Abstract
BackgroundIncreased uncoupling protein-2 (UCP-2) expression has been associated with impaired insulin secretion, whereas UCP-3 protein levels are decreased in the skeleton muscle of type-2 diabetic subjects. In the present studies we hypothesize an opposing effect of glucose on the regulation of UCP-2 and UCP-3 in pancreatic islets.MethodologyDominant negative UCP-2 and wild type UCP-3 adenoviruses were generated, and insulin release by transduced human islets was measured. UCP-2 and UCP-3 mRNA levels were determined using quantitative PCR. UCP-2 and UCP-3 protein expression was investigated in human islets cultured in the presence of different glucose concentrations. Human pancreatic sections were analyzed for subcellular localization of UCP-3 using immunohistochemistry.Principal FindingsDominant negative UCP-2 expression in human islets increased insulin secretion compared to control islets (p<0.05). UCP-3 mRNA is expressed in human islets, but the relative abundance of UCP-2 mRNA was 8.1-fold higher (p<0.05). Immunohistochemical analysis confirmed co-localization of UCP-3 protein with mitochondria in human beta-cells. UCP-2 protein expression in human islets was increased ∼2-fold after high glucose exposure, whereas UCP-3 protein expression was decreased by ∼40% (p<0.05). UCP-3 overexpression improved glucose-stimulated insulin secretion.ConclusionsUCP-2 and UCP-3 may have distinct roles in regulating beta-cell function. Increased expression of UCP-2 and decreased expression of UCP-3 in humans with chronic hyperglycemia may contribute to impaired glucose-stimulated insulin secretion. These data imply that mechanisms that suppress UCP-2 or mechanisms that increase UCP-3 expression and/or function are potential therapeutic targets to offset defects of insulin secretion in humans with type-2 diabetes.
Highlights
Prolonged exposure of islets to high glucose or free fatty acid concentrations causes attenuated glucose-stimulated insulin secretion (GSIS) [1,2]
In order to evaluate the effect of free fatty acids on uncoupling protein-2 (UCP-2) protein expression in the presence of high glucose, isolated human islets were cultured for 24 hr in 11 mM glucose containing medium with or without 0.45 mM oleic acid
Oleic acid potentiated the effect of high glucose by increasing UCP-2 expression 1.560.1-fold (p,0.05) in human islets in the presence of 11 mM glucose when compared to islets cultured with 11 mM glucose without oleic acid
Summary
Prolonged exposure of islets to high glucose or free fatty acid concentrations causes attenuated glucose-stimulated insulin secretion (GSIS) [1,2]. To the extent that protons reenter beta-cell mitochondria via uncoupling proteins and release energy in the form of heat, they will be unavailable for ATP synthase to generate ATP [8]. Increased uncoupling protein-2 (UCP-2) expression has been associated with impaired insulin secretion, whereas UCP-3 protein levels are decreased in the skeleton muscle of type-2 diabetic subjects. UCP-2 protein expression in human islets was increased ,2-fold after high glucose exposure, whereas UCP-3 protein expression was decreased by ,40% (p,0.05). Increased expression of UCP-2 and decreased expression of UCP-3 in humans with chronic hyperglycemia may contribute to impaired glucose-stimulated insulin secretion. These data imply that mechanisms that suppress UCP-2 or mechanisms that increase UCP-3 expression and/or function are potential therapeutic targets to offset defects of insulin secretion in humans with type-2 diabetes
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