Insulin and Sarcopenia in the Elderly - Full Text View

Purpose

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.

Condition	Intervention
Sarcopenia	Drug: Insulin Regular Drug: L-NMMA Drug: Sodium Nitroprusside Other: mixed meal


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Basic Science
Official Title:	Insulin and Sarcopenia in the Elderly

Resource links provided by NLM:

MedlinePlus related topics: Diabetes Medicines

Drug Information available for: Insulin Insulin human

U.S. FDA Resources

Further study details as provided by The University of Texas, Galveston:

Primary Outcome Measures:

muscle protein synthesis [ Time Frame: 5 and 8 hours ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

blood flow [ Time Frame: 5 and 8 hours ] [ Designated as safety issue: No ]


Enrollment:	88
Study Start Date:	September 2005
Study Completion Date:	August 2012
Primary Completion Date:	August 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: CMAY Insulin in young	Drug: Insulin Regular insulin, 0.2 mU/kg/min for 3 hours
Experimental: IMAY L-NMMA + insulin in young	Drug: Insulin Regular insulin, 0.2 mU/kg/min for 3 hours Drug: L-NMMA variable rate for 3 hours
Experimental: SNPY SNP in young	Drug: Sodium Nitroprusside variable rate for 3 hours
Active Comparator: CSNP Insulin in elderly	Drug: Insulin Regular insulin, 0.2 mU/kg/min for 3 hours
Experimental: ISNP SNP in elderly	Drug: Insulin Regular insulin, 0.2 mU/kg/min for 3 hours Drug: Sodium Nitroprusside variable rate for 3 hours
Experimental: SNPE SNP in elderly	Drug: Sodium Nitroprusside variable rate for 3 hours
Active Comparator: CMealO Meal in elderly	Other: mixed meal mixed meal
Experimental: SMealO SNP+meal in elderly	Drug: Sodium Nitroprusside variable rate for 3 hours Other: mixed meal mixed meal
Active Comparator: MealY meal in young	Other: mixed meal mixed meal
Experimental: ExIns insulin+exercise in elderly	Drug: Insulin Regular insulin, 0.2 mU/kg/min for 3 hours
Experimental: ExMeal meal+exercise in elderly	Other: mixed meal mixed meal

Detailed Description:

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:

Insulin-induced increases in blood flow and muscle perfusion are necessary for the physiological stimulation of muscle protein synthesis and anabolism by insulin.
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.
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.

Eligibility


Ages Eligible for Study:	18 Years to 85 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

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

Exclusion Criteria:

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)
Exercise training (>2 weekly sessions of moderate to high intensity aerobic or resistance exercise)
Pregnancy or nursing women.
Significant heart, liver, kidney, blood or respiratory disease
Peripheral vascular disease
Diabetes mellitus or other untreated endocrine disease
Active cancer
Recent (within 6 months) treatment with anabolic steroids, or corticosteroids.
Alcohol or drug abuse
Severe depression (>5 on the 15-item Geriatric Depression Scale, GDS)
Potential subjects who have recently donated blood in the past 60 days will be excluded from participating in the study.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00690534

Locations


United States, Texas
Sealy Center on Aging, University of Texas Medical Branch
Galveston, Texas, United States, 77555-0460

Sponsors and Collaborators

The University of Texas, Galveston

Investigators


Principal Investigator:	Elena Volpi, MD, PhD	The University of Texas Medical Branch at Galveston

More Information

Publications:

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 Jun;27(3):447-56. doi: 10.1016/j.clnu.2008.01.012. Epub 2008 Mar 14.

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 (1985). 2008 May;104(5):1452-61. doi: 10.1152/japplphysiol.00021.2008. 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.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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. doi: 10.3945/ajcn.111.020800. Epub 2012 May 9.


Responsible Party:	The University of Texas, Galveston
ClinicalTrials.gov Identifier:	NCT00690534 History of Changes
Other Study ID Numbers:	05-090, R01 AG18311
Study First Received:	May 27, 2008
Last Updated:	January 15, 2015
Health Authority:	United States: Food and Drug Administration

Keywords provided by The University of Texas, Galveston:


sarcopenia aging muscle metabolism

Additional relevant MeSH terms:


Sarcopenia Atrophy Muscular Atrophy Nervous System Diseases Neurologic Manifestations Neuromuscular Manifestations Pathological Conditions, Anatomical	Signs and Symptoms Insulin Insulin, Globin Zinc Hypoglycemic Agents Pharmacologic Actions Physiological Effects of Drugs

ClinicalTrials.gov processed this record on February 27, 2015