Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans

Effects of free fatty acids (FFAs) on endogenous glucose production (EGP) and gluconeogenesis (GNG) were examined in healthy subjects (n = 6) during stepwise increased Intralipid/heparin infusion (plasma FFAs 0.8 +/- 0.1, 1.8 +/- 0.2, and 2.8 +/- 0.3 mmol/l) and during glycerol infusion (plasma FFAs similar to 0.5 mmol/l), Rates of EGP were determined with D-[6,6-H-2(2)]glucose and contributions of GNG from H-2 enrichments in carbons 2 and 5 of blood glucose after (H2O)-H-2 ingestion. Plasma glucose concentrations decreased by similar to 10% (P <0.01), whereas plasma insulin increased by similar to 47% (P = 0.02) after 9 h of lipid infusion. EGP declined from 9.3 +/- 0.5 (Lipid) and 9.0 +/- 0.8 mu mol . kg(-1) . min(-1) (glycerol) to 8.4 +/- 0.5 and 8.2 +/- 0.7 mu mol . kg(-1) . min(-1), respectively (P < 0.01), Contribution of GNG similarly rose (P < 0.01) from 46 +/- 4 and 52 +/- 3% to 65 +/- 8 and 78 +/- 7%, To exclude interaction of FFAs with insulin secretion, the study was repeated at fasting plasma insulin (similar to 35 pmol/l) and glucagon (similar to 90 ng/ml) concentrations using somatostatin-insulin-glucagon clamps. Plasma glucose increased by similar to 50% (P < 0.005) during lipid but decreased by similar to 12% during glycerol infusion (P < 0.005), EGP remained unchanged over the 9-h period (9.9 +/- 1.2 vs. 9.0 +/- 1.1 mu mol . kg(-1) . min(-1)). GNG accounted for 62 +/- 5 (lipid) and 60 +/- 6% (glycerol) of EGP at time 0 and rose to 74 +/- 3% during lipid infusion only (P < 0.05 vs. glycerol: 64 +/- 4%), In conclusion, high plasma FFA concentrations increase the percent contribution of GNG to EGP and may contribute to increased rates of GNG in patients with type 2 diabetes.