Non-esterified fatty acids impair insulin-mediated glucose uptake and disposition in the liver

Aims/hypothesis. We investigated the effect of elevated circulating NEFA on insulin-mediated hepatic glucose uptake (HGU) and whole-body glucose disposal (M) in eight healthy male subjects. Methods. Studies were performed using positron emission tomography (PET) and [F-18]-2-fluoro-2-deoxyglucose ([F-18]FDG) during euglycaemic hyperinsulinaemia (0-120 min) and an Intralipid/heparin infusion (IL/Hep; -90-120 min). On a different day, similar measurements were taken during euglycaemic hyperinsulinaemia and saline infusion (SAL). Graphical and compartmental analyses were used to model liver data. Results. Circulating NEFA increased approximately three-fold during IL/Hep, and declined by 81+/-7% in the SAL study (pless than or equal to0.01). Both M (-28+/-7%) and HGU (-25+/-9%) were significantly lowered by NEFA elevation (p=0.004 and p=0.035 respectively). In the whole data set, the decreases in M and HGU were positively correlated (r=0.78, p=0.038). No evidence of [F-18]FDG outflow was detected during the scanning time. HGU was correlated with the phosphorylation rate parameter (r=0.71, p=0.003) as derived by compartmental modelling. Conclusions/interpretation. In healthy men, NEFA impair insulin-mediated HGU and whole-body glucose uptake to a similar extent. Our data suggest that multiple intracellular NEFA targets may concur to down-regulate glucose uptake by the liver.