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Oleic Acid Glucose-Independently Stimulates Glucagon Secretion by Increasing Cytoplasmic Ca²⁺ via Endoplasmic Reticulum Ca²⁺ Release and Ca²⁺ Influx in the Rat Islet -Cells

Division of Integrative Physiology (K.F., F.M., K.D., M.N., T.Yad.), Department of Physiology, and Division of Histology and Cell Biology (K.F., T.Yas.), Department of Anatomy, Jichi Medical University, School of Medicine, Shimotsuke, Tochigi 329-0498, Japan

Address all correspondence and requests for reprints to: Dr. T. Yada, Department of Physiology, Jichi Medical University, School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. E-mail: tyada{at}jichi.ac.jp.

The effect of long-chain free fatty acids on glucagon secretion from islet -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 -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 -cells, irrespective of glucose concentrations (1.4, 2.8, and 8.3 mM). OA at 10 µM increased [Ca²⁺]_i in 90% of -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 [Ca²⁺]_i increases was reduced substantially by Ca²⁺-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 [Ca²⁺]_i in rat pancreatic -cells and that the [Ca²⁺]_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 -cells may operate under hypoglycemic conditions when plasma free fatty acids levels are elevated, possibly playing a role in maintaining glucose metabolism.

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