Lack of TRPM2 impaired insulin secretion and glucose metabolisms in mice.
- Kunitoshi Uchida1,2,
- Katsuya Dezaki3,
- Boldbaatar Damdindorj3,
- Hitoshi Inada1,
- Tetsuya Shiuchi2,4,
- Yasuo Mori5,
- Toshihiko Yada3,6,
- Yasuhiko Minokoshi2,4 and
- Makoto Tominaga ()1,2
- 1 Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Japan
- 2 Department of Physiological Sciences, The Graduate University for Advanced Studies, Okazaki, Japan, 3 Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Tochigi, Japan, 4 Division of Endocrinology and Metabolism, National Institute for Physiological Sciences, Okazaki, Japan
- 3 Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Tochigi, Japan
- 4 Division of Endocrinology and Metabolism, National Institute for Physiological Sciences, Okazaki, Japan
- 5 Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
- 6 Department of Developmental Physiology, Division of Adaptation Development, National Institute for Physiological Sciences, Okazaki, Japan
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.
- Copyright © American Diabetes Association