Impact of mitochondrial calcium on the coupling of metabolism to insulin secretion in the pancreatic β-cell

Mitochondria play an essential rote in metabolism-secretion coupling in the pancreatic p-cell. Dysfunction of the organelle leads to impaired glucose-stimulated insulin secretion, as exemplified by the rare disease mitochondrial. diabetes, which is caused by mutations in the mitochondrial DNA. In the excitable P-cell, mitochondria generate ATP and possibly other coupling factors that promote plasma membrane depolarization and calcium influx triggering insulin exocytosis. Cytosolic calcium signals are relayed into the mitochondria, where the ion potentiates oxidative metabolism. Hormones such as glucagon-like peptide 1 (GLP-1) or neurotransmitter secretagogues stimutate the beta-cell by activating different signal transduction pathways eventually also raising mitochondrial. calcium. Likewise, pharmacological inhibition of the Na+/Ca2+ exchanger of the inner mitochondrial. membrane augments intraorganellar calcium and insulin secretion. Islets obtained after autopsy from type 2 diabetic patients have altered mitochondrial morphology impaired glucose oxidation and reduced ATP generation, explaining defective insulin secretion. We hypothesize that the improvement of glucose-stimulated insulin secretion by sulfonylurea compounds in type 2 diabetic patients is in part due to their capacity to raise mitochondrial calcium, which is beneficial for the generation of metabolic coupling factors. (c) 2007 Elsevier Ltd. All rights reserved.