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Mitochondrial Methylation in Type 2 Diabetes

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ClinicalTrials.gov Identifier: NCT04126551
Recruitment Status : Recruiting
First Posted : October 15, 2019
Last Update Posted : October 15, 2019
Sponsor:
Information provided by (Responsible Party):
Dawn K Coletta, University of Arizona

Brief Summary:
The overarching goal of this proposal is to determine whether DNA methylation of the mitochondrial DNA impairs mitochondrial function in insulin resistant states such as obesity and type 2 diabetes.

Condition or disease Intervention/treatment
Obesity Diabetes Mellitus, Type 2 Insulin Resistance Other: Methylation status

Detailed Description:
To determine whether differences in human skeletal muscle DNA methylation patterns in the mitochondrial and nuclear genome can explain the lower abundance of ETC and OXPHOS mRNA and protein observed in insulin resistant skeletal muscle of obese and type 2 diabetic participants. To determine whether patterns of human skeletal muscle DNA methylation in the mitochondrial and nuclear genome are predictive of ETC function. We will isolate skeletal muscle mitochondria from metabolically well-characterized lean insulin sensitive, obese insulin resistant nondiabetic and obese insulin resistant type 2 diabetic volunteers, and functionally evaluate each ETC complex (I - IV) and complex V (ATP synthase).

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Study Type : Observational
Estimated Enrollment : 36 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Unraveling the Role of Mitochondrial DNA Methylation in Type 2 Diabetes
Actual Study Start Date : July 23, 2019
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Lean, healthy control
Lean, healthy control subjects. Volunteers will be matched for sex and age 35-55 years old. Ethnicities studied will be self-reported. We will attempt to match on race/ethnicities with equal numbers of non-Hispanic/Latinos and Hispanics/Latinos.
Other: Methylation status
Participants will be recruited, and muscle biopsies will be obtained for methylation analyses and measuring mitochondrial function

Obese nondiabetic
Obese nondiabetic subjects. Obesity will be defined using a body mass index of greater than or equal to 30 kg/m2. Volunteers will be matched for sex and age 35-55 years old. Ethnicities studied will be self-reported. We will attempt to match on race/ethnicities with equal numbers of non-Hispanic/Latinos and Hispanics/Latinos.
Other: Methylation status
Participants will be recruited, and muscle biopsies will be obtained for methylation analyses and measuring mitochondrial function

Type 2 diabetes
Participants with type 2 diabetes diagnosed accordingly to ADA criteria. Volunteers will be matched for sex and age 35-55 years old. Ethnicities studied will be self-reported. We will attempt to match on race/ethnicities with equal numbers of non-Hispanic/Latinos and Hispanics/Latinos.
Other: Methylation status
Participants will be recruited, and muscle biopsies will be obtained for methylation analyses and measuring mitochondrial function




Primary Outcome Measures :
  1. Mitochondrial DNA methylation [ Time Frame: 3 years ]
    Mitochondrial DNA methylation and D-loop of mitochondria is altered in insulin resistant states such as obesity and type 2 diabetes


Secondary Outcome Measures :
  1. Mitochondrial Function [ Time Frame: 3 years ]
    The extent of mitochondrial function impairment in insulin resistant participants corresponds to the degree of methylation of the mitochondrial genome and D-loop


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:   35 Years to 55 Years   (Adult)
Sexes 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
Criteria

Inclusion Criteria:

  1. Subjects must be 35-55 years old
  2. Body Mass Index:

    Lean, healthy BMI ≤25 Obese, non-diabetic BMI 30-50 Obese with Type 2 Diabetes (per the American Diabetes Association criteria) BMI 30-50

  3. Subjects must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent.
  4. Female subjects must be non-lactating and will be eligible only if they have a negative pregnancy test throughout the study period, and must agree to use acceptable birth control (hormonal contraceptives, barrier methods, have an intrauterine device, or surgical sterilization)
  5. Subjects must have the following laboratory values:

    • Hematocrit ≥ 35 vol%
    • Serum creatinine ≤ 1.6 mg/dl
    • AST (SGOT) < 2 times upper limit of normal
    • ALT (SGPT) < 2 times upper limit of normal
    • Alkaline phosphatase < 2 times upper limit of normal
    • Triglycerides < 150 mg/dl for nondiabetics
    • Triglycerides <300 for diabetics
    • INR ≤ 1.3
    • HbA1c ≤ 10

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 must not be taking estrogens or other hormonal replacement therapy unless the subject has been on these agents on a stable dose for the prior three months. Subjects taking systemic glucocorticoids are excluded. Patients with type 2 diabetes will be excluded if they are taking thiazolidinediones.
  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>160, diastolic BP>95, 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): NCT04126551


Contacts
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Contact: Dawn K Coletta, PhD 520-626-9316 dcoletta@email.arizona.edu
Contact: Maria Gordon 520-626-5472 mgordon@email.arizona.edu

Locations
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United States, Arizona
Clinical and Translational Research Center (CaTS) Recruiting
Tucson, Arizona, United States, 85724
Contact: Maria Gordon    520-626-5472    mgordon@email.arizona.edu   
Contact: Alma Leon    520-626-7006    almadleon@email.arizona.edu   
Principal Investigator: Dawn K Coletta, PhD         
Sponsors and Collaborators
University of Arizona
Investigators
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Principal Investigator: Dawn K Coletta, PhD University of Arizona

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Responsible Party: Dawn K Coletta, Associate Professor of Medicine, University of Arizona
ClinicalTrials.gov Identifier: NCT04126551     History of Changes
Other Study ID Numbers: 1901254125
First Posted: October 15, 2019    Key Record Dates
Last Update Posted: October 15, 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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Diabetes Mellitus
Insulin Resistance
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Hyperinsulinism