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Epigenetics of Muscle Insulin Resistance

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ClinicalTrials.gov Identifier: NCT03259984
Recruitment Status : Completed
First Posted : August 24, 2017
Last Update Posted : October 14, 2019
Sponsor:
Information provided by (Responsible Party):
Dawn K Coletta, University of Arizona

Brief Summary:
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.

Condition or disease
Diabetes Mellitus, Type 2 Obesity

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.

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Study Type : Observational
Actual Enrollment : 72 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Epigenetics and the Origin of Muscle Insulin Resistance in Humans Aims 1-3
Actual Study Start Date : November 2016
Actual Primary Completion Date : November 2, 2018
Actual Study Completion Date : November 2, 2018

Resource links provided by the National Library of Medicine


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.



Primary Outcome Measures :
  1. DNA methylation of genes in insulin resistance [ Time Frame: 9 months ]
    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.


Secondary Outcome Measures :
  1. mRNA expression of genes [ Time Frame: 9 months ]
    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.


Biospecimen Retention:   Samples With DNA
DNA will be extracted from vastus lateralis skeletal muscle biopsies and blood samples


Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03259984


Locations
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United States, Arizona
University of Arizona
Tucson, Arizona, United States, 85724
Sponsors and Collaborators
University of Arizona
Investigators
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Principal Investigator: Dawn K Coletta, Ph.D. University of Arizona
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Responsible Party: Dawn K Coletta, Associate Professor of Medicine, University of Arizona
ClinicalTrials.gov Identifier: NCT03259984    
Other Study ID Numbers: 1612045470
First Posted: August 24, 2017    Key Record Dates
Last Update Posted: October 14, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Insulin Resistance
Diabetes Mellitus, Type 2
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Diabetes Mellitus
Endocrine System Diseases