Free Fatty Acids and Vascular Function in Subjects With Diabetes

During the past two decades, there has been a steady increase in the incidence of diabetes mellitus, such that nearly 17 million people are now afflicted. The vast majority of these have type 2 diabetes. Over the next 40 years, the type 2 diabetic population in the United States is expected to increase to nearly 30 million.

Diabetes substantially increases the risk of atherosclerosis, and thereby, cardiovascular morbidity and mortality. Indeed, cardiovascular disease causes more than 50% of the mortality in patients with diabetes. People with type 2 diabetes manifest two cardinal signs of dysmetabolism: hyperglycemia and insulin resistance. Insulin resistance is a progressive phenomenon that occurs well before the onset of frank diabetes, and results in alterations in insulin signaling. Experimental studies suggest that insulin signaling is required for vascular homeostasis, and its impairment is associated with endothelial dysfunction. In the clinical setting, insulin resistance is associated with atherosclerosis and predicts cardiovascular events independent of hyperglycemia. Therefore, we will study the importance of insulin signaling in endothelial biology in humans and the effects of free fatty acids on endothelial function in people with type 2 diabetes.

Inclusion criteria

• type 2 diabetes mellitus (as defined by the National Diabetes Data Group)
• normal cardiovascular exam
• non smoker (for 1 year prior to entry)
• Healthy volunteers
• no known medical problems
• normal cardiovascular exam
• fasting glucose < 110 mg/dL
• non-smoker (for 1 year prior to entry)

Exclusion criteria

Type 2 Diabetics

• untreated hypertension (>140/90 mmHg)
• untreated hypercholesterolemia (LDL > 75th percentile for age)
• cigarette smoking within 1 year
• neuropathy requiring medication
• nephropathy (> 300mg/24 hour urinary albumin, or serum creatinine > 1.4 mg/dL
• abnormal cardiovascular exam
• treatment with thiazolidinedione within 1 year
• post-menopausal women taking hormone replacement therapy

(Note: subjects taking angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) must stop these medications for 2 weeks prior to taking study drug. If blood pressure rises to >140/90, subjects will be prescribed an alternative medication or be withdrawn from the study.

Healthy Volunteers

• abnormal cardiovascular exam
• use of prescription medications
• fasting glucose > 110mg/dL
• cigarette smoking within 1 year