Mitochondrial Dysfunction and <i>β</i> -Cell Failure in Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is the most common human endocrine disease and is characterized by peripheral insulin resistance and pancreatic islet β -cell failure. Accumulating evidence indicates that mitochondrial dysfunction is a central contributor to β -cell failure in the evolution of T2DM. As reviewed elsewhere, reactive oxygen species (ROS) produced by β -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 to β -cell failure. ROS activate UCP2, which results in proton leak across the mitochondrial inner membrane, and this leads to reduced β -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 cytochrome