Background: Physiological elevations of free fatty acids (FFAs) occur in a dynamic bell-shaped fashion lasting some hours, e.g. nocturnally and during exercise. In order to define the metabolic role of physiological elevations in relation to diurnal fluctuations in insulin sensitivity, the present study was designed to identify the metabolic effects of a dynamic 4 hour elevation of FFAs during a glucose clamp.
Materials and methods: 8 lean, healthy men were examined twice in a cross-over design: 1) Control (saline), and 2) 4 h graded infusion of intralipid (20%)/heparin. Insulin sensitivity and EGP were assessed by the isotope dilution (3H-glucose) technique during an 8 h hyperinsulinemic-euglycaemic clamp (0.5 mU/kg/min). Before the study, the protocol was approved by the Aarhus County Ethical Scientific Committee; the purpose and potential risks of the study were explained to all subjects; and informed, written consent was obtained from all participants.
Results: Infusion of intralipid caused a significant increase of average FFA levels (Area under the curve (AUC)) compared with saline reaching peak levels ∼1.9 mmol/L and markedly impairing insulin sensitivity [iAUCglucose Rate of disappearance (Rd) (mg/kg): 709±25 vs. 380±112, P=0.04). There was a lag phase of 300 minutes from initiation of intralipid infusion until glucose Rd was significantly reduced. Glucose Rd returned to control levels after a further 150 minutes. Average insulin sensitivity was negatively correlated with average FFA level (r2=0.52, P=0.002). EGP was equally suppressed by hyperinsulinaemia regardless of treatment.
Conclusions: Our data suggest that physiological FFA elevations induce insulin resistance in the periphery after a lag of 45 h and that normal insulin sensitivity is restored 12 h after FFA values have returned to normal. It is therefore likely that FFA plays an important role in circadian variations of insulin sensitivity (e.g. the Dawn phenomenon and during exercise).