Mitochondrial Methylation in Type 2 Diabetes

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

Study Description

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).

Study Design

• 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

Groups and Cohorts

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

Outcome Measures

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

Eligibility Criteria

• 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.

Contacts and Locations

Contacts

Contact: Dawn K Coletta, PhD; 520-626-9316; dcoletta@email.arizona.edu

Contact: Maria Gordon; 520-626-5472; mgordon@email.arizona.edu

Locations

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

• Principal Investigator: Dawn K Coletta, PhD; University of Arizona

More Information

• 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
• Last Update Posted: October 15, 2019
• Last Verified: October 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Diabetes Mellitus; Insulin Resistance; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism