UCP-2 and UCP-3 proteins are differentially regulated in pancreatic beta-cells.
BACKGROUND
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. In the present studies we hypothesize an opposing effect of glucose on the regulation of UCP-2 and UCP-3 in pancreatic islets.


METHODS
Dominant 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.


RESULTS
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 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 approximately 2-fold after high glucose exposure, whereas UCP-3 protein expression was decreased by approximately 40% (p<0.05). UCP-3 overexpression improved glucose-stimulated insulin secretion.


CONCLUSIONS
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.
Li
Yunfeng
Y
Larry L. Hillblom Islet Research Center, The David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
Maedler
Kathrin
K
Shu
Luan
L
Haataja
Leena
L
D000256:Adenoviridae / Q000235:genetics; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007473:Ion Channels / Q000235:genetics*; D007515:Islets of Langerhans / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D014161:Transduction, Genetic; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
D017931:DNA Primers; D005227:Fatty Acids; D007473:Ion Channels; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; C000604389:UCP2 protein, human; C000604392:UCP3 protein, human; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D005947:Glucose