Mitochondrial Dysfunction in Diabetes (PGC-1)

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Lawrence Mandarino, Mayo Clinic
ClinicalTrials.gov Identifier:
NCT01724502
First received: November 7, 2012
Last updated: May 8, 2014
Last verified: May 2014
  Purpose

The purpose of this study is to determine whether insulin resistance is accompanied by "exercise resistance". Investigators will use mass spectrometry and proteomics analysis to test the hypothesis is that a bout of exercise that increases mitochondrial protein abundance in lean, healthy individuals is less effective in insulin resistant patients.


Condition Intervention
Diabetes
Obese
Behavioral: Exercise 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, Aims 4 & 5

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Protein Concentration of Mitochondria [ Time Frame: Study Day 4 (30 min after exercise) and (24 hours after exercise) ] [ Designated as safety issue: No ]
    Protein concentration will be determined from muscle biopsies 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.


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 exercise and muscle biopsies.
Behavioral: Exercise and muscle biopsies
Subjects will undergo a euglycemic clamp, VO_2 max determination, exercise periods and muscle biopsies.
Experimental: Type 2 Diabetic Subjects
All subjects on this arm will undergo exercise and muscle biopsies.
Behavioral: Exercise and muscle biopsies
Subjects will undergo a euglycemic clamp, VO_2 max determination, exercise periods and muscle biopsies.
Experimental: Healthy Control Subjects
All subjects on this arm will undergo exercise and muscle biopsies.
Behavioral: Exercise and muscle biopsies
Subjects will undergo a euglycemic clamp, VO_2 max determination, exercise periods and muscle biopsies.

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.

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 4 times. On Study Day 1 Subjects will be screened with a medical history & physical and a 75 g oral glucose tolerance test to determine if they are eligible for the study. On Study Day 2, subjects will report to the clinic after an overnight fast, undergo a euglycemic clamp (using deuterated glucose) to determine insulin sensitivity, and in addition have a muscle biopsy (basal biopsy for comparison). On Study Day 3, subjects will report to the clinic after an overnight fast, and undergo a Volume Oxygen Maximum (VO_2 max) determination. On Study Day 4, subjects will report to the clinic after an overnight fast to perform an exercise bout with muscle biopsy 30 minutes after the end of exercise. This will be followed by an overnight fast, and an additional muscle biopsy at 24 hours post exercise.

  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: NCT01724502

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, Ph.D., Mayo Clinic
ClinicalTrials.gov Identifier: NCT01724502     History of Changes
Other Study ID Numbers: 11-006065 Aim 4, R01DK066483
Study First Received: November 7, 2012
Last Updated: May 8, 2014
Health Authority: United States: Food and Drug Administration

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 18, 2014