CD36 in Nutrient Delivery and Its Dysfunction

• ClinicalTrials.gov Identifier: NCT03012386
• Recruitment Status: Active, not recruiting
• First Posted: January 6, 2017
• Last Update Posted: January 19, 2021
• Sponsor: Vanderbilt University Medical Center
• Collaborator: Washington University School of Medicine
• Information provided by (Responsible Party): Cyndya Shibao, Vanderbilt University Medical Center

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Insulin Resistance; Endothelial Dysfunction	Drug: Sildenafil Citrate	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 83 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Role of CD36 in Nutrient Delivery and Its Dysfunction in African Americans
• Actual Study Start Date: January 2017
• Estimated Primary Completion Date: July 2021
• Estimated Study Completion Date: October 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Sildenafil citrate; Sildenafil citrate 20 mg three times a day	Drug: Sildenafil Citrate; phosphodiesterase 5 inhibitor; Other Name: viagra, revatio,

Outcome Measures

Primary Outcome Measures :

1. insulin-stimulated microvascular recruitment. [ Time Frame: 4 weeks ]
   The primary endpoint is the change in microvascular blood volume (ΔMBV) during insulin infusion from baseline, an index of insulin-stimulated microvascular recruitment.

Secondary Outcome Measures :

1. Insulin sensitivity [ Time Frame: 4 weeks ]
   Glucose infusion rate during hyperinsulinemic euglycemic clamp

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

Sponsors and Collaborators

Vanderbilt University Medical Center

Washington University School of Medicine

Investigators

• Principal Investigator: Cyndya Shibao, MD; Vanderbilt University Medical Center

More Information

• Responsible Party: Cyndya Shibao, Assistant Professor of Medicine, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT03012386
• Other Study ID Numbers: 160955
• First Posted: January 6, 2017
• Last Update Posted: January 19, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Cyndya Shibao, Vanderbilt University Medical Center:

CD36; Endothelial dysfunction; African Americans

Additional relevant MeSH terms:

Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Sildenafil Citrate; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Urological Agents