Exercise Resistance in Type 2 Diabetes

STUDY OBJECTIVES/ENDPOINTS

1. The primary endpoint of the study is the maximal capacity for mitochondrial ATP
synthesis measured using 31P magnetic resonance spectroscopy (MRS).

2. The principal secondary endpoint is the relationship between exercise-induced changes in
mitochondrial function in vivo and exercise mimetic-induced changes in mitochondrial
function in vitro.

3. The principal tertiary endpoint is the relationship between the basal promoter
methylation status of key genes involved in fuel metabolism and known to be activated by
exercise in skeletal muscle tissue and cells and the exercise-induced response in
mitochondrial function.

As exercise has an array of metabolic effects, and we are well positioned with our
cutting-edge methodologies here at the Translational Research Institute (TRI), we will also
measure whole body insulin sensitivity and metabolic flexibility by
hyperinsulinemic-euglycemic clamp, substrate oxidation and energy expenditure in the whole
room calorimeter/metabolic chamber and intramyocellular lipid content.

Type 2 Diabetes Inclusion Criteria (Group 1)

- Age 30 to 65 years.

- Male

- Hispanic or Non-Hispanic Caucasian

- Type 2 diabetes determined by self-report or by a fasting glucose > 126mg/dl

- POCT HbA1c result is 5.7-8.8

- HbA1c between 6.0% and 8.5%, if a participant misses the screening HbA1c by a small
margin (HbA1c ± 0.1%), the HbA1c can be repeated once.

- Not involved in regular exercise program

- Willing to exercise every day for the study period

- If applicable, those currently taking anti-diabetic medication are taking metformin, a
sulfonylurea, DPP IV inhibitor, alpha-glucosidase inhibitor, a meglitinide,
colesevelam, cycloset or a SGLT2 inhibitor. Those taking 2 of these medications may
proceed.

- If applicable, willing to cease anti-diabetic medication use for the duration of the
intervention.

- BMI ≥ 22 kg/m2

Young Athletes Inclusion Criteria (Group 2)

- Age 18 to 50 years

- Male

- Hispanic or Non-Hispanic Caucasian

- Engaged in a minimum of 4 cumulative hours of moderate to vigorous intensity aerobic
exercise, over a minimum of 3 days per week.

- BMI between 18 and 29.9 kg/m2

- VO2max greater than or less than 45 ml/min/kg BW

General Exclusion Criteria A=all groups, Ex=exercise group only

- Resting blood pressure ≥ 160/100 mm Hg (A)

- Triglycerides greater than or less than 500 mg/dL (A)

- Previous or current use of an insulin pump or multiple insulin injections per day or
any diabetes medications that the participant cannot refrain from for the duration of
the study. (A)

- Treatment with thiazolidinediones (TZDs) or GLP-1 agonists within the last 3 months.
(A)

- Unable or unwilling to communicate with staff or to provide written informed consent.
(A)

- Failure to complete baseline testing. (A)

- Not physically capable of performing the exercise required of the study protocols.
(Ex)

- Consuming >14 alcoholic beverages per week. (A)

- Plans to be away >2 weeks in the next 3 months. (A)

- Lack of support from primary health care provider and/or family members.(Ex)

- Significant weight loss in the past year (>20 lbs) or current use of weight loss
medications. (A)

- Bariatric surgery or planning bariatric surgery in the next 6 months.(Ex)

- Presence of clinically significant abnormalities on ECG (A)

- Anyrenal, cardiac, liver, lung, or neurological disease that in the opinion of the
Investigator would compromise participant safety (A)

- Use of drugs known to affect energy metabolism or body weight: including, but not
limited to: orlistat, sibutramine, ephedrine, phenylpropanolamine, corticosterone, etc
(A)

- Current treatment with blood thinners or anti-platelet medications that cannot be
safely stopped for testing procedures. (A)

- New onset (<3 months on a stable regime) hormone replacement therapy. (A)

- Alcohol or other drug abuse (A)

- Current smokers (smoking within the past 3 months) (A)

- Gait problems (Ex)

- Unwilling or unable to abstain from caffeine, alcohol or strenuous exercise (48h)
prior to metabolic rate measurements (A)

- Increased liver function tests (AST/ALT/GGT/or alkaline phosphatase greater than 2.5
times the upper limit of normal) (A)

- Metal objects that would interfere with the measurement of body composition /MRS such
as implanted rods, surgical clips, etc (A)

- Any NYHA class of CHF (A)

- Abnormal blood count/Anemia, blood transfusion or blood donation within the last 2
months. (A)

- Major surgery on the abdomen, pelvis, or lower extremities within previous 3 months
(A)

- Bariatric surgery or liposuction within the previous 3 years (Ex)

- Cancer (active malignancy with or without concurrent chemotherapy) (A)

- Rheumatoid disease (A)

- Bypass graft in limb (A)

- Known genetic factor (Factor V Leiden, etc) or hypercoagulable state (A)

- Peripheral neuropathy, involving more than the toes (A)

- Claustrophobia (A)

- Major Depression (Ex)

- Presence of an eating disorder or eating attitudes/behaviors that could interfere with
the study completion (Ex)

- Presence of any condition that, in the opinion of the investigator, compromises
participant safety or data integrity or the participants' ability to complete the
training protocol.