Involvement of cAMP-EPAC-TRPM2 activation in glucose- and incretin-induced insulin secretion.

  1. Masafumi Kakei1,*
  1. 1Internal Medicine, Jichi Medical University, 1-847 Amanuma Omiya, Saitama 330-8503, Japan.
  2. 2Integrative Physiology, Jichi Medical University, 3311-1 Yakushiji Shimotsuke 329-0498, Japan.
  3. 3National Institute of Physiological Science, 5-1 Higashiyama Myodaiji, Okazaki 4444-8787, Japan.
  4. 4Nerima Hikarigaoka, 2-11-1 Nerima 179-0072, Japan.
  1. *Correspondence to: Masafumi Kakei: E-mail: mkakei{at}jichi.ac.jp

Abstract

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.

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  1. Diabetes
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