Free fatty acids increase basal hepatic glucose production and induce hepatic insulin resistance at different sites

Departments of 1 Physiology and 2 Medicine, University of Toronto, Toronto, Canada M5S 1A8; and 3 Department of Nutrition, University of Montreal, Montreal, Quebec, Canada H3C 3J7 To investigate the sites of the free fatty acid (FFA) effects to increase basal hepatic glucose production and to impair hepatic insulin action, we performed 2-h and 7-h Intralipid + heparin (IH) and saline infusions in the basal fasting state and during hyperinsulinemic clamps in overnight-fasted rats. We measured endogenous glucose production (EGP), total glucose output (TGO, the flux through glucose-6-phosphatase), glucose cycling (GC, index of flux through glucokinase = TGO EGP), hepatic glucose 6-phosphate (G-6- P ) content, and hepatic glucose-6-phosphatase and glucokinase activities. Plasma FFA levels were elevated about threefold by IH. In the basal state, IH increased TGO, in vivo glucose-6-phosphatase activity (TGO/G-6- P ), and EGP ( P