Diabetes Mellitus, Type 2, Insulin Resistance, Obesity, Overweight
Conditions
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 overweight/obesity and type 2 diabetes.
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).
Interventions
OTHERMethylation status
Participants will be recruited, and muscle biopsies will be obtained for methylation analyses and measuring mitochondrial function
Sponsors
University of Arizona
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
21 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mitochondrial DNA methylation | 3 years | Mitochondrial DNA methylation and D-loop of mitochondria is altered in insulin resistant states such as overweight/obesity and type 2 diabetes |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mitochondrial Function | 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 |
Countries
United States
Outcome results
None listed