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This Article Full Text Full Text (PDF) Supplementary data All Versions of this Article: JOE-09-0117v1 203/1/33    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Lee, S. C Articles by Wheeler, M. B Search for Related Content PubMed PubMed Citation Articles by Lee, S. C Articles by Wheeler, M. B

Departments of Physiology and Medicine, University of Toronto, 1 King's College Circle (Room 3352), Toronto, Ontario, Canada M5S 1A8

(Correspondence should be addressed to M B Wheeler; Email: michael.wheeler{at}utoronto.ca)

^* (S C Lee and C A Robson-Doucette contributed equally to this work)

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 -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 - and β-cells had chronically higher cellular reactive oxygen species (ROS) levels than the WT prior to STZ application, which correlated with increased basal β- and -cell mass. Overall, we suggest that increased chronic ROS signaling as a result of UCP2-deficiency contributes to enhanced β-cell function and impairment of -cell function, leading to an attenuation of STZ-induced hyperglycemia development.

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