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

Abstract

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.

Conflict of interest statement

Duality of interest: The authors declare that there is no duality of interest associated with this manuscript

Figures

Figure 1

Blood flow and muscle protein fractional synthetic rate (FSR) in older volunteers at baseline and during the intra-arterial infusion of insulin at two different rates, which were chosen to increase the femoral vein insulin concentrations to either a postprandial level (PD: n=8) or a supraphysiological high level (HD: n=6). Data from a group of younger (n=7, age 31 ± 2), BMI-matched volunteers undergoing an insulin infusion at postprandial dose are also reported. Values are the mean±SE. *P#P<0.01 vs. PD

Figure 2

Phosphorylation of Akt/PKB, S6K1, 4E-BP1 and eEF2 in older volunteers at baseline and during the intra-arterial infusion of insulin at two different rates, chosen to increase the femoral vein insulin concentrations to either a postprandial level (PD: n=6 for Akt/PKB and S6K1; n=5 for 4E-BP1 and eEF2) or a supraphysiological high level (HD: n=6 for all proteins). Values are the mean ± SE. *P #P<0.05 vs. PD