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

Abstract

OBJECTIVEExcess 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 METHODSThe 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.RESULTSβ-Cells exposed to AGEs displayed acute glucose-stimulated insulin secretory defects, mitochondrial abnormalities including excess superoxide generation, a decline in ATP content, loss of MnSOD activity, reduced calcium flux, and increased glucose uptake, all of which were improved with alagebrium treatment or with MnSOD adenoviral overexpression. Isolated mouse islets exposed to AGEs had decreased glucose-stimulated insulin secretion, increased mitochondrial superoxide production, and depletion of ATP content, which were improved with alagebrium or with MnTBAP, an SOD mimetic. In rats, transient or chronic exposure to AGEs caused progressive insulin secretory defects, superoxide generation, and β-cell death, ameliorated with alagebrium. NODLt mice had increased circulating AGEs in association with an increase in islet mitochondrial superoxide generation, which was prevented by alagebrium, which also reduced the incidence of autoimmune diabetes. Finally, at-risk children who progressed to T1D had higher AGE concentrations than matched nonprogressors.CONCLUSIONSThese findings demonstrate that AGEs directly cause insulin secretory defects, most likely by impairing mitochondrial function, which may contribute to the development of T1D.

Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis

“…Mitochondrial ATP was measured using a Molecular Probes bioluminescence ATP determination kit (Life Technologies, Melbourne, VIC, Australia), as described previously (19,20) with the following modifications. A 10-point standard curve was prepared, ranging from 50,000 to 125 nmol/L.…”

Effects of High-Density Lipoprotein Elevation With Cholesteryl Ester Transfer Protein Inhibition on Insulin Secretion

“…28,29 Ex Vivo Insulin Secretion From MIN6N8 Pancreatic β-Cells Insulin secretion was assessed in murine MIN6N8 pancreatic β-cells provided by Jun-ichi Miyagaki (Osaka University, Osaka, Japan) 30 using a modified protocol. 31 MIN6N8 pancreatic β-cells were grown in 5 mmol/L glucose DMEM supplemented with 10% fetal calf serum plus 1% penicillin/streptomycin (37ºC, 95% O 2 /5% CO 2 ) to subconfluence and then placed in 5 mmol/L glucose DMEM with 2% fetal calf serum. Cells were incubated with 3.5% CETPi plasma, placebo plasma, lipoprotein-free plasma, HDL-spiked (1.8 mmol/L) plasma, DMSO, or 100 ng/mL CETPi for 72 hours along with oxLDL (50 μg/mL) to simulate the pathophysiology of type 2 diabetes mellitus.…”

Decrease in Circulating Concentrations of Soluble Receptors for Advanced Glycation End Products at the Time of Seroconversion to Autoantibody Positivity in Children With Prediabetes

“…More recent evidence suggests a role for AGEs and RAGE in the pathogenesis of type 1 diabetes (5,10,11). Further, excess dietary AGE intake can induce pancreatic b-cell dysfunction in animal models (12), while AGE-lowering strategies such as a low-AGE diet or pharmacotherapy decrease the incidence of autoimmune diabetes in NODLt mice (12,13). N-´(carboxymethyl)lysine (CML) is one of the most prominent AGEs physiologically.…”