Dynamic in Vivo PET Imaging and ex Vivo Biopsies From Skeletal Muscle and Adipose Tissue to Investigate the Effects of Exercise on Insulin Resistance and Mitochondrial Energetics in Type 2 Diabetes

Study Overview
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Brief Summary
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The overall aim of this pilot study is to investigate the effects of exercise training on skeletal muscle and adipose tissue insulin resistance in subjects with Type 2 Diabetes (T2D).

Official Title
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Dynamic in Vivo PET Imaging and ex Vivo Biopsies From Skeletal Muscle and Adipose Tissue to Investigate the Effects of Exercise on Insulin Resistance and Mitochondrial Energetics in Type 2 Diabetes

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Other: Maximal ATP Production (ATPmax)
* Other: Exercise Testing (VO2max)
* Procedure: Muscle Biopsy
* Procedure: Adipose Tissue Biopsy
* Other: Hyperinsulinemic euglycemic clamp
* Other: PET imaging


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 30-65 years Men and women Body mass index (BMI) between 25 and 45 kg/m2 Sedentary (1 day or less per week of structured exercise) Type 2 diabetes mellitus determined by self-report or by a fasting glucose >126mg/dl Weight stable (± 2 kg) for prior 3 months Willing to commit to the schedule of assessment visits, including the exercise intervention Exclusion Criteria: Currently taking insulin, injectable incretin mimetics and thiazolidinediones Taking more than two glucose-lowering medications Resting blood pressure ≥ 160/100 mm Hg Triglycerides ≥ 500 mg/dL Any renal, cardiac, liver, lung, or neurological disease that in the opinion of the principal investigator would compromise participant safety or the participants' ability to complete the exercise training protocol Any significant disease or unstable medical condition (i.e., coronary heart disease, chronic renal failure, chronic hepatic disease, severe pulmonary disease) Presence of clinically significant abnormalities on electrocardiogram (ECG) that is a contra-indication to exercise training Pulse check (Allen test) indicates participant has poor blood flow in the hands Cancer (active malignancy with or without concurrent chemotherapy; except for basal cell carcinoma) Pregnancy during the previous 6 months, lactating, or planned pregnancy in the next year Use of drugs known to affect energy metabolism or body weight: including, but not limited to orlistat, sibutramine, ephedrine, phenylpropanolamine, corticosterone, etc Current treatment with blood thinners or anti-platelet medications that cannot be safely stopped for testing procedures Participant is currently taking anti-inflammatory medication or has had inflammatory medication within 1 week prior to screening (including over the counter formulations: e.g. Aleve, Motrin, Ibuprofen, Naproxen, low dose ASA. New onset (<3 months on a stable regime) hormone replacement therapy Current use of beta-adrenergic blocking agents Major surgery on the abdomen, pelvis, or lower extremities within previous 3 months Increased liver function tests (AST/ALT/GGT/or alkaline phosphatase greater than 2.5 times the upper limit of normal) Abnormal blood count/anemia, blood transfusion or blood donation within the last 2 months Current smokers (smoking within the past 3 months prior to screening visit, including any/all tobacco products) Current drug or alcohol abuse/dependence Metal implants (pace-maker, aneurysm clips) based on investigator's judgment at screening Not physically capable of performing the exercise required of the study protocols Plans to be away >2 weeks in the next 3 months Unable to participate in Magnetic Resonance Imaging (MRI) assessments due to physical limitations of equipment tolerances (e.g. MRI bore size) based on investigator's judgment at screening. Unable to tolerate MRI or claustrophobia. Nickel allergy Lidocaine allergy Unable or unwilling to communicate with staff or to provide written informed consent

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Interventional Model Description: This is a single-site, pre-post design pilot study with no control group.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: All Participants<br> | Other: Maximal ATP Production (ATPmax)<br>* ATPmax will be measured in order to determine in vivo mitochondrial capacity. The magnetic resonance scans to measure mitochondrial energetics will also be performed.<br>Other: Exercise Testing (VO2max)<br>* Aerobic fitness level will be assessed while participant pedals on a stationary bicycle/walk on a treadmill. The volume of oxygen intake and carbon dioxide (CO2) production will be measured.<br>Procedure: Muscle Biopsy<br>* Sample muscle cells from the left leg Vastus Lateralis (thigh) muscle.<br>Procedure: Adipose Tissue Biopsy<br>* Sample fat tissue from the abdomen.<br>Other: Hyperinsulinemic euglycemic clamp<br>* Measurement of insulin sensitivity.<br>Other: PET imaging<br>* After an overnight fast, an intravenous catheter will be placed in each arm (one with arterial line for PET infusion, and the other for infusion of insulin, glucose, and 6,6 D2 glucose tracer. FDG-glucose will be injected followed by 90-minute PET scanning of the thigh.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Individual steps of muscle glucose uptake (pre-exercise) | Muscle glucose uptake will be assessed two times (pre and post exercise intervention) on the biceps femoris and vastus lateralis through PET imaging and hyperinsulinemic euglycemic clamp. | 24 hours | 
| Individual steps of muscle glucose uptake (post-exercise) | Muscle glucose uptake will be assessed two times (pre and post exercise intervention) on the biceps femoris and vastus lateralis through PET imaging and hyperinsulinemic euglycemic clamp. | 24 hours |