Influence of Endothelial Function on Central and Peripheral Causes Of Exercise Impairment in Type 2 Diabetes

Not Applicable

Completed

Brief Summary: This study will evaluate the effects of impaired blood flow regulation on exercise. It will also determine whether the effects are more important in the heart or in the skeletal muscle tissue during exercise. In addition, this study will decide whether temporarily reversing these problems will improve blood flow control, improve heart and muscle tissue function and help improve exercise capacity in person with type 2 diabetes. This study will do so using two methods: (1) by giving vitamin C intravenously (IV) and (2) a three month exercise training program. Up to 100 subjects will be enrolled in this study.

Detailed Description: The investigators have found that persons with type 2 diabetes have an impaired ability to perform exercise even without clinically apparent complications. The reasons for this marked abnormality are unknown but are important as the decreased ability to exercise could contribute to the decreased expenditure of physical activity frequently observed in this population and may potentially constitute an early marker of cardiovascular disease.

The investigators wish to evaluate the effects of impaired blood flow regulation on exercise capacity and whether the effects are more important in the heart or in the skeletal muscle tissue during exercise. In addition, the investigators are determining whether correcting these abnormalities by two methods of improving blood flow regulation (acutely infusing Vitamin C or three months of chronic exercise training) leads to improved blood flow regulation, improved heart and skeletal muscle tissue function and hence to better exercise capacity in person with type 2 diabetes. This information will provide a more mechanistic understanding of causes of abnormal exercise responses observed in person with type 2 diabetes as well as whether and to what degree responses are modifiable. Interventions that reverse the exercise defect may facilitate patient adherence to prescribed physical activity programs and potentially decrease cardiovascular mortality in this large segment of the population.

Recruitment & Eligibility

Inclusion Criteria

Men and women with uncomplicated Type 2 Diabetes
Healthy men and women without Type 2 Diabetes
Patients with Type 2 Diabetes may be taking metformin or sulfonylurea drugs to treat diabetes
Persons with history of hypercholesteremia if controlled with statins and/or diet
Patients who are moderately overweight (BMI 25-37.5)
Must be sedentary (defined as regular exercise < 2 times a week at a low to moderate level).
Patients with Hemoglobin A1c (HBA1C) <8%
Patients between the ages of 30 to 55 years
Premenopausal women.
Former smokers who have quit smoking for at least one year
Absence of comorbid conditions
Mild neuropathy is O.K. as long as it will not hamper exercise performance.
Resting systolic blood pressure (SBP) < 140, Resting diastolic blood pressure (DBP) < 90
Total Cholesterol < 205 Triglycerides < 250 low density lipoprotein (LDL) < 130
Control subjects with a normal A1C and fasting glucose

Exclusion Criteria

People with T2DM taking oral medications, other than metformin or sulfonylurea drugs to control their diabetes.
Persons treated with insulin will be excluded
People who are currently smoking or have not quit for at least one year
Controls who have immediate family history of T2DM
Peri-menopausal or post-menopausal women.
Peripheral neuropathy
Total cholesterol > 205
Regional wall motion abnormalities
LV wall thickness ≥1.1 cm
Decreased contractility (fractional shortening <30%)
Ischemic heart disease (abnormal resting or exercise ECG)
Presence of angina that would limit exercise performance
Pulmonary problems that would limit exercise performance
Systolic blood pressure >140 mmHg at rest or >250 mmHg with exercise or diastolic pressure >90 mmHg at rest or >105 mmHg with exercise
Persons with autonomic insufficiency, assessed by measuring variation in RR intervals with cycled breathing and by presence of a >20 mm fall in upright blood pressure without a change in heart rate
Proteinuria (urine protein >200 mg/dl) or a creatinine > 2 mg/dl
Renal disease

Arm && Interventions

Group	Intervention	Description
Ascorbic acid	Exercise program	All study subjects have ascorbic acid infusion during one exercise visit as well as a three month exercise training intervention.
Ascorbic acid	Ascorbic Acid (Vitamin C)	All study subjects have ascorbic acid infusion during one exercise visit as well as a three month exercise training intervention.

Primary Outcome Measures

Name	Time	Method
Percent Change in Circumferential Strain Before and After Exercise at Baseline, After Vitamin C Infusion, and After Exercise Training	7 months; Measures are made at rest and after exercise for baseline, at rest and after infusion for Vitamin C administration, and at rest and after exercise following the exercise training	Characterize the purported cardiac dysfunction during exercise in people with type 2 diabetes (T2D). In a normal patient when measuring circumferential strain, results are negative with downward tracing (as strain is a relative change in length). Circumferential strain is a measurement of ventricular circumference within the heart vessels, measured via echocardiography.
Ejection Fraction: Percentage of Blood Leaving the Heart Before and After Exercise at Baseline, After a Vitamin C Infusion, and After Exercise Training	7 months; Measures are made at rest for baseline, at rest for Vitamin C administration, and at rest following the exercise training	Evaluate potential changes in cardiac function by echocardiography following 2 interventions: Three months of exercise training and acute vitamin C administration. Ejection fraction (EF) is a measurement of the percentage of blood leaving your heart each time it contracts, typically measure by echocardiography. Numbers listed are absolute EF values.

Secondary Outcome Measures