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 [¹⁸F]-2-fluoro-2-deoxyglucose ([¹⁸F]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 (p0.01). 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 [¹⁸F]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.Abbreviations FDG 2-fluoro-2-deoxyglucose - HGU hepatic glucose uptake - HKi influx rate constant - M whole-body glucose uptake - PET positron emission tomography - ROI region of interest - SGU splanchnic glucose uptake - SS sum of squares