Insulin action and non-esterified fatty acids

Abstract

Non-esterified fatty acids (NEFA) are the primary energy fuel for most tissues under fasting conditions. Their release into the circulation results partly from the hydrolysis of triacylglycerol-rich lipids under the action of lipoprotein lipase (EC 3.1.1.34; LPL). The circulating NEFA pool is in dynamic equilibrium with an interstitial pool, into which NEFA are also released from tissue triacylglycerol depots under the influence of hormone-sensitive lipase (EC 3.1.1.3; HSL). NEFA removal is dependent on tissue uptake for oxidation or re-esterification. Insulin is a potent regulator of circulating NEFA con-centrations through a stimulatory effect on LPL and an inhibitory effect on HSL; by enhancing glucose uptake and glycolysis, insulin also provides a-glycerophosphate, the substrate for NEFA re-esterification (Campbell et al. 1992). The net effect of systemic insulinization is a prompt, marked decline in circulating NEFA concentrations, which marks the switch of energy production from dominant fat oxidation to prevalent carbo-hydrate utilization. This action of insulin is impaired in patients with non-insulin-depen-dent diabetes (NIDDM), in whom day-long plasma NEFA levels are elevated despite normal plasma insulin concentrations (Golay et al. 1986~). Raised NEFA concentrations have also been reported in non-diabetic obese subjects (Golay et al. 1986b; Frayn et al. 1996). According to the concept of substrate competition (Randle et al. 1963), the ability of insulin to restrain lipolysis is part of its action on glucose metabolism. By reducing fatty substrate availability, insulin promotes glucose transfer into target tissues by a combination of push (activation of membrane transport) and pull mechanisms (stimulation of glycogen synthesis, anaerobic glycolysis, and pyruvate oxidation; Groop & Ferrannini, 1993). Thus, insulin resistance in the lipolytic pathway is associated with insulin resistance of glucose metabolism as well as abnormal lipid metabolism (Reaven et al. 1988; Groop et al. 1991; McGany, 1992). The relative influence of obesity and insulin resistance on plasma NEFA concentrations has not been established, nor has the impact of physiological factors such as sex and age been considered. In the present work, we have assessed the relationship between NEFA and insulin action by retrospective analysis of the database of the European Group for the Study of Insulin Resistance (EGIR; Ferrannini et al. 1996). This database, collected at twenty-one European centres, includes data from 1146 healthy Caucasian men and women, ranging in age from 18 to 85 years, in whom insulin action was determined by the euglycaemic insulin clamp technique. This population sample is the largest so far in which insulin action has been measured directly.