Regulation of insulin secretion by uncoupling protein.
UCPs (uncoupling proteins) can regulate cellular ATP production by uncoupling oxidative phosphorylation. UCP2 is expressed in islet beta-cells and its induction reduces glucose-stimulated insulin secretion. Under physiological conditions, superoxide, formed as a by-product of respiration, activates UCP2. This leads to reduced ATP production, which impairs closure of the ATP-dependent K+ channels to prevent insulin secretion. It is suggested that the physiological role of UCP2 is to prevent excessive superoxide generation through a feedback loop. UCP2 induction may also alter fatty acid metabolism by altering NAD/NADH or by facilitating cycling of fatty acid anions. Recently, UCP2 has been proposed to keep insulin secretion low during starvation, a function under the control of the transcription co-repressor, surtuin-1, which has been shown to bind to the UCP2 promoter. Pathological UCP2 expression or activation may suppress glucose-stimulated insulin secretion to the extent that diabetes onset is hastened. In ob/ob mice, induction of UCP2 at age 5 weeks precedes development of insulin secretion defects and hyperglycaemia. Activating protein kinase A-dependent pathways can normalize insulin secretion in UCP2-overexpressing islets. Conversely, lowering UCP2 expression may promote increased insulin secretion. UCP2 knockout mice were protected from the diabetogenic effects of a high-fat diet and their islets exhibited increased sensitivity to glucose and elevated ATP/ADP. These results support a role for UCP2 as a gene contributing to the pathogenesis of Type 2 diabetes.
Chan
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CB
Department of Biomedical Sciences, University of Prince Edward Island, 550 University Avenue, Charlottetown, PE, Canada C1A 4P3. cchan@upei.ca
Kashemsant
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N
D003920:Diabetes Mellitus / Q000503:physiopathology*; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007473:Ion Channels / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D000071246:Uncoupling Protein 2
D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2