The Oxidative Stress-Sensitive Ca²⁺ Channel, TRPM2, Contributes to Diabetes Progression Accompanied by ER Stress

Abstract

Beta cell dysfunction is a critical factor contributing to decreases in insulin secretion. A growing body of evidence suggests the involvement of endoplasmic reticulum (ER) stress in beta cell dysfunction, which leads to the development of diabetes. On the other hand, oxidative stress also plays a role in the development of diabetes with beta cell dysfunction. Transient receptor potential melastatin 2 (TRPM2) is a Ca²⁺-permeable channel activated by oxidative stress and is highly expressed in beta cells. Some studies have claimed that Ca²⁺ influxes via TRPM2 in response to oxidative stress are involved in beta cell dysfunction accompanied by cell death. Although ER stress and oxidative stress form a mutually reinforcing cycle, the relationship in diabetes development between ER stress and the oxidative stress-sensitive TRP channel, TRPM2, has yet to be investigated. Therefore, we herein examined this relationship using Akita mice. Akita mice develop diabetes by ER stress-induced beta cell dysfunction accompanied by cell death. We found that increases in blood glucose in Akita mice were attenuated by the disruption of Trpm2. Additionally, in a glucose tolerance test, abnormal blood glucose increases with glucose loading in Akita mice were attenuated by the disruption of Trpm2. The results of this study using Akita mice suggest that the oxidative stress-sensitive channel, TRPM2, contributes to diabetes progression associated with ER stress.