PGC-1 and Mitochondrial Dysfunction in Diabetes

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Lawrence Mandarino, Mayo Clinic
ClinicalTrials.gov Identifier:
NCT01724515
First received: November 7, 2012
Last updated: May 8, 2014
Last verified: May 2014
  Purpose

The purpose of this study is determine if you have too much fat in your body that it will decrease the conversion of food energy into energy that your body can use.


Condition Intervention
Diabetes
Obese
Other: Lipid infusion and muscle biopsies

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: PGC-1 and Mitochondrial Dysfunction in Diabetes

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Mitochondrial Respiration [ Time Frame: Study Day 2, muscle biopsy approximately 6 hours after lipid infusion initiation ] [ Designated as safety issue: No ]
    Mitochondrial respiration will be measured by micropolarography.


Secondary Outcome Measures:
  • Protein Concentration of Mitochondria [ Time Frame: Study Day 2, muscle biopsy approximately 6 hours after lipid infusion initiation ] [ Designated as safety issue: No ]
    Protein concentration will be determined by the method of Lowry. 75 micrograms of muscle lysate proteins will be separated on a 10% Sodium Dodecyl Sulfate Polyacrylamide Gel, and then visualized with Coomassie stain. The gel lane will be cut into cubes, digested with trypsin and cleaned, then protein abundance will be determined using spectral counting.

  • Phosphorylation of proteins [ Time Frame: Study Day 2, muscle biopsy approximately 6 hours after lipid infusion initiation ] [ Designated as safety issue: No ]
    Phosphopeptides will be measured by mass spectrometry.


Enrollment: 16
Study Start Date: September 2012
Study Completion Date: March 2014
Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Obese Non-Diabetic Subjects
All subjects on this arm will undergo lipid infusion and muscle biopsies.
Other: Lipid infusion and muscle biopsies
Subjects will undergo a baseline muscle biopsy, a lipid infusion for 5 hours (60 ml/hr), and a muscle biopsy after the lipid infusion.
Experimental: Type 2 Diabetic Subjects
All subjects on this arm will undergo lipid infusion and muscle biopsies.
Other: Lipid infusion and muscle biopsies
Subjects will undergo a baseline muscle biopsy, a lipid infusion for 5 hours (60 ml/hr), and a muscle biopsy after the lipid infusion.
Experimental: Healthy Control Subjects
All subjects on this arm will undergo lipid infusion and muscle biopsies.
Other: Lipid infusion and muscle biopsies
Subjects will undergo a baseline muscle biopsy, a lipid infusion for 5 hours (60 ml/hr), and a muscle biopsy after the lipid infusion.

Detailed Description:

The investigators' prior research has focused on defining the changes in expression of nuclear encoded mitochondrial genes that predict changes in insulin sensitivity in skeletal muscle, with the goal of defining the molecular mechanisms underlying the connection between mitochondrial dysfunction and insulin resistance in skeletal muscle.

The purpose of this study is to determine whether experimental lipid oversupply decreases mitochondrial respiratory function. We will use mitochondrial respiration studies in vitro and mass spectrometry and proteomics analysis to test the hypothesis that experimental lipid oversupply:

  1. Decreases mitochondrial respiration in response to lipid fuels.
  2. Reduces abundance of mitochondrial proteins.
  3. Alters phosphorylation of proteins in the electron transport chain.

Three groups of subjects will be studied: lean, healthy control subjects (n=12), obese non-diabetic subjects (n=12) and patients with type 2 Diabetes Mellitus (n=12) for a total of 36 subjects. Twenty subjects have completed the study at Arizona State University; the remaining 16 subjects will be accrued at the Mayo Clinic in Arizona.

Subjects will come to the Mayo Clinic 2 times. On study Day 1 subjects will be screened with a medical history and physical exam, and a 75 g oral glucose tolerance test, measure body fat percentage, and an electrocardiogram (EKG). On Study Day 2, subjects will report to the clinic after an overnight fast. Female subjects will take a urine pregnancy test. A muscle biopsy will be performed to take a small sample from one thigh. A lipid infusion will be performed for 5 hours (60 ml/hr), with blood samples taken at 8 intervals during the infusion. At the end of the 5 hour period, a second muscle biopsy will be taken from the other thigh. The fat infusion will stop, subjects will be given lunch and allowed to leave the clinic.

  Eligibility

Ages Eligible for Study:   21 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Subjects must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent.
  2. 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.
  3. Subjects must range in age as described in each specific protocol.
  4. Subjects must have the following laboratory values:

    1. Hematocrit ≥ 35 vol%
    2. Serum creatinine ≤ 1.6 mg/dl
    3. Aspartate Aminotransferase (AST) (SGOT) < 2 times upper limit of normal
    4. Alanine Aminotransferase (ALT) (SGPT) < 2 times upper limit of normal
    5. Alkaline phosphatase < 2 times upper limit of normal
    6. Triglycerides < 150 mg/dl.
    7. Prothrombin Time (PT) 11.7 - 14.3 seconds (during Intralipid/heparin infusion, PT will be determined to insure that it is < 1.5-2.0 times the normal value.)
    8. Partial Thromboplastin Time (PTT) 23.0-37.0 seconds.

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.
  2. 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.
  3. 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01724515

Locations
United States, Arizona
Mayo Clinic in Arizona
Scottsdale, Arizona, United States, 85259
Sponsors and Collaborators
Mayo Clinic
Investigators
Principal Investigator: Lawrence Mandarino, Ph.D Mayo Clinic
  More Information

Additional Information:
No publications provided

Responsible Party: Lawrence Mandarino, PI, Mayo Clinic
ClinicalTrials.gov Identifier: NCT01724515     History of Changes
Other Study ID Numbers: 11-006065 Aim 5, R01DK066483
Study First Received: November 7, 2012
Last Updated: May 8, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Mayo Clinic:
insulin resistance

Additional relevant MeSH terms:
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases

ClinicalTrials.gov processed this record on September 22, 2014