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 triglycerides and a lowered EC50 (concentration at half-maximal stimulation) for glucose-induced insulin secretion. Culturing islets with long-chain fatty acids (FAs) replicates the basal insulin hypersecretion. In a previous study, we showed that the mechanism involved deinhibition of hexokinase by a 60% decrease in glucose-6-phosphate (G-6-P). The key event was proposed to be an increased phosphofructokinase (PFK) Vmax secondary to an upregulatory effect of the FA metabolite, long-chain acyl-coenzyme A (LC-CoA). We now show another contributory factor, a lowered content of the PFK inhibitor citrate. Citrate synthase Vmax and citrate levels were lowered 45% in rat islets cultured with 250 micromol/l oleate for 24 h. Both effects were reversed by triacsin C, an inhibitor of fatty acyl-CoA synthetase, the enzyme that generates LC-CoA. Culturing islets with high doses of glucose (16.7 mmol/l) for 48 h should also raise cytosolic LC-CoA. As predicted, citrate synthase Vmax was lowered and PFK Vmax was increased, both in a triacsin C-reversible fashion. These results show shared selected functional and biochemical properties in beta-cells of so-called glucotoxicity and lipotoxicity.
Liu
Y Q
YQ
Division of Endocrinology, Diabetes and Metabolism, University of Vermont, Burlington, USA.
Tornheim
K
K
Leahy
J L
JL
D000818:Animals; D002950:Citrate (si)-Synthase / Q000187:drug effects* / Q000378:metabolism; D002951:Citrates / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000187:drug effects* / Q000201:enzymology; D007700:Kinetics; D019301:Oleic Acid / Q000008:administration & dosage / Q000494:pharmacology; D010592:Pharmaceutic Aids / Q000008:administration & dosage / Q000494:pharmacology; D010732:Phosphofructokinase-1 / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D002951:Citrates; D005227:Fatty Acids; D010592:Pharmaceutic Aids; D019301:Oleic Acid; D002950:Citrate (si)-Synthase; D010732:Phosphofructokinase-1; D005947:Glucose