Objective- TRPM2 is a Ca2+ permeable non-selective cation channel activated by adenosine dinucleotides. We previously demonstrated that TRPM2 is activated by co-application of heat and intracellular cyclic adenosine 5′-diphosphoribose, which has been suggested to be involved in intracellular Ca2+ increase in immunocytes and pancreatic β-cells. To clarify the involvement of TRPM2 in insulin secretion, we analyzed TRPM2 knock-out (TRPM2-KO) mice.
Research Design And Methods- Oral and intraperitoneal glucose tolerance tests (OGTT and IPGTT) were performed in TRPM2-KO and wild-type (WT) mice. We also measured cytosolic free Ca2+ in single pancreatic cells using fura-2 microfluorometry, and insulin secretion from pancreatic islets.
Results- Basal blood glucose levels were higher in TRPM2-KO mice than in WT 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 WT mice, which was associated with an impairment in insulin secretion. In isolated β-cells, smaller intracellular Ca2+ increase was observed in response to high concentrations of glucose and incretin hormone in TRPM2-KO cells than in WT cells. Moreover, insulin secretion from the islets of TRPM2-KO mice in response to glucose and incretin hormone treatment was impaired while 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.
- Received February 25, 2010.
- Accepted September 24, 2010.
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