Mechanisms of the Stimulation of Insulin Release by Saturated Fatty Acids: A Study of Palmitate Effects in Mouse β-cells

Abstract

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)

Interaction between specific fatty acids, GLP-1 and insulin secretion in humans

“…Short-term in vitro incubation of islets with longchain fatty acids increased insulin release during glucose stimulation [10,11]. This was also seen in healthy volunteers after a short-term increase of plasma NEFA concentrations by Intralipid and heparin [12,13,14].…”

“…From numerous isolated islet studies it has become clear that fatty acids have a direct effect on the beta cell and that short-term incubation of fatty acids gives rise to an amplified insulin response, increasing with chain length and degree of saturation [10,19]. A direct stimulatory effect of fatty acids upon islets provides a plausible explanation for the greater insulinotropic effect with increased NEFA concentrations, as seen in this study, although in vivo, other factors, such as insulin sensitivity, hepatic insulin clearance and other stimulants have to be considered.…”

Pleiotropic effects of fatty acids on pancreatic β‐cells

“…This condition is characterized by hyperglycemia and hyperinsulinemia, as found in type 2 diabetes and obesity (Randle et al, 1963;McGarry, 1992;Littman et al, 2000). FA are recognized to stimulate insulin secretion in vitro (Malaisse and Malaisse-Lagae, 1968;Opara et al, 1992) and to modulate the stimulatory effect of glucose on insulin release (Vara et al, 1988;Warnotte et al, 1994). A direct effect of the FA on insulin secretion in vivo explains the coexistence of hyperlipidemia and hyperinsulinemia.…”

“…A direct effect of the FA on insulin secretion in vivo explains the coexistence of hyperlipidemia and hyperinsulinemia. Although, it has been accepted that fatty acid oxidation is necessary for fatty acid stimulation of insulin secretion (Malaisse et al, 1985;Warnotte et al, 1994), the complete mechanism by which FA may stimulate insulin secretion remains unknown. In particular, the subsequent events downstream to fatty acid oxidation remain to be determined.…”

“…In particular, the subsequent events downstream to fatty acid oxidation remain to be determined. It had been suggested that fatty acid oxidation results in increased ATP production, which is thought to initiate the process of insulin secretion induced by glucose (Warnotte et al, 1994). However, the ATP-mediated hypothesis for nutrient stimulation of insulin secretion has sometimes been questioned (MacDonald, 1990), leading propositions for the existence of both ATPdependent and ATP-independent pathways for glucose induction of insulin secretion (Aizawa et al, 1994;Meredith et al, 1995).…”