SHARED BIOCHEMICAL-PROPERTIES OF GLUCOTOXICITY AND LIPOTOXICITY IN ISLETS DECREASE CITRATE SYNTHASE ACTIVITY AND INCREASE PHOSPHOFRUCTOKINASE ACTIVITY

Diabetic states are characterized by a raised serum/islet level of tri glycerides and a lowered EC,, (concentration at half-maximal stimulati on) for glucose-induced insulin secretion. Culturing islets with long- chain fatty acids (FAs) replicates the basal insulin hypersecretion. I n a previous study, we showed that the mechanism involved deinhibition of hexokinase by a 60% decrease in glucose-g-phosphate (G-6-P). The k ey event was proposed to be an increased phosphofructokinase (PFK) V-m ax secondary to an upregulatory effect of the FA metabolite, long-chai n acyl-coenzyme A (LC-CoA). We now show another contributory factor, a lowered content of the PFK inhibitor citrate. Citrate synthase V-max and citrate levels were lowered 45% in rat islets cultured with 250 mu mol/l oleate for 24 h. Both effects were reversed by triacsin C, an i nhibitor of fatty acyl-CoA synthetase, the enzyme that generates LC-Co A. Culturing islets with high doses of glucose (16.7 mmol/l) for 48 h should also raise cytosolic LC-CoA. As predicted, citrate synthase V-m ax was lowered and PFK V-max was increased, both in a triacsin C-rever sible fashion. These results show shared selected functional and bioch emical properties in beta-cells of so-called glucotoxicity and lipotox icity.