Insulin and Sarcopenia in the Elderly

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Insulin and Sarcopenia in the Elderly

Conditions
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Sarcopenia

Intervention / Treatment
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* Drug: Insulin Regular
* Drug: L-NMMA
* Drug: Sodium Nitroprusside
* Other: mixed meal


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CMAY<br>Insulin in young | Drug: Insulin Regular<br>* insulin, 0.2 mU/kg/min for 3 hours<br>|
| Experimental: IMAY<br>L-NMMA + insulin in young | Drug: Insulin Regular<br>* insulin, 0.2 mU/kg/min for 3 hours<br>Drug: L-NMMA<br>* variable rate for 3 hours<br>|
| Experimental: SNPY<br>SNP in young | Drug: Sodium Nitroprusside<br>* variable rate for 3 hours<br>|
| Active Comparator: CSNP<br>Insulin in elderly | Drug: Insulin Regular<br>* insulin, 0.2 mU/kg/min for 3 hours<br>|
| Experimental: ISNP<br>SNP in elderly | Drug: Insulin Regular<br>* insulin, 0.2 mU/kg/min for 3 hours<br>Drug: Sodium Nitroprusside<br>* variable rate for 3 hours<br>|
| Experimental: SNPE<br>SNP in elderly | Drug: Sodium Nitroprusside<br>* variable rate for 3 hours<br>|
| Active Comparator: CMealO<br>Meal in elderly | Other: mixed meal<br>* mixed meal<br>|
| Experimental: SMealO<br>SNP+meal in elderly | Drug: Sodium Nitroprusside<br>* variable rate for 3 hours<br>Other: mixed meal<br>* mixed meal<br>|
| Active Comparator: MealY<br>meal in young | Other: mixed meal<br>* mixed meal<br>|
| Experimental: ExIns<br>insulin+exercise in elderly | Drug: Insulin Regular<br>* insulin, 0.2 mU/kg/min for 3 hours<br>|
| Experimental: ExMeal<br>meal+exercise in elderly | Other: mixed meal<br>* mixed meal<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| muscle protein synthesis |  | 5 and 8 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| blood flow |  | 5 and 8 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sarcopenia, aging, muscle metabolism