CHRONIC PERIFUSION OF RAT ISLETS WITH PALMITATE SUPPRESSES GLUCOSE-STIMULATED INSULIN RELEASE

To test the hypothesis that the high circulating FFA levels in the dia betes of obesity could contribute to the altered dynamics of insulin s ecretion seen in that condition, insulin release was measured in isola ted perifused rat islet cells, without or with added palmitate. Acutel y, as in other systems, palmitate (1 mM) stimulated insulin release. P almitate (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 e ffect 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 oxidat ion was suppressed in islets incubated with 1 mM palmitate for 4 h. In hibitors of fat oxidation, alpha-bromostearate (1 mM) and methyl-3-tet radecylglycidate (100 muM) reversed the effects of palmitate on glucos e-stimulated insulin release and glucose oxidation. Thus, prolonged in cubation of rat islet cells with 1 mM palmitate could suppress the glu cose-stimulated release of insulin from perifused rat islets. This sup pression could be reversed by inhibitors of fat oxidation. This suppor ts the hypothesis that elevated FFA levels and/or increased fat oxidat ion could contribute to the altered dynamics of insulin secretion in o bese diabetics by fuel antagonism as well as the previously documented suppression of peripheral glucose uptake and stimulation of hepatic g luconeogenesis and may be a key link between obesity and the developme nt of diabetes.