. Differential effect of saturated and polyunsaturated fatty acids on hepatic glucose metabolism in humans. Am J Physiol Endocrinol Metab 287: E358 -E365, 2004. First published April 13, 2004 10.1152/ajpendo.00360.2003.-Prolonged infusions of lipid and heparin that achieve high physiological free fatty acid (FFA) concentrations inhibit hepatic (and peripheral) insulin sensitivity in humans. These infusions are composed largely of polyunsaturated fatty acids (PUFA; linoleic and linolenic). It is not known whether fatty acid composition per se affects hepatic glucose metabolism in humans. To address this issue, we examined the impact of enteral infusions of either palm oil (48% palmitic, 35% oleic, and 8% linoleic acids) or safflower oil (6% palmitic, 12% oleic, 74% linoleic acids) in 14 obese nondiabetic subjects.2 H2O was administered to determine the contribution of gluconeogenesis to endogenous glucose production (EGP), and a primed continuous infusion of [6,6-2 H]glucose was administered to assess glucose appearance. As a result of the lipid infusions, plasma FFA concentrations increased significantly in both the palm oil (507.5 Ϯ 47.4 to 939.3 Ϯ 61.3 mol/l, P Ͻ 0.01) and safflower oil (588.2.0 Ϯ 43.0 to 857.8 Ϯ 68.7 mol/l, P Ͻ 0.01) groups after 4 h. EGP was similar at baseline (12.4 Ϯ 1.8 vs. 11.2 Ϯ 1.0 mol ⅐ kg FFM Ϫ1 ⅐ min Ϫ1 ). During a somatostatin-insulin clamp, the glucose infusion rate was significantly lower (AUC glucose infusion rate 195.8 Ϯ 50.7 vs. 377.8 Ϯ 38.0 mol/kg FFM, P Ͻ 0.01), and rates of EGP were significantly higher (10.7 Ϯ 1.4 vs. 6.5 Ϯ 1.5 mol ⅐ kg FFM Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.01) after palm oil compared with safflower oil, respectively. Baseline rates of gluconeogenesis and glycogenolysis were also similar. However, after lipid infusion, rates of glycogenolysis were suppressed by safflower oil but not by palm oil. Thus these studies demonstrate, for the first time in humans, a differential effect of saturated fatty acids and PUFA on hepatic glucose metabolism. hepatic autoregulation; gluconeogenesis; glycogenolysis A ROLE FOR FATTY ACIDS in hepatic insulin resistance is well established (22,45). Experimental elevations in plasma free fatty acids (FFA) are associated with impaired suppression of endogenous glucose production (EGP) by insulin (7,22). There is also evidence for a link between increased FFA availability and increased gluconeogenesis in humans (13,17,48,52). However, the stimulation or suppression of gluconeogenesis in vivo is not generally associated with changes in EGP. In fact, gluconeogenesis is increased in obese nondiabetic individuals without an increase in EGP (21, 25). Thus regulation of hepatic glycogen storage is increasingly recognized as a critical component to the regulation of EGP and fasting hyperglycemia (17,25,52). Evidence that fatty acids play an important role in the regulation of liver glycogen is provided by recent studies that examined glycogenolysis directly by nuclear magnetic resonance during infusions of saline or Intralipid. In association with the...