title: Niflumic acid-sensitive ion channels play an important role in the induction of glucose-stimulated insulin secretion by cyclic AMP in mice.
abstract: OBJECTIVE
  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(+) (K(ATP)) 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 K(ATP) 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 K(ATP) 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
  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.
authors.affiliation: Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
authors.forename: W
authors.initials: W
authors.lastname: Fujimoto
authors.forename: T
authors.initials: T
authors.lastname: Miki
authors.forename: T
authors.initials: T
authors.lastname: Ogura
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Seino
authors.forename: L S
authors.initials: LS
authors.lastname: Satin
authors.forename: H
authors.initials: H
authors.lastname: Nakaya
authors.forename: S
authors.initials: S
authors.lastname: Seino
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000494:pharmacology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D017931:DNA Primers; D005947:Glucose / Q000494:pharmacology*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma; D007421:Intestine, Small / Q000502:physiology; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009544:Niflumic Acid / Q000494:pharmacology*; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099161:Kcnj11 Channel
chemical_list: D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D017931:DNA Primers; D005947:Glucose; D007041:Hypoxanthine Phosphoribosyltransferase; D007328:Insulin; D007473:Ion Channels; D009544:Niflumic Acid; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel