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 mu M) 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 epinophrine, 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 Kf-channels because the fatty acid only barely decreased Rb-86 efflux and did not depolarize beta-cells in 3 mM glucose. The small effect on Rb-86 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 Rb-86 efflux under these conditions. Measurements of P-cell membrane potential (intracellular microelectrodes) and of free cytoplasmic calcium (Ca-i(2+)) 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. The rise in Ca-i(2+) produced by palmitate was accompanied by an increase in insulin release only if the concentration of glucose was sufficiently high. The beta-cell response to palmitate thus differs from the responses to glucose and other metabolized nutrients in several respects. Saturated fatty acids appear to potentiate insulin release through an increase in Ca-i(2+) and another, yet unidentified, fuel-dependent mechanism.