Mechanisms of fatty acid-induced inhibition of glucose uptake.

Abstract

Increased plasma FFA reduce insulin-stimulated glucose up- take. The mechanisms responsible for this inhibition, however, remain uncertain. It was the aim of this study to determine whether the FFA effect was dose dependent and to investigate its mechanism. We have examined in healthy volunteers (13 male/1 female) the effects of three steady state plasma FFA levels ( -50, -550, -750 MuM) on rates of glucose uptake, glycolysis (both with 3-3H-glucose), glycogen synthesis (de- termined with two independent methods), carbohydrate (CHO) oxidation (by indirect calorimetry), hepatic glucose output, and nonoxidative glycolysis (glycolysis minus CHO ox- idation) during euglycemic-hyperinsulinemic clamping. In- creasing FFA concentration (from -50 to -750 gM) de- creased glucose uptake in a dose-dependent fashion (from -9 to -4 mg/kg per min). The decrease was caused mainly (-2/3) by a reduction in glycogen synthesis and to a lesser extent ( 1/3) by a reduction in CHO oxidation. We have iden- tified two independent defects in glycogen synthesis. The first consisted of an impairment of muscle glycogen synthase activ- ity. It required high FFA concentration ( -750MM), was asso- ciated with an increase in glucose-6-phosphate, and developed after 4-6 h of fat infusion. The second defect, which preceded the glycogen synthase defect, was seen at medium ( -550MM) FFA concentration, was associated with a decrease in muscle glucose-6-phosphate concentration, and was probably due to a reduction in glucose transport/phosphorylation. In addition, FFA and/or glycerol increased insulin-suppressed hepatic glucose output by -50%. We concluded that fatty acids caused a dose-dependent inhibition of insulin-stimulated glucose uptake (by decreasing glycogen synthesis and CHO oxidation) and that FFA and/or glycerol increased insulin-suppressed hepatic glucose output and thus caused insulin resistance at the peripheral and the hepatic level. (J. Clin. Invest. 1994 . 93 :2438- 2446.) Key words: glycogen synthesis * glycolysis -carbohy- drate oxidation * glycogen synthase * glycogen phosphorylase state fatty acid levels (-50, 550, -750 uM) on rates of glucose uptake, glycolysis, glycogen synthesis, carbohydrate (CHO) oxidation, nonoxidative glycolysis (lactate/alanine fluxes), and on hepatic glucose output (HGO) in healthy vol- unteers during euglycemic hyperinsulinemia. Methods Subjects 14 healthy, normal weight volunteers (13 men and 1 woman) were studied. We were unable to recruit more women, largely because ofthe 1.