Mechanisms of the stimulation of insulin release by saturated fatty acids. A study of palmitate effects in mouse beta-cells.
The mechanisms by which fatty acids increase insulin release are not known. In this study, mouse islets were used as a model and palmitate as a reference compound to study in vitro how saturated fatty acids influence pancreatic beta-cells. Palmitate (625 microM) was bound to albumin. It did not affect basal insulin release (3 mM glucose) but increased the release induced by 10-15 mM glucose. This effect was dependent on the concentration of free rather than total palmitate. It was reversible and abolished by epinephrine, diazoxide, nimodipine, or omission of extracellular Ca. Bromopalmitate and methyl palmoxirate, two inhibitors of fatty acid oxidation, were ineffective alone, and only bromopalmitate partially inhibited the effects of palmitate on insulin release. The increase in insulin release produced by palmitate could not be ascribed to a blockade of ATP-sensitive K(+)-channels because the fatty acid only barely decreased 86Rb efflux and did not depolarize beta-cells in 3 mM glucose. The small effect on 86Rb efflux might be attributed to a slight rise in the ATP/ADP ratio. No such rise occurred when palmitate was tested in 15 mM glucose, and the fatty acid consistently accelerated 86Rb efflux under these conditions. Measurements of beta-cell membrane potential (intracellular microelectrodes) and of free cytoplasmic calcium (Cai2+) in beta-cells (Fura 2 technique) showed that palmitate increases Ca2+ influx; it also caused a very small mobilization of intracellular Ca. The persistence of this stimulation of Ca2+ influx in the presence of diazoxide and high K+ suggests that palmitate might act on Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)
Warnotte
C
C
Endocrinology and Metabolism Unit, University of Louvain, Faculty of Medicine, Brussels, Belgium.
Gilon
P
P
Nenquin
M
M
Henquin
J C
JC
D000227:Adenine Nucleotides / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D009553:Nimodipine / Q000494:pharmacology; D010168:Palmitates / Q000494:pharmacology; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000494:pharmacology*; D012413:Rubidium / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D013997:Time Factors
D000227:Adenine Nucleotides; D004852:Epoxy Compounds; D005227:Fatty Acids; D007328:Insulin; D010168:Palmitates; D010169:Palmitic Acids; C022776:2-bromopalmitate; D012710:Serum Albumin, Bovine; D019308:Palmitic Acid; D009553:Nimodipine; D005947:Glucose; D012413:Rubidium; C021756:2-tetradecylglycidic acid; D002118:Calcium