Advanced Glycation End Products Are Direct Modulators of b-Cell Function

OBJECTIVE—Excess accumulation of advanced glycation end products (AGEs) contributes to aging and chronic diseases. We aimed to obtain evidence that exposure to AGEs plays a role in the development of type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS—The effect of AGEs was examined on insulin secretion by MIN6N8 cells and mouse islets and in vivo in three separate rodent models: AGE-injected or high AGE–fed Sprague-Dawley rats and nonobese diabetic (NODLt) mice. Rodents were also treated with the AGE-lowering agent alagebrium. RESULTS—b-Cells exposed to AGEs displayed acute glucose-stimulated insulin secretory defects, mitochondrial abnormalities including excess superoxide generation, a decline in ATP con-tent, loss of MnSOD activity, reduced calcium flux, and increased glucose uptake, all of which were improved with alagebriu