Advanced Glycation End Products Inhibit Glucose-Stimulated Insulin Secretion through Nitric Oxide-Dependent Inhibition of Cytochrome c Oxidase and Adenosine Triphosphate Synthesis

• Published in: Endocrinology (Philadelphia) Vol. 150; no. 6; pp. 2569 - 2576
• Main Authors: Zhao, Zhengshan, Zhao, Chunying, Zhang, Xu Hannah, Zheng, Feng, Cai, Weijing, Vlassara, Helen, Ma, Zhongmin Alex
• Format: Journal Article
• Language: English
• Published: Chevy Chase, MD Endocrine Society 01.06.2009; The Endocrine Society
• Subjects: Adenosine Triphosphate - antagonists & inhibitors; Adenosine Triphosphate - metabolism; Animals; Biological and medical sciences; Cells, Cultured; Diabetes Mellitus - metabolism; Disease Models, Animal; Electron Transport Complex IV - antagonists & inhibitors; Electron Transport Complex IV - metabolism; Female; Fundamental and applied biological sciences. Psychology; Glucose - physiology; Glycation End Products, Advanced - physiology; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Male; Mice; Mice, Inbred C57BL; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - metabolism; Vertebrates: endocrinology; Pancreatic hormone; Purine nucleoside; Adenosine; Enzyme; Secretion; Reaction product; Cytochrome-c oxidase; Biosynthesis; Triphosphates; Glucose; Insulin; Glycation; Nitric oxide; Oxidoreductases; Inhibition
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2008-1342

Advanced glycation end products (AGEs) are implicated in diabetic complications. However, their role in β-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 β-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. Advanced glycation end products impair the function of pancreatic β-cells through nitric oxide-dependent inhibition of cytochrome c oxidase and ATP production.