Epigenetics and the Origin of Muscle Insulin Resistance in Humans

Study Overview
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Brief Summary
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The investigators are trying to understand the role of DNA (deoxyribonucleic acid) methylation in insulin resistance in skeletal muscle and blood tissues. DNA methylation is a normal chemical process in the body that modifies DNA. By studying this, the investigators hope to better understand the causes of insulin resistance.

Detailed Description
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Insulin resistance is defined as the decreased ability of insulin to perform its biological function in the muscle, liver and fat. Genetic and environmental factors are known to influence insulin sensitivity. It is not known how this is mediated. This study looks at the role of epigenetics (modifications of proteins associated with DNA and methylation of DNA) in alterations in insulin resistance. We will study lean healthy people, obese non-diabetic people and people with type 2 diabetes to characterize the DNA methylation patterns in muscle in each group. The second aim of the study is to see how a single bout of exercise affects the DNA methylation in the muscle. The third aim looks at the effect of 8 weeks of supervised exercise on the DNA methylation.

Official Title
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Epigenetics and the Origin of Muscle Insulin Resistance in Humans

Conditions
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Diabetes Mellitus Type 2 in Obese, Obesity

Participation Criteria
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Eligibility Criteria
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Volunteers must be: 21 - 55 years old must be non-lactating, non-pregnant not taking medications known to affect glucose or if taking them, on stable doses. free of significant heart or lung disease

Ages Eligible for Study
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Minimum Age: 21 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Insulin resistance epigenetics<br>This experiment will use the Infinium methylation assay to perform epigenome mapping and define patterns of DNA methylation in skeletal muscle and whole blood tissue of metabolically well-characterized lean healthy, obese nondiabetic, and type 2 diabetic volunteers. We will test the hypotheses that (1) There is an increased methylation of genes involved in mitochondrial biogenesis and oxidative phosphorylation and altered methylation of promoters of genes coding for extracellular matrix and cytoskeletal proteins in insulin resistance, (2) The altered methylation patterns observed correspond to protein and mRNA expression changes, and (3) There are coordinated patterns of DNA methylation between the skeletal muscle and whole blood tissues in insulin resistance. | |
| Single bout of exercise<br>This experiment will test the hypotheses in lean healthy, obese non-diabetic and type 2 diabetic volunteers that Increased methylation of the PGC-1α promoter predicts a decreased response of this gene to a single bout of exercise, and Altered methylation of promoters of nuclear encoded mitochondrial genes predicts a decreased response of this gene to a single bout of exercise. | |
| Eight weeks of exercise<br>This experiment will test the hypothesis in lean healthy, obese non-diabetic and type 2 diabetic volunteers that There is decreased methylation of genes involved in mitochondrial biogenesis and oxidative phosphorylation, and the altered methylation corresponds to protein and mRNA (messenger ribonucleic acid) expression changes, There is altered methylation of genes involved in inflammation and cytoskeletal structure. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DNA methylation of genes in insulin resistance | DNA methylation of genes involved in mitochondrial biogenesis, oxidative phosphorylation, extracellular matrix and cytoskeleton proteins in insulin resistance, with an acute episode of exercise, and with eight weeks of training exercise. | Baseline to visit 33 (approx 2 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| mRNA expression of genes | mRNA expression of genes involved in mitochondrial biogenesis, oxidative phosphorylation, extracellular matrix and cytoskeletal signaling are altered in insulin resistance, with an acute episode of exercise and with 8 weeks of exercise training. | Baseline to visit 33 approx 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin resistance, Exercise, Type 2 diabetes mellitus, Obesity, Epigenetic studies