CD36 in Nutrient Delivery and Its Dysfunction

Purpose

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.

Conditions

  • Insulin Resistance
  • Endothelial Dysfunction

Eligibility

Eligible Ages
Between 18 Years and 50 Years
Eligible Genders
All
Accepts Healthy Volunteers
Yes

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

Study Design

Phase
Phase 1/Phase 2
Study Type
Interventional
Allocation
N/A
Intervention Model
Single Group Assignment
Primary Purpose
Basic Science
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Sildenafil citrate
Sildenafil citrate 20 mg three times a day
  • Drug: Sildenafil Citrate in G allele carrier
    chronic use of phosphodiesterase 5 inhibitor in G allele carrier
    Other names:
    • viagra, revatio,
  • Drug: Sildenafil Citrate in non G allele carrier
    chronic use of phosphodiesterase 5 inhibitor in Non G allele carrier
    Other names:
    • viagra, revatio

More Details

Status
Completed
Sponsor
Vanderbilt University Medical Center

Study Contact

Detailed Description

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.