CD36 in Nutrient Delivery and Its Dysfunction

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Role of CD36 in Nutrient Delivery and Its Dysfunction in African Americans

Conditions
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Insulin Resistance, Endothelial Dysfunction

Intervention / Treatment
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* Drug: Sildenafil Citrate in G allele carrier
* Drug: Sildenafil Citrate in non G allele carrier


Participation Criteria
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Eligibility Criteria
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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 Pulmonary hypertension Use of a PDE5 inhibitor for erectile dysfunction 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. 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 History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack History or presence of immunological or hematological disorders 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 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sildenafil citrate<br>Sildenafil citrate 20 mg three times a day | Drug: Sildenafil Citrate in G allele carrier<br>* chronic use of phosphodiesterase 5 inhibitor in G allele carrier<br>* Other names: viagra, revatio,;Drug: Sildenafil Citrate in non G allele carrier<br>* chronic use of phosphodiesterase 5 inhibitor in Non G allele carrier<br>* Other names: viagra, revatio;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Microvascular Blood Volume (MBV) During Insulin Infusion | Insulin induces microvascular recruitment. Changes in MBV during Insulin infusion signifies insulin sensitivity. MBV is measured in the forearm brachioradialis muscle with contrast enhanced ultrasonography during minutes 120-150 of a hyperinsulinaemic euglycaemic (HIE) clamp (insulin infusion rate up to 80 mU/m2.min-1 ). In the last 30 minutes, L-arginine was infused (10 mg/kg/min for 30 minutes) and ultrasound measurements were repeated upon infusion completion (approximately minute 180). | Baseline to end of procedure (approximately 180 minutes) | 
| Change in Microvascular Blood Volume (MBV) During Insulin Infusion After 4 Weeks of Sildenafil Treatment in Both Groups | Chronic treatment with sildenafil increases vascularity and muscle glucose uptake. Changes in MBV during Insulin infusion signifies insulin sensitivity . Insulin sensitivity was tested after 4 weeks of treatment with Sildenafil in both groups. Subjects receive IV infusion of 20% Intralipid (45ml/h) and heparin (200 units/hr). MBV is measured in the forearm brachioradialis muscle with contrast enhanced ultrasonography during minutes 120-150 of a HIE clamp (insulin infusion rate up to 80 mU/m2.min-1 ) In the last 30 minutes, L-arginine was infused (10 mg/kg/min for 30 minutes) and ultrasound measurements were repeated upon infusion completion (approximately minute 180). | Baseline to 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD36, Endothelial dysfunction, African Americans