title: Beta-cell uncoupling protein 2 regulates reactive oxygen species production, which influences both insulin and glucagon secretion.
abstract: OBJECTIVE
  The role of uncoupling protein 2 (UCP2) in pancreatic β-cells is highly debated, partly because of the broad tissue distribution of UCP2 and thus limitations of whole-body UCP2 knockout mouse models. To investigate the function of UCP2 in the β-cell, β-cell-specific UCP2 knockout mice (UCP2BKO) were generated and characterized.
  
  
  METHODS
  UCP2BKO mice were generated by crossing loxUCP2 mice with mice expressing rat insulin promoter-driven Cre recombinase. Several in vitro and in vivo parameters were measured, including respiration rate, mitochondrial membrane potential, islet ATP content, reactive oxygen species (ROS) levels, glucose-stimulated insulin secretion (GSIS), glucagon secretion, glucose and insulin tolerance, and plasma hormone levels.
  
  
  RESULTS
  UCP2BKO β-cells displayed mildly increased glucose-induced mitochondrial membrane hyperpolarization but unchanged rates of uncoupled respiration and islet ATP content. UCP2BKO islets had elevated intracellular ROS levels that associated with enhanced GSIS. Surprisingly, UCP2BKO mice were glucose-intolerant, showing greater α-cell area, higher islet glucagon content, and aberrant ROS-dependent glucagon secretion under high glucose conditions.
  
  
  CONCLUSIONS
  Using a novel β-cell-specific UCP2KO mouse model, we have shed light on UCP2 function in primary β-cells. UCP2 does not behave as a classical metabolic uncoupler in the β-cell, but has a more prominent role in the regulation of intracellular ROS levels that contribute to GSIS amplification. In addition, β-cell UCP2 contributes to the regulation of intraislet ROS signals that mediate changes in α-cell morphology and glucagon secretion.
authors: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: Christine A
authors: CA
authors: Robson-Doucette
authors: Sobia
authors: S
authors: Sultan
authors: Emma M
authors: EM
authors: Allister
authors: Jakob D
authors: JD
authors: Wikstrom
authors: Vasilij
authors: V
authors: Koshkin
authors: Alpana
authors: A
authors: Bhattacharjee
authors: Kacey J
authors: KJ
authors: Prentice
authors: Samuel B
authors: SB
authors: Sereda
authors: Orian S
authors: OS
authors: Shirihai
authors: Michael B
authors: MB
authors: Wheeler
mesh_terms: D000818:Animals; D017930:Genes, Reporter; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D007473:Ion Channels / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D046509:Tissue Culture Techniques; D000071246:Uncoupling Protein 2
chemical_list: D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D005934:Glucagon