Supraphysiological hyperinsulinaemia is necessary to stimulate skeletal muscle protein anabolism in older adults: Evidence of a true age-related insulin resistance of muscle protein metabolism

Aims/hypothesis: The physiological increase in muscle protein anabolism induced by insulin is blunted in healthy, glucose-tolerant older adults. We hypothesised that the age-related defect in muscle protein anabolism is a true insulin resistance state and can be overridden by supraphysiological hyperinsulinaemia. Methods: We used dye dilution, stable isotopic and immunoblotting techniques to measure leg blood flow, muscle protein synthesis, protein kinase B/mammalian target of rapamycin (Akt/mTOR) signalling, and amino acid kinetics in 14 healthy, glucose-tolerant older volunteers at baseline, and during an insulin infusion at postprandial (PD, 0.15 mU min^-1 100 ml^-1) or supraphysiologically high (HD, 0.30 mU min^-1 100 ml^-1) doses. Results: Leg blood flow, muscle protein synthesis, and Akt/mTOR signalling were not different at baseline. During hyperinsulinaemia, leg blood flow (p∈<∈0.01) and muscle protein synthesis increased in the HD group only (PD [%/h]: from 0.063∈±∈0.006 to 0.060∈±∈0.005; HD [%/h]: from 0.061∈±∈0.007 to 0.098∈±∈0.007; p∈<∈0.01). Muscle Akt phosphorylation increased in both groups, but the increase tended to be greater in the HD group (p∈=∈0.07). The level of p70 ribosomal S6 kinase 1 (S6K1) phosphorylation increased in the HD group only (p∈<∈0.05). Net amino acid balance across the leg improved in both groups, but a net anabolic effect was observed only in the HD group (p∈<∈0.05). Conclusions/interpretation: We conclude that supraphysiological hyperinsulinaemia is necessary to stimulate muscle protein synthesis and anabolic signalling in healthy older individuals, suggesting the existence of a true age-related insulin resistance of muscle protein metabolism.