Impact of Acute Exercise on Vascular Insulin Sensitivity in Metabolic Syndrome

Study Overview
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Brief Summary
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Obesity is an independent risk factor for type 2 diabetes and cardiovascular disease. The increased prevalence of obesity worldwide is a major concern among the scientific and medical communities. Insulin resistance is a common factor associated with obesity, metabolic syndrome, hypertension, and type 2 diabetes. Individuals affected by these conditions often experience endothelial dysfunction as well. Insulin resistance provides a key link between metabolic syndrome risk factors and vascular disease. Development of strategies aimed at preventing vascular dysfunction and future disease caused by metabolic disturbances is needed. Although the relationship between obesity and various diseases is well known, the acute effects of insulin on vascular function in obese individuals have yet to be fully determined. Additionally, the effects of acute exercise on insulin-stimulated endothelial function are unknown. Exercise may be an effective and potent treatment that protects against endothelial dysfunction, insulin resistance, and future cardiometabolic disease commonly present with obesity. However, less attention has been placed on vascular insulin sensitivity. The purpose of this study is to test the hypothesis that a single bout of exercise increases insulin-stimulated blood flow at the macro- and micro-vasculature level in obese individuals with metabolic syndrome to similar levels as healthy obese control. Our laboratory has available non-invasive methods to quantify vascular function and the gold-standard technique for assessing insulin sensitivity (euglycemic-hyperinsulinemic clamp). The investigators will assess vascular function (flow-mediated dilation, post-ischemic flow velocity and contrast-enhanced ultrasound) as well as arterial stiffness (augmentation index and pulse wave velocity) before and at the end of the clamp protocol performed the morning following a bout of exercise and a control (no-exercise) condition in 1) metabolic syndrome and 2) obese adults. If our hypothesis is sustained, it will suggest that a key role of the vasculature exists in regulating insulin following exercise and will provide insight into the link between the vasculature, obesity, metabolic syndrome and cardiovascular disease and may confer decreased risk for cardiometabolic disease.

Official Title
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Impact of Acute Exercise on Vascular Insulin Sensitivity in Metabolic Syndrome

Conditions
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Metabolic Syndrome, Obesity

Intervention / Treatment
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* Behavioral: Single Bout of Exercise
* Behavioral: Control Condition


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females, ages 40-70 years Never diagnosed with type 2 diabetes and/or cardiovascular disease Not currently engaged in > 60 min/wk of exercise Inclusion criteria specific to health obese vs. metabolic syndrome potential participants: Healthy Obese: (BMI ≥ 30 kg/m2 but ≤ 45 kg/m2) and no other metabolic syndrome risk factors, excluding waist circumference. Metabolic Syndrome: (BMI ≥ 30 kg/m2 but ≤ 45 kg/m2) and must meet at least 3 out of 5 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 currently taking medication (Rx) Reduced HDL-cholesterol (<40mg/dl in men, <50 mg/dl in women) or currently taking medication (Rx) High blood pressure (≥130 mmHg systolic or ≥85mmHg diastolic) or currently taking medication (Rx) Elevated fasting glucose (≥100 mg/dl) Subject may participate if on the following drugs: Diuretics, ace-inhibitors and ARBs for treatment of hypertension Statins Exclusion Criteria: Morbidly obese patients (BMI >45 kg/m2) and overweight/lean patients (BMI <30 kg/m2). Subjects who have not been weight stable (>2kg weight change in past 3 months). Currently participating in a regular exercise training program ( >30 min. of physical activity per day, >2 days/week) Medication or food supplement that is known to affect insulin sensitivity or endothelial function (TZDs, sulfonylureas, biguanides, alpha-glucosidase inhibitors, phosphodiesterase inhibitors, beta-blockers, alpha-blockers, fibrates, glucocorticoids, fish oil, allopurinol) Subjects with abnormal estimated glomerular filtration rate (eGFR). Hypertriglyceridemic (>400 mg/dl) subjects. Hypertensive (>160/100 mmHg) Subjects taking vasoactive medications also known to affect heart rate and rhythm (i.e. Ca++ channel blockers, nitrates, alpha- or beta-blockers). Subjects with a history of significant metabolic, cardiac, congestive heart failure, cerebrovascular, hematological, pulmonary, gastrointestinal, liver, renal, or endocrine disease or cancer that in the investigator's opinion would interfere with or alter the outcome measures, or impact subject safety. Smoking presently or in the past 1 year. HbA1c ≥ 6.5 Subjects currently taking Metformin or any active weight suppression medication (e.g. phentermine, orlistat, lorcaserin, naltrexone-bupropion in combination, liraglutide, benzphetamine, diethylpropion, phendimetrazine) Pregnant (as evidenced by positive pregnancy test) or breastfeeding Subjects with contraindications to participation in an exercise program Known hypersensitivity to perflutren (contained in Definity)

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control<br>Subjects with simple obesity will complete 2 different testing conditions in a counterbalanced order with at least one week between conditions. 10-12 hrs post test condition the subject will report for a Euglycemic-Hyperinsulinemic clamp study, where Flow Mediated Dilation (FMD) and Contrast Enhanced Ultrasound (CEU) will be performed. | Behavioral: Single Bout of Exercise<br>* An exercise condition, which will be walking at a moderate intensity ( 70% VO2peak). Time will vary based upon individual fitness levels to burn  400kcals (estimated 0.5 - 1hr). Oxygen consumption will be measured during exercise via a metabolic cart to confirm energy expenditure. Participants will then rest following the exercise procedure for 20 minutes. Between 20 and 45 minutes following exercise, oxygen consumption will be measured to understand and capture excess post-exercise oxygen consumption (EPOC). Following this, participants will be provided with a standardize dinner and snack to consume in the AMP lab.<br>Behavioral: Control Condition<br>* A control (no-exercise) condition. Participants will report to the AMP lab to rest for the same duration as the exercise bout and consume the standardized dinner and snack.<br>|
| Active Comparator: Metabolic Syndrome<br>Subjects with metabolic syndrome will complete 2 different testing conditions in a counterbalanced order with at least one week between conditions. 10-12 hrs post test condition the subject will report for a Euglycemic-Hyperinsulinemic clamp study, where Flow Mediated Dilation (FMD) and Contrast Enhanced Ultrasound (CEU) will be performed. | Behavioral: Single Bout of Exercise<br>* An exercise condition, which will be walking at a moderate intensity ( 70% VO2peak). Time will vary based upon individual fitness levels to burn  400kcals (estimated 0.5 - 1hr). Oxygen consumption will be measured during exercise via a metabolic cart to confirm energy expenditure. Participants will then rest following the exercise procedure for 20 minutes. Between 20 and 45 minutes following exercise, oxygen consumption will be measured to understand and capture excess post-exercise oxygen consumption (EPOC). Following this, participants will be provided with a standardize dinner and snack to consume in the AMP lab.<br>Behavioral: Control Condition<br>* A control (no-exercise) condition. Participants will report to the AMP lab to rest for the same duration as the exercise bout and consume the standardized dinner and snack.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of single bout of exercise on FMD | Flow Mediated Dilation (FMD) as a percentage | Baseline clamp study | 
| Effect of single bout of exercise on CEU | Contrast Enhanced Ultrasound (CEU) as a percentage | Baseline Clamp Study | 
| Comparison of insulin stimulated FMD response | Flow mediated dilation as a percentage of fasting values | Through study completion, up to about 4 weeks | 
| Comparison of insulin stimulated CEU response | Contrast Enhanced Ultrasound (CEU) as a percentage of fasting values | Through study completion, up to about 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systemic Arterial stiffness | Augmentation Index as a percentage | Through study completion, up to about 4 weeks | 
| Central Arterial Stiffness | Pulse wave velocity in m/s | Through study completion, up to about 4 weeks | 
| Metabolic Flexibility | Respiratory gases in fasted and insulin-stimulated states in arbitrary units | Through study completion, up to about 4 weeks | 
| Fasting glucose | Comparison of glucose collected at baseline in mg/dl | Through study completion, up to about 4 weeks | 
| Fasting insulin | Comparison of insulin collected at baseline in uU/ml | Through study completion, up to about 4 weeks | 
| Free Fatty Acids | Comparison of free fatty acids collected at baseline in mEq/L | Through study completion, up to about 4 weeks | 
| Adiponectin | Comparison of inflammatory in ng/ml | Through study completion, up to about 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Exercise, Endothelial Function, Simple Obesity, Metabolic Syndrome