Lack of TRPM2 Impaired Insulin Secretion and Glucose Metabolisms in Mice

摘要

Objective-trpm2 is a ca~(2+)-permeable nonselective cation channel activated by adenosine dinucleotides. We previously demonstrated that trpm2 is activated by coapplication of heat and intracellular cyclic adenosine 5'-diphosphoribose, which has been suggested to be involved in intracellular ca~(2+) increase in immunocytes and pancreatic β-cells. To clarify the involvement of trpm2 in insulin secretion, we analyzed trpm2 knockout (trpm2-ko) mice. Research design and methods-oral and intraperito-neal glucose tolerance tests (ogtt and ipgtt) were performed in trpm2-ko and wild-type mice. We also measured cytosolic free ca~(2+) in single pancreatic cells using fura-2 microfluorometry and insulin secretion from pancreatic islets. Results-basal blood glucose levels were higher in trpm2-k0 mice than in wild-type mice without any difference in plasma insulin levels. The ogtt and ipgtt demonstrated that blood glucose levels in trpm2-ko mice were higher than those in wild-type mice, which was associated with an impairment in insulin secretion. In isolated p-cells, smaller intracellular ca~(2+) increase was observed in response to high concentrations of glucose and incretin hormone in trpm2-ko cells than in wild-type cells. Moreover, insulin secretion from the islets of trpm2-k0 mice in response to glucose and incretin hormone treatment was impaired, whereas the response to tolbutamide, an atp-sensitive potassium channel inhibitor, was not different between the two groups. Conclusions-these results indicate that trpm2 is involved in insulin secretion stimulated by glucose and that further potentiated by incretins. Thus, trpm2 may be a new target for diabetes therapy. Diabetes 60:119-126, 2011