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

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.

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.

Eligibility Criteria:
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