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

Abstract

The effect of long-chain free fatty acids on glucagon secretion from islet α-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 Ca2+ concentration ([Ca2+]i) in single α-cells by fura-2 fluorescence imaging. OA at 30 μM 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 μM concentration- dependently increased [Ca2+]i in α-cells, irrespective of glucose concentrations (1.4, 2.8, and 8.3 mM). OA at 10 μM increased [Ca2+]i in 90% of α-cells. OA-induced [Ca2+]i increases were strongly inhibited by the endoplasmic reticulum Ca2+-pump inhibitors cyclopiazonic acid and thapsigargin and by 2-aminoethoxydiphenyl borate, the blocker of both inositol 1,4,5-trisphosphate receptors and store-operated Ca2+ 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 Ca2+ 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 α-cells and that the [Ca 2+]i increase is triggered by Ca2+ release from endoplasmic reticulum and amplified by Ca2+ influx possibly via store-operated channels and via voltage-dependent L-type Ca2+ channels. The glucose-independent action of OA to stimulate glucagon release from α-cells may operate under hypoglycemic conditions when plasma free fatty acids levels are elevated, possibly playing a role in maintaining glucose metabolism. Copyright © 2007 by The Endocrine Society.