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

Diabetologia. 2009 Sep;52(9):1889-98. doi: 10.1007/s00125-009-1430-8. Epub 2009 Jul 9.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biopsy
  • Blood Glucose / metabolism
  • Body Mass Index
  • Female
  • Femoral Artery / drug effects
  • Femoral Artery / physiology
  • Humans
  • Hyperinsulinism / pathology*
  • Hyperinsulinism / physiopathology
  • Insulin / administration & dosage
  • Insulin / pharmacology
  • Insulin Resistance / physiology
  • Leg / blood supply
  • Male
  • Metabolism
  • Muscle Proteins / biosynthesis
  • Muscle Proteins / drug effects
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / pathology*
  • Reference Values
  • Regional Blood Flow / drug effects


  • Blood Glucose
  • Insulin
  • Muscle Proteins