Mitochondrial Dysfunction andβ-Cell Failure in Type 2 Diabetes Mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is the most common human endocrine disease and is characterized by peripheral insulin resistance and pancreatic isletβ-cell failure. Accumulating evidence indicates that mitochondrial dysfunction is a central contributor toβ-cell failure in the evolution of T2DM. As reviewed elsewhere, reactive oxygen species (ROS) produced byβ-cell mitochondria as a result of metabolic stress activate several stress-response pathways. This paper focuses on mechanisms whereby ROS affect mitochondrial structure and function and lead toβ-cell failure. ROS activate UCP2, which results in proton leak across the mitochondrial inner membrane, and this leads to reducedβ-cell ATP synthesis and content, which is a critical parameter in regulating glucose-stimulated insulin secretion. In addition, ROS oxidize polyunsaturated fatty acids in mitochondrial cardiolipin and other phospholipids, and this impairs membrane integrity and leads to cytochromecrelease into cytosol and apoptosis. Group VIA phospholipase A2(iPLA2β) appears to be a component of a mechanism for repairing mitochondrial phospholipids that contain oxidized fatty acid substituents, and genetic or acquired iPLA2β-deficiency increasesβ-cell mitochondrial susceptibility to injury from ROS and predisposes to developing T2DM. Interventions that attenuate ROS effects onβ-cell mitochondrial phospholipids might prevent or retard development of T2DM.