Mitochondrial Methylation in Type 2 Diabetes

Unraveling the Role of Mitochondrial DNA Methylation in Type 2 Diabetes

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 overweight/obesity and type 2 diabetes.

Study Overview

• Status: Recruiting
• Conditions: Obesity; Diabetes Mellitus, Type 2; Overweight; Insulin Resistance
• Intervention / Treatment: 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 overweight/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, overweight/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 Type: Observational
• Enrollment (Anticipated): 36

Contacts and Locations

• Study Contact: Name: Maria Gordon; Phone Number: 520-626-5472; Email: mgordon@email.arizona.edu
• Study Contact Backup: Name: Dawn K Coletta, PhD; Phone Number: 520-626-9316; Email: dcoletta@email.arizona.edu

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Recruiting
      • Clinical and Translational Research Center (CaTS)
      • Contact: Maria Gordon; Phone Number: 520-626-5472; Email: mgordon@email.arizona.edu
      • Contact: Alma Leon; Phone Number: 520-626-7006; Email: almadleon@email.arizona.edu
      • Principal Investigator: Dawn K Coletta, PhD

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) overweight/obese volunteers without type 2 diabetes, and 3) volunteers with type 2 diabetes

Description

Inclusion Criteria:

1. Subjects must be 21-55 years old

2. Body Mass Index:

   Lean, healthy BMI ≤25; Overweight,non-diabetic BMI 25-29.9; Obese, non-diabetic BMI 30-50; Type 2 Diabetes (per the American Diabetes Association criteria)

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.

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	Intervention / Treatment
Lean, healthy control; Lean, healthy control subjects. Volunteers will be matched for sex and age 21-55 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
Overweight/obese nondiabetic; Overweight/Obese nondiabetic subjects. Overweight and obesity will be defined using the standard body mass index cutoffs. Volunteers will be matched for sex and age 21-55 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 will be diagnosed accordingly to ADA criteria. Volunteers will be matched for sex and age 21-55 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mitochondrial DNA methylation	Mitochondrial DNA methylation and D-loop of mitochondria is altered in insulin resistant states such as overweight/obesity and type 2 diabetes	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mitochondrial Function	The extent of mitochondrial function impairment in insulin resistant participants corresponds to the degree of methylation of the mitochondrial genome and D-loop	3 years

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2019
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: October 11, 2019
• First Submitted That Met QC Criteria: October 11, 2019
• First Posted (Actual): October 15, 2019

Study Record Updates

• Last Update Posted (Estimate): January 16, 2023
• Last Update Submitted That Met QC Criteria: January 13, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Body Weight; Hyperinsulinism; Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin Resistance; Overweight
• Other Study ID Numbers: 1901254125

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