Exercise Dose and Metformin for Vascular Health in Metabolic Syndrome

Inclusion Criteria:

• Male or female ≥40 and ≤80 years old.

• Has a body mass index ≥25 and ≤47 kg/m2.

• Not diagnosed with Type 2 or Type 1 diabetes

• Not currently engaged in > 150 min/wk of exercise

• Weight stable (<2kg weight change in past 3 months)

• Non-smoking >5 years

At minimum, subject will have abdominal obesity (increased waist circumference as defined below) and may have any additional National Cholesterol Education Adult Treatment Panel III Metabolic Syndrome criteria:

• Increased waist circumference (≥102 cm in men; ≥88 cm in women)

• Elevated triglycerides (≥150 mg/dl), or on medication for treating the condition

• Reduced HDL-cholesterol (<40mg/dl in men, <50 mg/dl in women), or on medication fortreating the condition

• High blood pressure (≥130 mmHg systolic or ≥85mmHg diastolic), or on medication fortreating the condition

• Elevated fasting glucose (≥100 mg/dl), or on medication for treating the condition

• Other major risk factors to be noted based on the Framingham Risk Score

• HbA1c 5.7-6.4%

• LDL > 130 mg/dL

• Family history of type 2 diabetes (immediate family, i.e. parent/sibling)

• History of gestational diabetes

• History of Polycystic Ovarian Syndrome

• Family history of pre-mature cardiovascular disease (immediate family i.e.parent/sibling) before 55 for males or 65 for females that can include heart attack,peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid arterydisease or clinical coronary heart disease)

• Age ( > 45 years old for men; > 55 years old for women)

• Black/African American, Mexican, Asian, and/or Hispanic

• Subjects currently taking medications that affect heart rate and rhythm (i.e. Ca++channel blockers, nitrates, alpha- or beta-blockers)

Exclusion Criteria:

• Subjects prescribed metformin or have taken metformin within 1 year.

• Subjects with abnormal estimated glomerular filtration rate (eGFR).

• Hypertriglyceridemic (>400 mg/dl) and hypercholesterolemic (>260 mg/dl) subjects

• Hypertensive (>160/100 mmHg)

• Subjects with a history of significant metabolic, cardiac, congestive heart failure,cerebrovascular, hematological, pulmonary, gastrointestinal, liver, renal, orendocrine disease or cancer that in the investigator's opinion would interfere withor alter the outcome measures, or impact subject safety.

• Pregnant (as evidenced by positive pregnancy test) or nursing women

• Subjects with contraindications to participation in an exercise training program

• Currently taking active weight suppression medication (e.g. phentermine,orlistat,lorcaserin, naltrexone-bupropion in combination, liraglutide, benzphetamine,diethylpropion, phendimetrazine)

• Known hypersensitivity to perflutren (contained in Definity)

• Subjects who are considered non-English speaking individuals