Involvement of cAMP-EPAC-TRPM2 activation in glucose- and incretin-induced insulin secretion.
- Masashi Yoshida1,
- Katsuya Dezaki2,
- Kunitoshi Uchida3,
- Shiho Kodera1,
- Nien V. Lam1,
- Kiyonori Ito1,
- Rauza S. Rita2,
- Hodaka Yamada1,
- Kenju Shimomura2,
- San-e Ishikawa1,
- Hitoshi Sugawara1,
- Masanobu Kawakami1,4,
- Makoto Tominaga3,
- Toshihiko Yada2,3 and
- Masafumi Kakei1,*
- 1Internal Medicine, Jichi Medical University, 1-847 Amanuma Omiya, Saitama 330-8503, Japan.
- 2Integrative Physiology, Jichi Medical University, 3311-1 Yakushiji Shimotsuke 329-0498, Japan.
- 3National Institute of Physiological Science, 5-1 Higashiyama Myodaiji, Okazaki 4444-8787, Japan.
- 4Nerima Hikarigaoka, 2-11-1 Nerima 179-0072, Japan.
- *Correspondence to: Masafumi Kakei: E-mail:
In pancreatic β-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-4, GLP-1 and its analogue 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 PKA activators and was activated by exendin-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 present study reveals a new mechanism for regulating electrical excitability in β-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.
- Received December 11, 2013.
- Accepted May 2, 2014.
- © 2014 by the American Diabetes Association.
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