Chronic perifusion of rat islets with palmitate suppresses glucose- stimulated insulin release

Abstract

To test the hypothesis that the high circulating FFA levels in the diabetes of obesity could contribute to the altered dynamics of insulin secretion seen in that condition, insulin release was measured in isolated perifused rat islet cells, without or with added palmitate. Acutely, as in other systems, palmitate (1 mM) stimulated insulin release. Palmitate (1 mM) suppressed both first and second phase insulin release after 2, 3, or 4 h of perifusion, but not after 1 h. No significant effect was noted with 0.3 mM palmitate, and the effect was maximal at 1 mM. The stimulatory effects of arginine were essentially unaffected. Tolbutamide (1 mM) reversed or counteracted the effect. Glucose oxidation was suppressed in islets incubated with 1 mM palmitate for 4 h. Inhibitors of fat oxidation, alpha-bromostearate (1 mM) and methyl-3-tetradecylglycidate (100 microM) reversed the effects of palmitate on glucose-stimulated insulin release and glucose oxidation. Thus, prolonged incubation of rat islet cells with 1 mM palmitate could suppress the glucose-stimulated release of insulin from perifused rat islets. This suppression could be reversed by inhibitors of fat oxidation. This supports the hypothesis that elevated FFA levels and/or increased fat oxidation could contribute to the altered dynamics of insulin secretion in obese diabetics by fuel antagonism as well as the previously documented suppression of peripheral glucose uptake and stimulation of hepatic gluconeogenesis and may be a key link between obesity and the development of diabetes.

Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

“…The deleterious effect of high glucose is well established [2,3], but increased NEFA at physiological glucose concentrations were also able to significantly alter GSIS and insulin content. These results are in accordance with previous studies [6,10,33], but argue against the hypothesis that increased glucose is a prerequisite for the deleterious effect of NEFA on betacell function [11,12,13,14]. We also found that in-action is, at least in part, mediated by modifications in gene expression [9,17].…”

“…The marked increase in CPT-I expression induced by NEFA, and its negative correlation with GSIS suggest that CPT-I could exert a central role in the loss of beta-cell signal recognition induced by NEFA. Those results are concordant with the glucose fatty acid cycle reported in rat islets [6,7,10]. This hypothesis proposes that an increase in NEFA oxidation leads to a decrease in glucose metabolism in beta-cells, according to the Randle cycle observed in other tissues [40].…”

“…The consequence is a reduction in insulin secretion, since it is linked to glucose oxidation. This hypothesis is supported by (i) the restoration of insulin secretion by inhibition of NEFA oxidation and (ii) the specificity of the altered response to glucose, as opposed to other secretagogues [6,7,10]. We report, however, that the concomitant presence of increased glucose and NEFA also induced ACC gene expression in islets.…”

“…ity, was confirmed by in vitro exposure of isolated islets to NEFA [6,7,8]. However, whether glucose and NEFA alter beta-cell function synergistically or separately, remains controversial.…”

“…However, whether glucose and NEFA alter beta-cell function synergistically or separately, remains controversial. Some authors have shown that beta-cell failure was induced by increased glucose alone [2,9] or increased NEFA alone [6,10], while others have suggested that excess glucose or NEFA are not deleterious separately, but synergize in causing glucolipotoxicity [11,12,13,14].…”