
W
Vlassara
Helen
H
Ma
Zhongmin Alex
ZA
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000378:metabolism; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000502:physiology*; D017127:Glycation End Products, Advanced / Q000502:physiology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism
D017127:Glycation End Products, Advanced; D007328:Insulin; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D052247:Nitric Oxide Synthase Type II; D003576:Electron Transport Complex IV; D005947:Glucose