Epigenetics and the Origin of Muscle Insulin Resistance in Humans

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.

Study Overview

• Status: Completed
• Conditions: Obesity; Diabetes Mellitus Type 2 in Obese

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 46

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Arizona

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Three groups of volunteers will be studied: 1) lean, healthy volunteers, 2)obese volunteers without type 2 diabetes, and 3) volunteers with type 2 diabetes.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Insulin resistance epigenetics; 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; 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; 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?

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

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Investigators: Principal Investigator: Lori Roust, MD, Mayo Clinic; Principal Investigator: Dawn K Coletta, Ph.D., Mayo Clinic

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): November 21, 2016
• Study Completion (Actual): November 21, 2016

Study Registration Dates

• First Submitted: November 8, 2012
• First Submitted That Met QC Criteria: November 9, 2012
• First Posted (Estimate): November 15, 2012

Study Record Updates

• Last Update Posted (Actual): January 16, 2018
• Last Update Submitted That Met QC Criteria: January 11, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: Exercise; Obesity; Insulin resistance; Type 2 diabetes mellitus; Epigenetic studies
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism; Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin Resistance
• Other Study ID Numbers: 11-007028