CD36 in Nutrient Delivery and Its Dysfunction
This proposal will test the hypothesis that chronic treatment with sildenafil with and without the use of nitric oxide substrate, L-arginine, protects against fatty acid induced impairment of endothelial function, improves insulin-stimulated microvascular recruitment, insulin sensitivity and glucose uptake in CD36 rs3211938 G-allele carriers.
- Insulin Resistance
- Endothelial Dysfunction
- Eligible Ages
- Between 18 Years and 50 Years
- Eligible Genders
- Accepts Healthy Volunteers
- African American men and women.
- Age 18-50 years
- BMI 25-40 kg/m2
- 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
- Phase 1/Phase 2
- Study Type
- Intervention Model
- Single Group Assignment
- Primary Purpose
- Basic Science
- None (Open Label)
|Sildenafil citrate 20 mg three times a day||
- Vanderbilt University Medical Center
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.