University of California, Los Angeles (UCLA)

The Role of Uncoupling Proteins in Glucose-stimulated Insulin Secretion in Diabetes

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UCP-2 and UCP-3 Proteins are Differentially Regulated in Pancreatic Beta-cells: 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. We hypothesized an opposing effect of glucose on the regulation of UCP-2 and UCP-3 in pancreatic islets. We generated dominant negative UCP-2 adenovirus and measured insulin release from transduced human islets using perifusion. We studied UCP-2 and UCP-3 mRNA and protein levels in human islets cultured in the presence of different glucose concentrations and analyzed UCP3 expression in human pancreatic sections using immunohistochemistry. Dominant 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 is 8-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).

These results suggest that UCP-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