Inducible Deletion of UCP2 in Pancreatic β-Cells Enhances Insulin Secretion

Abstract

In pancreatic β-cells, uncoupling protein 2 (UCP2) is thought to negatively regulate insulin secretion; however, its role is still debated, in part due to the confounding effects of long-term UCP2 deletion in current knockout mouse models. We have now generated an inducible β-cell-specific UCP2 deletion model by crossing loxUCP2 mice with those that express a Cre recombinase-estrogen receptor fusion protein driven by the mouse insulin promoter (MIPCreER). Because tamoxifen, which was used to induce UCP2 deletion, is an uncoupling agent, we initially determined whether tamoxifen affected glycemia. Initially, C57BL/6 control mice were injected intraperitoneally with tamoxifen or vehicle (corn oil [CO]) 3 times in 1 week, and the mice examined 2 weeks postinjection. Both groups of mice displayed similar glucose tolerance and in vivo and in vitro insulin secretion, suggesting no effects of tamoxifen on glucose homeostasis and β-cell function. MIPCreER×loxUCP2 male littermates were then injected with tamoxifen to induce β-cell-specific UCP2 deletion (ind.UCP2BKO) or with CO as described above. UCP2 deletion was confirmed by polymerase chain reaction (PCR) analysis of islets. There were no differences in fasting glucose, glucagon or insulin in ind.UCP2BKO mice and glucose (OGTT) and insulin tolerance tests revealed similar levels of glucose and insulin sensitivity. However, ind.UCP2BKO mice sustained significantly higher plasma insulin levels during an OGTT and isolated islets secreted more insulin in response to high glucose. Together, these results suggest that short-term deletion of β-cell UCP2 in adult mice leads to the direct enhancement of insulin secretion.