PGC-1 & Muscle Mitochondrial Dysfunction in Diabetes

NCT02282423 | Terminated DMC

• 1 other identifier: 13-006411
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this study is to understand how and why insulin resistant individuals respond differently to exercise as compared with insulin sensitive individuals at the skeletal muscle and gene expression level.

Conditions

Diabetes; Obesity

Outcome Measures

Primary Outcomes (1)

• Transcription Factor Response to Exercise

  To determine whether expression of the transcription factor MZF1 is induced by exercise to a greater degree in control patients than in those with type 2 diabetes mellitus. MZF1 expression will be determined using quantitative rt-PCR analysis on RNA isolated from muscle biopsies taken from the patients. An repeated measures analysis of variance will be performed on the PCR data, for the three groups (lean, obese, type 2 diabetic), with the difference between the lean and diabetic groups being the primary measure. A P value of 0.05 will be considered significant.

  4-6 weeks

Study Arms (4)

Lean Controls

EXPERIMENTAL

Lean controls will have BMI of 25 or less, gender specific normal body fat, and not be taking any medication that affects glucose metabolism. Interventions include OGTT, Clamp, VO2 Max, Exercise Test and Muscle Biopsy

Behavioral: Pre-study dietary and exercise instruction.; Procedure: Screening examination and oral glucose tolerance test; Procedure: Euglycemic clamp; Procedure: VO2max.; Behavioral: Acute exercise bout; Procedure: Percutaneous needle muscle biopsies

Obese, Non-diabetic

EXPERIMENTAL

Obese nondiabetics will have a BMI between 30-50 and not be taking any medication that affects glucose metabolism. Interventions include OGTT, Clamp, VO2 Max, Exercise Test and Muscle Biopsy

Behavioral: Pre-study dietary and exercise instruction.; Procedure: Screening examination and oral glucose tolerance test; Procedure: Euglycemic clamp; Procedure: VO2max.; Behavioral: Acute exercise bout; Procedure: Percutaneous needle muscle biopsies

Diabetic

EXPERIMENTAL

Diabetic patients will have a BMI between 30-50. We will recruit patients with mild or newly diagnosed type 2 diabetes who are treated with diet, sulfonylureas, or other drugs working through enhanced insulin secretion. Patients taking metformin or TZDs will not be recruited due to the effects of those drugs on insulin action. Interventions include OGTT, Clamp, VO2 Max, Exercise Test and Muscle Biopsy

Behavioral: Pre-study dietary and exercise instruction.; Procedure: Screening examination and oral glucose tolerance test; Procedure: Euglycemic clamp; Procedure: VO2max.; Behavioral: Acute exercise bout; Procedure: Percutaneous needle muscle biopsies

Non-diabetic

EXPERIMENTAL

Patients will be nondiabetic, although we will include patients with impaired glucose tolerance. Patients will meet criteria for treatment with fibrates to lower plasma triglyceride concentrations (triglyceride\>300 mg/dl for nondiabetics, 250 mg/dl for patients with impaired glucose tolerance). We will aim at recruiting equal numbers of men and women. All participants will be between the ages of 30 and 59. Patients will have a BMI of 25-50 and not be taking any other medication that affects glucose metabolism. All participants will be sedentary (not reporting more than 10 minutes per day of light to vigorous leisure time physical activity. Interventions include OGTT, Clamp, VO2 Max, Exercise Test and Muscle Biopsy

Behavioral: Pre-study dietary and exercise instruction.; Procedure: Screening examination and oral glucose tolerance test; Procedure: Euglycemic clamp; Procedure: VO2max.; Behavioral: Acute exercise bout; Procedure: Percutaneous needle muscle biopsies

Interventions

Pre-study dietary and exercise instruction. BEHAVIORAL

All subjects will be instructed to continue their normal diet during the three days prior to study, to not consume alcohol the day before study, and to not engage in exercise for 48 hours before all studies.

Diabetic; Lean Controls; Non-diabetic; Obese, Non-diabetic

Screening examination and oral glucose tolerance test PROCEDURE

All subjects will have screening exam and OGTT at the Clinical Studies Infusion Unit at Mayo Clinic in Arizona at 7-8 am after having eaten nothing after 10 PM the night before, and have a screening examination and 75 g OGTT, as described

Also known as: OGTT

Diabetic; Lean Controls; Non-diabetic; Obese, Non-diabetic

Euglycemic clamp PROCEDURE

On a separate day, subjects will have a two-hour euglycemic clamp ((80 mU insulin/(m2.min)) at the Clinical Studies Unit at Mayo Clinic Arizona at 7-8 am after an overnight fast. A muscle biopsy will be taken before the insulin infusion, to serve as the resting biopsy (3). Biopsy specimens (150-300 mg) will be frozen immediately in liquid nitrogen and stored in liquid nitrogen until they are processed

Diabetic; Lean Controls; Non-diabetic; Obese, Non-diabetic

VO2max. PROCEDURE

VO2max.

Diabetic; Lean Controls; Non-diabetic; Obese, Non-diabetic

Acute exercise bout BEHAVIORAL

The single acute exercise bout will be performed as described (3). It consists of 4 sets of 12 min each (8 min @ 70% VO2max, 2 min @ 90%, 2 min rest, repeat X 4). Biopsies are taken 30 min and 24 hr after end of exercise. Resting biopsies are taken on the glucose clamp day

Diabetic; Lean Controls; Non-diabetic; Obese, Non-diabetic

Percutaneous needle muscle biopsies PROCEDURE

Skeletal muscle biopsies, blotted free from blood, are frozen within 30 seconds in liquid nitrogen, and stored in liquid nitrogen until processing. We routinely obtain 150-300 mg muscle (wet weight), which is more than sufficient for the analyses proposed, with some muscle remaining for any additional validation assays that may arise during the course of the research. Muscle will be processed either for isolation of mRNA/microRNA or protein, as described (2, 3, 12).

Diabetic; Lean Controls; Non-diabetic; Obese, Non-diabetic

Eligibility Criteria

• Age: 30 Years - 59 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age 30-59
• BMI: Lean, BMI less than or equal to 25; Obese, BMI between 30-40; type 2 diabetic, BMI between 30-40.
• Subjects must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent.
• 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.
• Subjects must range in age as described in each specific protocol.
• 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 (except for Aim 4).
• Aim 4
• Age 30-59
• BMI: Lean, BMI less than or equal to 25; Obese, BMI between 30-40.

You may not qualify if:

• 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. Patients with type 2 diabetes will be excluded if they are taking metformin or thiazolidinediones, but may be taking sulfonylureas or other medications known to work through effects on insulin secretion.
• Subjects receiving Gemfibrozil must not also be receiving a statin.
• 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.
• 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.

Sponsors & Collaborators

• Mayo Clinic: lead
• Arizona State University: collaborator

Study Sites (1)

Mayo Clinic

Scottsdale, Arizona, 85259, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus; Obesity

Interventions

Glucose Tolerance Test; Glucose Clamp Technique

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Blood Chemical Analysis; Clinical Chemistry Tests; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Endocrine; Investigative Techniques; Chemistry Techniques, Analytical

Study Officials

• Lawrence J. Mandarino, Ph.D.

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

• Lori Roust, MD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 29, 2014
• First Posted: November 4, 2014
• Study Start: May 1, 2014
• Primary Completion: April 1, 2016
• Study Completion: April 1, 2016
• Last Updated: May 12, 2016

Record last verified: 2016-05

Locations

US (1)