Oleic acid glucose-independently stimulates glucagon secretion by increasing cytoplasmic Ca2+ via endoplasmic reticulum Ca2+ release and Ca2+ influx in the rat islet alpha-cells

Endocrinology. 2007 May;148(5):2496-504. doi: 10.1210/en.2006-1156. Epub 2007 Feb 8.


The effect of long-chain free fatty acids on glucagon secretion from islet alpha-cells has been a controversial issue. This study examined direct effects of oleic acid (OA) on glucagon release from rat pancreatic islets and on cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) in single alpha-cells by fura-2 fluorescence imaging. OA at 30 microM increased glucagon release from isolated islets in the presence of low (2.8 mM) and elevated (8.3 mM) glucose concentrations. OA at 6-10 microm concentration-dependently increased [Ca(2+)](i) in alpha-cells, irrespective of glucose concentrations (1.4, 2.8, and 8.3 mM). OA at 10 mum increased [Ca(2+)](i) in 90% of alpha-cells. OA-induced [Ca(2+)](i) increases were strongly inhibited by the endoplasmic reticulum Ca(2+)-pump inhibitors cyclopiazonic acid and thapsigargin and by 2-aminoethoxydiphenyl borate, the blocker of both inositol 1,4,5-trisphosphate receptors and store-operated Ca(2+) channels. Furthermore, the amplitude, but not incidence, of OA-induced [Ca(2+)](i) increases was reduced substantially by Ca(2+)-free conditions and mildly by an L-type Ca(2+) channel blocker, nitrendipine, and an ATP-sensitive K(+) channel activator, diazoxide. OA-induced glucagon release was also inhibited mildly by nitrendipine and strongly by 2-aminoethoxydiphenyl borate. These results indicate that OA glucose-independently stimulates glucagon release by increasing [Ca(2+)](i) in rat pancreatic alpha-cells and that the [Ca(2+)](i) increase is triggered by Ca(2+) release from endoplasmic reticulum and amplified by Ca(2+) influx possibly via store-operated channels and via voltage-dependent L-type Ca(2+) channels. The glucose-independent action of OA to stimulate glucagon release from alpha-cells may operate under hypoglycemic conditions when plasma free fatty acids levels are elevated, possibly playing a role in maintaining glucose metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Boron Compounds / pharmacology
  • Calcium / metabolism*
  • Cytoplasm / metabolism
  • Dose-Response Relationship, Drug
  • Endoplasmic Reticulum / metabolism
  • Enzyme Inhibitors / pharmacology
  • Fluorescent Dyes
  • Fura-2
  • Glucagon / metabolism*
  • Glucagon-Secreting Cells / drug effects*
  • Glucagon-Secreting Cells / metabolism*
  • Glucose / pharmacology*
  • Indoles / pharmacology
  • Oleic Acid / pharmacology*
  • Rats
  • Rats, Wistar
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / antagonists & inhibitors
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Thapsigargin / pharmacology


  • Boron Compounds
  • Enzyme Inhibitors
  • Fluorescent Dyes
  • Indoles
  • Oleic Acid
  • Thapsigargin
  • Glucagon
  • 2-aminoethoxydiphenyl borate
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Glucose
  • Calcium
  • Fura-2
  • cyclopiazonic acid