Uncoupling protein 2 regulates reactive oxygen species formation in islets and influences susceptibility to diabetogenic action of streptozotocin.
Currently, the physiological function of uncoupling protein-2 (UCP2) in pancreatic islets and its role in the development of diabetes is a matter of great debate. To further investigate the impact of UCP2 on diabetes development, we used streptozotocin (STZ) to experimentally generate diabetes in both wild-type (WT) and UCP2-knockout (UCP2KO) mice. While multiple low-dose STZ injections led to hyperglycemia development over a 14-day period in both WT and UCP2KO mice, we found the development of hyperglycemia to be significantly less severe in the UCP2KO mice. Measurement of insulin and glucagon secretion (in vitro), as well as their plasma concentrations (in vivo), indicated that UCP2-deficiency showed enhanced insulin secretion but impaired alpha-cell function. Glucagon secretion was attenuated, despite reduced insulin secretion after exposure to STZ, which together contributed to less severe hyperglycemia development in UCP2KO mice. Further experimentation revealed that UCP2-deficient alpha- and beta-cells had chronically higher cellular reactive oxygen species (ROS) levels than the WT prior to STZ application, which correlated with increased basal beta- and alpha-cell mass. Overall, we suggest that increased chronic ROS signaling as a result of UCP2-deficiency contributes to enhanced beta-cell function and impairment of alpha-cell function, leading to an attenuation of STZ-induced hyperglycemia development.
Lee
Simon C
SC
Department of Physiology, University of Toronto, 1 King's College Circle (Room 3352), Toronto, Ontario, Canada M5S 1A8.
Robson-Doucette
Christine A
CA
Wheeler
Michael B
MB
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D005934:Glucagon / Q000097:blood / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013311:Streptozocin / Q000008:administration & dosage; D000071246:Uncoupling Protein 2
D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D013311:Streptozocin; D005934:Glucagon