UCP2 is highly expressed in pancreatic alpha-cells and influences secretion and survival.
In pancreatic beta-cells, uncoupling protein 2 (UCP2) influences mitochondrial oxidative phosphorylation and insulin secretion. Here, we show that alpha-cells express significantly higher levels of UCP2 than do beta-cells. Greater mitochondrial UCP2-related uncoupling was observed in alpha-cells compared with beta-cells and was accompanied by a lower oxidative phosphorylation efficiency (ATP/O). Conversely, reducing UCP2 activity in alpha-cells was associated with higher mitochondrial membrane potential generated by glucose oxidation and with increased ATP synthesis, indicating more efficient metabolic coupling. In vitro, the suppression of UCP2 activity led to reduced glucagon secretion in response to low glucose; however, in vivo, fasting glucagon levels were normal in UCP2(-/-) mice. In addition to its effects on secretion, UCP2 played a cytoprotective role in islets, with UCP2(-/-) alpha-cells being more sensitive to specific death stimuli. In summary, we demonstrate a direct role for UCP2 in maintaining alpha-cell function at the level of glucose metabolism, glucagon secretion, and cytoprotection.
Diao
Jingyu
J
Departments of Physiology and Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8.
Allister
Emma M
EM
Koshkin
Vasilij
V
Lee
Simon C
SC
Bhattacharjee
Alpana
A
Tang
Christine
C
Giacca
Adria
A
Chan
Catherine B
CB
Wheeler
Michael B
MB
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007473:Ion Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D000071246:Uncoupling Protein 2
D007473:Ion Channels; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D000255:Adenosine Triphosphate; D005934:Glucagon