CD36 in Nutrient Delivery and Its Dysfunction

Subjects carrying the G-allele of CD36 coding SNP rs3211938 that results in 50% reduction of
CD36 levels in ~25% of African Americans have endothelial dysfunction. Endothelial
dysfunction results in impairment of insulin's vascular actions and eventually reduced
insulin sensitivity. Insulin induces microvascular recruitment via stimulation of nitric
oxide(NO)-cGMP pathway, which facilitates nutrient flux, e.g., glucose to skeletal muscle.
Elevated fatty acids impair insulin-stimulated microvascular recruitment and reduce insulin
sensitivity. Chronic treatment with sildenafil increases vascularity and muscle glucose
uptake in high fat fed mice. In humans, Drs. Shibao (PI) recently reported that a 3-month
treatment with sildenafil improves insulin sensitivity in patients with impaired glucose
tolerance. More relevant to this project, endothelial dysfunction improved after 4-week
treatment with sildenafil in G-allele carriers. This proposal will test the hypothesis that
chronic treatment with sildenafil with and without the use of NO substrate, L-arginine,
protects against fatty acids induced impairment of endothelial function, improves
insulin-stimulated microvascular.

The protocol design was changed to single arm design.

Inclusion criteria

- African American men and women.

- Age 18-50 years

- BMI 25-40 kg/m2

Exclusion criteria:

- Diabetes type 1 or type 2, as defined by a FPG > 126 mg/dL a two-hour plasma glucose >
200 mg/dL, or the use of anti-diabetic medication

- The use of nitrates or any disease that might require the use of nitrates

- Pulmonary hypertension

- Hypertension, defined as SBP/DBP >140/90 mm Hg or the use of anti- hypertensive agents

- Use of a PDE5 inhibitor for erectile dysfunction

- Use of an alpha blocker

- Pregnancy or breast-feeding. Women of child-bearing potential will be required to have
undergone tubal ligation or to be using an oral contraceptive or barrier methods of
birth control.

- The use of any potent CYP3A4 inhibitor.

- Cardiovascular disease such as myocardial infarction, presence of angina pectoris,
significant arrhythmia, congestive heart failure (left ventricular hypertrophy
acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart
block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy

- Allergies to eggs, soy products and Intralipid® infusion

- History of serious neurologic disease such as cerebral hemorrhage, stroke, or
transient ischemic attack

- History or presence of immunological or hematological disorders

- Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino
transaminase [ALT] > 3.0 x upper limit of normal range)

- Impaired renal failure (eGFR < 60 mL/min/1.73m2)

- Hematocrit < 34%

- Any underlying or acute disease requiring regular medication which could possibly pose
a threat to the subject or make implementation of the protocol or interpretation of
the study results difficult

- Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days
in 1 month)

- History of alcohol or drug abuse

- Treatment with any investigational drug in the one month preceding the study

- Mental conditions rendering a subject unable to understand the nature, scope and
possible consequences of the study

- Inability to comply with the protocol, e.g., uncooperative attitude, inability to
return for follow-up visits, unlikelihood of completing the study, and investigator
discretion