Insulin and Sarcopenia in the Elderly

Muscle loss with aging is a significant contributor to disability in older people. Our general hypothesis is that loss of muscle with aging, known as sarcopenia, may be due to inability of muscle to grow in response to insulin. Our goal is to determine the mechanisms underlying this age-related insulin resistance of muscle proteins, which will allow us to define in the future specific interventions to target this defect and provide the scientific basis for the prevention and treatment of sarcopenia.

Our general hypothesis is that a reduced response of muscle protein anabolism to insulin plays an important role in the loss of muscle mass with aging. Our goal is to determine the mechanisms underlying the age-related insulin resistance of muscle proteins, which will allow us to define specific interventions to target this defect and provide the scientific basis for the prevention and treatment of sarcopenia.

Our previous studies indicate that the response of muscle proteins to the anabolic action of insulin is impaired in healthy older adults as compared to younger controls, which hampers the anabolic effect of mixed feeding on muscle proteins. These changes are associated with an age-related reduction in the vasodilatory response to insulin, which, from our data, appears to be a potentially important mediator of the physiological anabolic effect of insulin on muscle proteins. Preliminary data from our laboratory also suggest that in older subjects a single bout of aerobic exercise may restore the normal response of blood flow, muscle protein synthesis and anabolism to insulin.

Therefore, we will test in healthy subjects the following specific hypotheses:

1. Insulin-induced increases in blood flow and muscle perfusion are necessary for the physiological stimulation of muscle protein synthesis and anabolism by insulin.
2. Aging reduces the vascular sensitivity to insulin, which prevents the physiological increase in blood flow and muscle perfusion in response to insulin, thereby decreasing the response of muscle protein synthesis and net balance to the anabolic action of insulin and mixed feeding.
3. Aerobic exercise can restore, in older subjects, the insulin-induced increase in blood flow and muscle perfusion to youthful levels, thus normalizing the anabolic effect of insulin and mixed feeding on muscle protein synthesis and net muscle protein balance.

We will use state-of the art stable isotope tracer techniques to measure muscle protein turnover, and a newly developed method to measure muscle perfusion in young and older subjects. The results of these studies will allow us to better define the physiological mechanisms of action of insulin on muscle protein anabolism, advance our knowledge on the pathophysiology of sarcopenia, and provide the scientific basis for the behavioral and/or pharmacological treatment of muscle loss with aging.

• Drug: Insulin Regular
  insulin, 0.2 mU/kg/min for 3 hours
• Drug: L-NMMA
  variable rate for 3 hours
• Drug: Sodium Nitroprusside
  variable rate for 3 hours
• Other: mixed meal
  mixed meal

• Active Comparator: CMAY
  Insulin in young
  Intervention: Drug: Insulin Regular
• Experimental: IMAY
  L-NMMA + insulin in young
  Interventions:

  • Drug: Insulin Regular
  • Drug: L-NMMA
• Experimental: SNPY
  SNP in young
  Intervention: Drug: Sodium Nitroprusside
• Active Comparator: CSNP
  Insulin in elderly
  Intervention: Drug: Insulin Regular
• Experimental: ISNP
  SNP in elderly
  Interventions:

  • Drug: Insulin Regular
  • Drug: Sodium Nitroprusside
• Experimental: SNPE
  SNP in elderly
  Intervention: Drug: Sodium Nitroprusside
• Active Comparator: CMealO
  Meal in elderly
  Intervention: Other: mixed meal
• Experimental: SMealO
  SNP+meal in elderly
  Interventions:

  • Drug: Sodium Nitroprusside
  • Other: mixed meal
• Active Comparator: MealY
  meal in young
  Intervention: Other: mixed meal
• Experimental: ExIns
  insulin+exercise in elderly
  Intervention: Drug: Insulin Regular
• Experimental: ExMeal
  meal+exercise in elderly
  Intervention: Other: mixed meal

• Rasmussen BB, Fujita S, Wolfe RR, Mittendorfer B, Roy M, Rowe VL, Volpi E. Insulin resistance of muscle protein metabolism in aging. FASEB J. 2006 Apr;20(6):768-9. Epub 2006 Feb 7.
• Bell JA, Volpi E, Fujita S, Cadenas JG, Sheffield-Moore M, Rasmussen BB. Skeletal muscle protein anabolic response to increased energy and insulin is preserved in poorly controlled type 2 diabetes. J Nutr. 2006 May;136(5):1249-55.
• Bell JA, Volpi E, Fujita S, Cadenas JG, Rasmussen BB. Dysregulation of muscle fatty acid metabolism in type 2 diabetes is independent of malonyl-CoA. Diabetologia. 2006 Sep;49(9):2144-52. Epub 2006 Jul 26.
• Timmerman KL, Volpi E. Amino acid metabolism and regulatory effects in aging. Curr Opin Clin Nutr Metab Care. 2008 Jan;11(1):45-9. Review.
• Fujita S, Volpi E. Amino acids and muscle loss with aging. J Nutr. 2006 Jan;136(1 Suppl):277S-80S. Review.
• Dreyer HC, Volpi E. Role of protein and amino acids in the pathophysiology and treatment of sarcopenia. J Am Coll Nutr. 2005 Apr;24(2):140S-145S. Review.
• Drummond MJ, Bell JA, Fujita S, Dreyer HC, Glynn EL, Volpi E, Rasmussen BB. Amino acids are necessary for the insulin-induced activation of mTOR/S6K1 signaling and protein synthesis in healthy and insulin resistant human skeletal muscle. Clin Nutr. 2008 Mar 12; [Epub ahead of print]
• Drummond MJ, Dreyer HC, Pennings B, Fry CS, Dhanani S, Dillon EL, Sheffield-Moore M, Volpi E, Rasmussen BB. Skeletal muscle protein anabolic response to resistance exercise and essential amino acids is delayed with aging. J Appl Physiol. 2008 May;104(5):1452-61. Epub 2008 Mar 6.
• Fujita S, Rasmussen BB, Cadenas JG, Drummond MJ, Glynn EL, Sattler FR, Volpi E. Aerobic exercise overcomes the age-related insulin resistance of muscle protein metabolism by improving endothelial function and Akt/mammalian target of rapamycin signaling. Diabetes. 2007 Jun;56(6):1615-22. Epub 2007 Mar 9.
• Fujita S, Rasmussen BB, Bell JA, Cadenas JG, Volpi E. Basal muscle intracellular amino acid kinetics in women and men. Am J Physiol Endocrinol Metab. 2007 Jan;292(1):E77-83. Epub 2006 Aug 8.
• Fujita S, Rasmussen BB, Cadenas JG, Grady JJ, Volpi E. Effect of insulin on human skeletal muscle protein synthesis is modulated by insulin-induced changes in muscle blood flow and amino acid availability. Am J Physiol Endocrinol Metab. 2006 Oct;291(4):E745-54. Epub 2006 May 16.
• Bell JA, Fujita S, Volpi E, Cadenas JG, Rasmussen BB. Short-term insulin and nutritional energy provision do not stimulate muscle protein synthesis if blood amino acid availability decreases. Am J Physiol Endocrinol Metab. 2005 Dec;289(6):E999-1006. Epub 2005 Jul 19.
• Timmerman KL, Dhanani S, Glynn EL, Fry CS, Drummond MJ, Jennings K, Rasmussen BB, Volpi E. A moderate acute increase in physical activity enhances nutritive flow and the muscle protein anabolic response to mixed nutrient intake in older adults. Am J Clin Nutr. 2012 Jun;95(6):1403-12. Epub 2012 May 9.

Inclusion Criteria:

1. Age 18-40 yrs, and 65-85 yrs.
2. Ability to sign consent form (score >23 on the 30-item Mini Mental State Examination, MMSE)
3. Stable body weight for at least 3 months

Exclusion Criteria:

1. Physical dependence or frailty (impairment in any of the Activities of Daily Living (ADL), history of falls (>2/year) or significant weight loss in the past year)
2. Exercise training (>2 weekly sessions of moderate to high intensity aerobic or resistance exercise)
3. Pregnancy or nursing women.
4. Significant heart, liver, kidney, blood or respiratory disease
5. Peripheral vascular disease
6. Diabetes mellitus or other untreated endocrine disease
7. Active cancer
8. Recent (within 6 months) treatment with anabolic steroids, or corticosteroids.
9. Alcohol or drug abuse
10. Severe depression (>5 on the 15-item Geriatric Depression Scale, GDS)
11. Potential subjects who have recently donated blood in the past 60 days will be excluded from participating in the study.