Mechanisms by Which Strength Training Ameliorates the Metabolic Syndrome

Study Overview
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Brief Summary
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Prevention and treatment strategies for diabetes use exercise as the cornerstone. Even though endurance training and strength training both improve insulin resistance, strength training may be better suited for persons at risk for type 2 diabetes. We will expand our pilot studies of muscle adaptation induced by resistance exercise training to determine the biochemical mechanisms that will cause people with the Metabolic Syndrome to secure major benefit from intense strength training.

Detailed Description
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Life style alterations can be powerful deterrents to developing type 2 diabetes and are cornerstones of the treatment of this condition. Both aerobic and resistance exercise improve diabetes blood glucose control and insulin resistance. These two types of exercise appear to exert their effects on different muscle fiber types - red for endurance and white for strength. Similar to the effects of endurance exercise training, strength training increases muscle glucose transporter isoform 4 (GLUT4), but in contrast, mitochondria numbers do not increase. We hypothesize (1) that strength training in persons with pre-diabetes may be effective in reversing insulin resistance by novel mechanisms that are distinct from the endurance training-induced mitochondrial biogenesis. We further hypothesize (2) that resistance exercise training enhances whole body insulin action primarily by increasing the white fiber size via the protein kinase mammalian target of rapamycin (mTOR) and improves insulin-stimulated glucose uptake by increased GLUT4 expression primarily in white fibers of the trained muscles. In this proposal, we will perform eight weeks of progressive strength training on ten subjects with the Metabolic Syndrome who are at high risk for developing type 2 diabetes and on ten sedentary control subjects. This project builds on our experience with a study of focused resistance training whose results are presented in this application. In this pilot study, subjects exercised on stationary bicycles for six weeks causing muscle GLUT4 and phopho-mTOR to increase substantially, but maximal oxygen uptake (VO2max), phospho-AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ co-activator (PGC-1α), and mitochondrial markers did not change. Our hypotheses will be tested by two Specific Aims. (1) Subjects at high risk for diabetes will undergo progressively increasing intensity resistance exercise training and increased strength and improved insulin responsiveness will both be quantified to demonstrate significant benefit, and (2) quantify the effect of resistance exercise training on anatomic and functional adaptation in muscle. We will characterize fiber type, fiber size, fiber-specific changes in mitochondrial DNA and enzymes, fiber-specific changes in the principle glucose transporters in muscle (GLUT4, GLUT5, and GLUT12), and evaluate changes in two distinct intramuscular pathways (AMPK, mTOR) and regulatory factors (PGC-1α, PPARγ, PPARδ) using immunoblots of muscle subcellular fractions and immunohistochemical techniques. These evaluations of molecular mechanisms will also include assessing changes in full human Affymetrix gene array data that may move us to new potential resistance training-regulated gene targets. It is the long-term goal of this team of investigators to understand the interplay between life style changes and pharmacological agents in the prevention and treatment of diabetes. Our results will facilitate the development of more effective clinical options to turn back the epidemic of obesity and diabetes in the United States.

Official Title
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Mechanisms by Which Strength Training Ameliorates the Metabolic Syndrome

Conditions
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Metabolic Syndrome

Intervention / Treatment
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* Behavioral: strength training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: obese family history of diabetes Exclusion Criteria: non-obese diabetes

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: metabolic syndrome<br>intervention is to undergo eight weeks of progressive strength training; metabolic syndrome subjects will have baseline and post-intervention assessments including muscle biopsies and insulin clamps | Behavioral: strength training<br>* eight weeks of progressively increasing resistance training will be done in both groups side-by-side<br>|
| Active Comparator: control subjects<br>intervention is to undergo eight weeks of progressive strength training; non-obese sedentary subjects will have the same assessments as the metabolic syndrome subjects and exercise training simultaneously. | Behavioral: strength training<br>* eight weeks of progressively increasing resistance training will be done in both groups side-by-side<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| euglycemic clamp steady state glucose infusion rate (clamp GIR) |  | pre- post- intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GLUT4 content of muscle |  | pre- post- intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes, metabolic syndrome, type 2 diabetes