Niflumic acid-sensitive ion channels play an important role in the induction of glucose-stimulated insulin secretion by cyclic AMP in mice

W. Fujimoto, T. Miki, T. Ogura, M. Zhang, Y. Seino, L. S. Satin, H. Nakaya, S. Seino

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

Aims/hypothesis: We have previously reported that glucose-stimulated insulin secretion (GSIS) is induced by glucagon-like peptide-1 (GLP-1) in mice lacking ATP-sensitive K+ (KATP) channels (Kir6.2 -/- mice [up-to-date symbol for Kir6.2 gene is Kcnj11]), in which glucose alone does not trigger insulin secretion. This study aimed to clarify the mechanism involved in the induction of GSIS by GLP-1. Methods: Pancreas perfusion experiments were performed using wild-type (Kir6.2 +/+ ) or Kir6.2 -/- mice. Glucose concentrations were either changed abruptly from 2.8 to 16.7 mmol/l or increased stepwise (1.4 mmol/l per step) from 2.8 to 12.5 mmol/l. Electrophysiological experiments were performed using pancreatic beta cells isolated from Kir6.2 -/- mice or clonal pancreatic beta cells (MIN6 cells) after pharmacologically inhibiting their KATP channels with glibenclamide. Results: The combination of cyclic AMP plus 16.7 mmol/l glucose evoked insulin secretion in Kir6.2 -/- pancreases where glucose alone was ineffective as a secretagogue. The secretion was blocked by the application of niflumic acid. In KATP channel-inactivated MIN6 cells, niflumic acid similarly inhibited the membrane depolarisation caused by cAMP plus glucose. Surprisingly, stepwise increases of glucose concentration triggered insulin secretion only in the presence of cAMP or GLP-1 in Kir6.2 +/+ , as in Kir6.2 -/- pancreases. Conclusions/ interpretation: Niflumic acid-sensitive ion channels participate in the induction of GSIS by cyclic AMP in Kir6.2 -/- beta cells. Cyclic AMP thus not only acts as a potentiator of insulin secretion, but appears to be permissive for GSIS via novel, niflumic acid-sensitive ion channels. This mechanism may be physiologically important for triggering insulin secretion when the plasma glucose concentration increases gradually rather than abruptly.

Original languageEnglish
Pages (from-to)863-872
Number of pages10
JournalDiabetologia
Volume52
Issue number5
DOIs
Publication statusPublished - 05-2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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