title: UCP2 regulates the glucagon response to fasting and starvation.
abstract: Glucagon is important for maintaining euglycemia during fasting/starvation, and abnormal glucagon secretion is associated with type 1 and type 2 diabetes; however, the mechanisms of hypoglycemia-induced glucagon secretion are poorly understood. We previously demonstrated that global deletion of mitochondrial uncoupling protein 2 (UCP2(-/-)) in mice impaired glucagon secretion from isolated islets. Therefore, UCP2 may contribute to the regulation of hypoglycemia-induced glucagon secretion, which is supported by our current finding that UCP2 expression is increased in nutrient-deprived murine and human islets. Further to this, we created α-cell-specific UCP2 knockout (UCP2AKO) mice, which we used to demonstrate that blood glucose recovery in response to hypoglycemia is impaired owing to attenuated glucagon secretion. UCP2-deleted α-cells have higher levels of intracellular reactive oxygen species (ROS) due to enhanced mitochondrial coupling, which translated into defective stimulus/secretion coupling. The effects of UCP2 deletion were mimicked by the UCP2 inhibitor genipin on both murine and human islets and also by application of exogenous ROS, confirming that changes in oxidative status and electrical activity directly reduce glucagon secretion. Therefore, α-cell UCP2 deletion perturbs the fasting/hypoglycemic glucagon response and shows that UCP2 is necessary for normal α-cell glucose sensing and the maintenance of euglycemia.
authors: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: Emma M
authors: EM
authors: Allister
authors: Christine A
authors: CA
authors: Robson-Doucette
authors: Kacey J
authors: KJ
authors: Prentice
authors: Alexandre B
authors: AB
authors: Hardy
authors: Sobia
authors: S
authors: Sultan
authors: Herbert Y
authors: HY
authors: Gaisano
authors: Dong
authors: D
authors: Kong
authors: Patrick
authors: P
authors: Gilon
authors: Pedro L
authors: PL
authors: Herrera
authors: Bradford B
authors: BB
authors: Lowell
authors: Michael B
authors: MB
authors: Wheeler
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D031204:Caloric Restriction / Q000009:adverse effects*; D005215:Fasting / Q000009:adverse effects*; D005934:Glucagon / Q000235:genetics / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000209:etiology*; D007473:Ion Channels / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D046509:Tissue Culture Techniques; D014475:Uncoupling Agents / Q000494:pharmacology; D000071246:Uncoupling Protein 2; D015854:Up-Regulation
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D014475:Uncoupling Agents; D000071246:Uncoupling Protein 2; D000255:Adenosine Triphosphate; D005934:Glucagon