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Exp Diabetes Res. 2012;2012:703538. doi: 10.1155/2012/703538. Epub 2011 Nov 9.

Mitochondrial dysfunction and β-cell failure in type 2 diabetes mellitus.

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1
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

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.

PMID:
22110477
PMCID:
PMC3216264
DOI:
10.1155/2012/703538
[Indexed for MEDLINE]
Free PMC Article
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