title: Mitochondrial dysfunction and β-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 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 c release 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 increases β-cell mitochondrial susceptibility to injury from ROS and predisposes to developing T2DM. Interventions that attenuate ROS effects on β-cell mitochondrial phospholipids might prevent or retard development of T2DM.
authors: Division of Experimental Diabetes and Aging, Department of Geriatrics and Palliative Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA. zhongmin.ma@mssm.edu
authors: Zhongmin Alex
authors: ZA
authors: Ma
authors: Zhengshan
authors: Z
authors: Zhao
authors: John
authors: J
authors: Turk
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D017209:Apoptosis; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D005231:Fatty Acids, Unsaturated / Q000737:chemistry; D054513:Group IV Phospholipases A2 / Q000172:deficiency / Q000502:physiology; D006801:Humans; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000502:physiology*; D007473:Ion Channels / Q000502:physiology; D015227:Lipid Peroxidation; D008928:Mitochondria / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000502:physiology; D024101:Mitochondrial Proteins / Q000502:physiology; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D005231:Fatty Acids, Unsaturated; D007473:Ion Channels; D024101:Mitochondrial Proteins; D010743:Phospholipids; D017382:Reactive Oxygen Species; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D000255:Adenosine Triphosphate; D054513:Group IV Phospholipases A2