Amino acid‐induced impairment of insulin sensitivity in healthy and obese rats is reversible

High‐protein diets (HPDs) promote weight loss but other studies implicate these diets and their constituent amino acids (AAs) in insulin resistance. We hypothesized that AA‐induced insulin resistance is a temporal and reversible metabolic event. L6 myotubes were serum deprived for 4 h and then incubated in AA and/or insulin (100 nmol/L). Another group of cells was incubated overnight in AA + insulin, starved again, and then reincubated with AA and insulin. Mammalian (mechanistic) target of rapamycin complex 1 (mTORC1) signaling and glucose uptake were then measured. Healthy or insulin‐resistant rats were gavaged with leucine (0.48 g/kg) and insulin sensitivity was examined. In myotubes, incubation with AA and insulin significantly (P <0.05) increased the phosphorylation of the mTORC1 substrate ribosomal protein S6 kinase 1 (S6K1, T389) and of insulin receptor substrate 1 (IRS‐1, serine residues), but suppressed insulin‐stimulated glucose uptake by 40% (P <0.01). These modifications were mTORC1‐dependent and were reversible. In vivo, leucine gavage reversibly increased S6K1 phosphorylation and IRS‐1 serine phosphorylation 5‐ to 12‐fold in skeletal muscle and impaired insulin tolerance of glucose (P <0.05) in lean rats. In insulin‐resistant rats, the impairment of whole blood glucose and AA metabolism induced by leucine gavage (0.001 < P <0.05) was more severe than that observed in lean rats; however, the impairment was reversible within 24 h of treatment. If these data are confirmed in long‐term studies, it would imply that the use of leucine/HPD in treating metabolic diseases is unlikely to have lasting negative effects on insulin sensitivity.