Glucose and insulin-induced inhibition of fatty acid oxidation: The glucose-fatty acid cycle reversed

In this study we have investigated a hypothesis that proposes the reverse of the so-called 'glucose-fatty acid cycle,' i.e., that accelerated carbohydrate metabolism directly inhibits fatty acid oxidation. We studied normal volunteers in the basal state and during a hyperinsulinemic, hyperglycemic clamp (plasma insulin = 1,789 ± 119 pmol/l, plasma glucose = 7.7 ± 0.2 mmol/l). We quantified fat oxidation using indirect calorimetry and stable isotopes ([1-¹³C]oleate). Plasma oleate enrichment and free fatty acid (FFA) concentration were kept constant by means of infusion of lipids and heparin. Glucose oxidation increased from basal 6.2 ± 0.8 to 22.3 ± 1.4 μmol · kg^-1 · min^-1 during the clamp (P < 0.01). Total (indirect calorimetry) and plasma fatty acid oxidation (isotopic determination) decreased from 2.6 ± 0.2 to 0.4 ± 0.3 (P < 0.01) and 2.2 ± 0.2 to 1.4 ± 0.1 μmol · kg^-1 · min^-1 (P < 0.05), respectively. We conclude that under the conditions of the present experiment, glucose and/or insulin directly inhibits fatty acid oxidation. Our findings suggest that, contrary to the prediction of the glucose-fatty acid cycle, the intracellular availability of glucose (rather than FFA) determines the nature of substrate oxidation in human subjects.