Epigenetics of Muscle Insulin Resistance

Epigenetics and the Origin of Muscle Insulin Resistance in Humans Aims 1-3

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

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. The investigators 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): 72

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• 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

Inclusion Criteria

1. Age 21-55
2. BMI: Lean, BMI less than or equal to 25; Obese, BMI between 30- 50; type 2 diabetic, BMI between 30- 50.
3. Subjects must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent.
4. Subjects may be of either sex with age as described in each protocol. Female subjects must be non-lactating and will be eligible only if they have a negative pregnancy test throughout the study period.
5. Subjects must range in age as described in each specific protocol.

6. Subjects must have the following laboratory values:

   1. Hematocrit ≥ 35 vol%
   2. Serum creatinine ≤ 1.6 mg/dl
   3. AST (SGOT) < 2 times upper limit of normal
   4. ALT (SGPT) < 2 times upper limit of normal
   5. Alkaline phosphatase < 2 times upper limit of normal
   6. Triglycerides < 150 mg/dl for nondiabetics
   7. Triglycerides <300 for diabetics
   8. INR ≤ 1.3

Exclusion Criteria

1. Subjects must not be receiving any of the following medications: thiazide or furosemide diuretics, beta-blockers, or other chronic medications with known adverse effects on glucose tolerance levels unless the patient has been on a stable dose of such agents for the past three months before entry into the study. Subjects may be taking a stable dose of estrogens or other hormonal replacement therapy, if the subject has been on these agents for the prior three months. Subjects taking systemic glucocorticoids are excluded. Patients with type 2 diabetes will be excluded if they are taking thiazolidinediones, but may be taking sulfonylureas or other medications known to work through effects on insulin secretion.
2. Subjects receiving Gemfibrozil must not also be receiving a statin.
3. Subjects with a history of clinically significant heart disease (New York Heart Classification greater than grade II; more than non-specific ST-T wave changes on the EKG), peripheral vascular disease (history of claudication), or pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation) will not be studied.
4. Recent systemic or pulmonary embolus, untreated high-risk proliferative retinopathy, recent retinal hemorrhage, uncontrolled hypertension, systolic BP>180, diastolic BP>105, autonomic neuropathy, resting heart rate >100, electrolyte abnormalities.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Aim 1; This experiment will use the next generation sequencing reduced representation bisulfite sequencing to 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. The investigators will test the hypotheses that: (a) 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, (b) The altered methylation patterns observed correspond to protein and mRNA expression changes, and (c) There are coordinated patterns of DNA methylation between the skeletal muscle and whole blood tissues in insulin resistance.
Aim 2; This experiment will test the hypotheses in lean healthy, obese non-diabetic and type 2 diabetic volunteers that: (a) Increased methylation of the PGC-1α promoter predicts a decreased response of this gene to a single bout of exercise, and (b) Altered methylation of promoters of nuclear encoded mitochondrial genes predicts a decreased response of this gene to a single bout of exercise.
Aim 3; This experiment will test the hypothesis in lean healthy, obese non-diabetic and type 2 diabetic volunteers that: (a) 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, (b) 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.	9 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.	9 months

Collaborators and Investigators

• Sponsor: University of Arizona
• Investigators: Principal Investigator: Dawn K Coletta, Ph.D., University of Arizona

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2016
• Primary Completion (Actual): November 2, 2018
• Study Completion (Actual): November 2, 2018

Study Registration Dates

• First Submitted: August 21, 2017
• First Submitted That Met QC Criteria: August 23, 2017
• First Posted (Actual): August 24, 2017

Study Record Updates

• Last Update Posted (Actual): October 14, 2019
• Last Update Submitted That Met QC Criteria: October 11, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperinsulinism; Diabetes Mellitus, Type 2; Insulin Resistance
• Other Study ID Numbers: 1612045470

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No