In vitro studies have established that free fatty acids (FFAs) are important regulators of hepatic glucose metabolism. FFAs can increase hepatic glucose release by increasing the amount and activity of glucose-6-phosphatase and multiple gluconeogenic enzymes. Elevated FFAs can also potentially decrease hepatic glucose uptake by decreasing hepatic glucokinase activity. In vivo studies in both animals and humans have shown a close correlation between changes in plasma FFAs and endogenous glucose production (EGP). Intervention studies have established that changes in plasma FFAs are accompanied by changes in the relative contribution of gluconeogenesis and glycogenolysis to EGP. The effects of a change in FFAs on EGP itself are more evident when compensatory changes in insulin secretion are prevented or when insulin secretion is impaired (eg, diabetes mellitus). The effects of elevated FFAs on splanchnic glucose uptake are less clear, in that they appear to have no effect in nondiabetic humans and may impair uptake in people with type 2 diabetes.