期刊
DIABETES
卷 63, 期 10, 页码 3394-3403出版社
AMER DIABETES ASSOC
DOI: 10.2337/db13-1868
关键词
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资金
- Japan Society for the Promotion of Science (JSPS) [24591340, 24890219]
- Japanese Diabetes Foundation
- Salt Science Research Foundation
- Pharmacological Research Foundation (Tokyo, Japan)
- Takeda Science Foundation
- Support Program for Strategic Research Platform for Private University from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan
- Japan Diabetes Foundation
- Uehara Memorial Foundation
- Sumitomo Foundation
- JSPS [23390044]
- MEXT
- Japan Keirin Autorace (JKA) through KEIRIN RACE
- Grants-in-Aid for Scientific Research [26870532, 26460916, 23390044, 24890219, 24591340, 23591320] Funding Source: KAKEN
In pancreatic beta-cells, closure of the ATP-sensitive K+ (K-ATP) channel is an initial process triggering glucose-stimulated insulin secretion. In addition, constitutive opening of background nonselective cation channels (NSCCs) is essentially required to effectively evoke depolarization as a consequence of K-ATP channel closure. Thus, it is hypothesized that further opening of NSCC facilitates membrane excitability. We identified a class of NSCC that was activated by exendin (ex)-4, GLP-1, and its analog liraglutide at picomolar levels. This NSCC was also activated by increasing the glucose concentration. NSCC activation by glucose and GLP-1 was a consequence of the activated cAMP/EPAC-mediated pathway and was attenuated in TRPM2-deficient mice. The NSCC was not activated by protein kinase A (PKA) activators and was activated by ex-4 in the presence of PKA inhibitors. These results suggest that glucose- and incretin-activated NSCC (TRPM2) works in concert with closure of the K-ATP channel to effectively induce membrane depolarization to initiate insulin secretion. The current study reveals a new mechanism for regulating electrical excitability in beta-cells and for mediating the action of glucose and incretin to evoke insulin secretion, thereby providing an innovative target for the treatment of type 2 diabetes.
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