Lipid-induced insulin resistance is associated with an impaired skeletal muscle protein synthetic response to amino Acid ingestion in healthy young men

The ability to maintain skeletal muscle mass appears to be impaired in insulin resistant conditions that are characterised by muscle lipid accumulation, such as type 2 diabetes. The present study investigated the effect of acutely increasing lipid availability on muscle protein synthesis. Seven healthy young male volunteers underwent a 7 h intravenous infusion of L-[ring-2H5]phenylalanine on two randomised occasions combined with either 0.9% saline or 10% Intralipid at 100 mL/h. After a 4 h 'basal' period, a 21 g bolus of amino acids was administered and a 3 h euglycaemic hyperinsulinemic clamp was commenced ('fed' period). Muscle biopsies were obtained from the vastus lateralis at 1.5, 4, and 7 h. Lipid infusion reduced fed whole-body glucose disposal by 20%. Furthermore, whereas mixed muscle fractional synthetic rate increased from the basal to fed period during saline infusion by 2.2-fold, no change occurred during lipid infusion, despite similar circulating insulin and leucine concentrations. This 'anabolic resistance' to insulin and amino acids with lipid infusion was associated with a complete suppression of muscle 4E-BP1 phosphorylation. We propose that increased muscle lipid availability may contribute to anabolic resistance in insulin resistant conditions by impairing translation initiation.