Endothelial Dysfunction, Insulin Resistance
Conditions
Keywords
CD36, Endothelial dysfunction, African Americans
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.
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.
Interventions
DRUGSildenafil Citrate in G allele carrier
chronic use of phosphodiesterase 5 inhibitor in G allele carrier
DRUGSildenafil Citrate in non G allele carrier
chronic use of phosphodiesterase 5 inhibitor in Non G allele carrier
Sponsors
Washington University School of Medicine
Vanderbilt University Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Microvascular Blood Volume (MBV) During Insulin Infusion | Baseline to end of procedure (approximately 180 minutes) | 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). |
| Change in Microvascular Blood Volume (MBV) During Insulin Infusion After 4 Weeks of Sildenafil Treatment in Both Groups | Baseline to 4 weeks | 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). |
Countries
United States
Participant flow
Recruitment details
35 subjects were screened, 9 were excluded for not meeting the inclusion criteria
Pre-assignment details
21 subjects completed the study
Participants by arm
| Arm | Count |
|---|---|
| Sildenafil Citrate in G Allele Carriers Sildenafil citrate 20 mg three times a day
Sildenafil Citrate: phosphodiesterase 5 inhibitor | 8 |
| Sildenafil Citrate in Non Carriers of G Allele Sildenafil citrate 20 mg three times a day
Sildenafil Citrate: phosphodiesterase 5 inhibitor | 18 |
| Total | 26 |
Baseline characteristics
| Characteristic | Sildenafil Citrate in G Allele Carriers | Sildenafil Citrate in Non Carriers of G Allele | Total |
|---|---|---|---|
| Age, Customized Age | 42 years STANDARD_DEVIATION 7.4 | 33.66 years STANDARD_DEVIATION 7.4 | 37.83 years STANDARD_DEVIATION 7.4 |
| BMI | 27.7 kg/m^2 STANDARD_DEVIATION 2.8 | 33.53 kg/m^2 STANDARD_DEVIATION 3.9 | 30.615 kg/m^2 STANDARD_DEVIATION 3.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 18 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Glucose | 81 mg/dl STANDARD_DEVIATION 10 | 83.5 mg/dl STANDARD_DEVIATION 17.7 | 82.25 mg/dl STANDARD_DEVIATION 17.7 |
| HDL | 51 mg/dl STANDARD_DEVIATION 13.8 | 53.38 mg/dl STANDARD_DEVIATION 13.3 | 52.1 mg/dl STANDARD_DEVIATION 13.6 |
| Height | 169 centimeters STANDARD_DEVIATION 9.3 | 166.22 centimeters STANDARD_DEVIATION 8.72 | 167.61 centimeters STANDARD_DEVIATION 9.3 |
| LDL | 106 mg/dl STANDARD_DEVIATION 36.2 | 100.88 mg/dl STANDARD_DEVIATION 28.25 | 103.44 mg/dl STANDARD_DEVIATION 32.2 |
| Sex: Female, Male Gender Female | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Gender Male | 3 Participants | 14 Participants | 17 Participants |
| Total cholesterol | 180 mg/dl STANDARD_DEVIATION 37.1 | 171.66 mg/dl STANDARD_DEVIATION 29.48 | 175.83 mg/dl STANDARD_DEVIATION 33.2 |
| Triglycerides | 116.37 mg/dl STANDARD_DEVIATION 73.85 | 87.11 mg/dl STANDARD_DEVIATION 47.42 | 101.74 mg/dl STANDARD_DEVIATION 60.6 |
| Weight | 79 Kg STANDARD_DEVIATION 8.34 | 92.95 Kg STANDARD_DEVIATION 14.8 | 85.9 Kg STANDARD_DEVIATION 14.8 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 26 |
| other Total, other adverse events | 7 / 26 |
| serious Total, serious adverse events | 2 / 26 |
Outcome results
Primary
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).
Time frame: Baseline to end of procedure (approximately 180 minutes)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G Allele Carriers | Change in Microvascular Blood Volume (MBV) During Insulin Infusion | 13.16 ml/kg | Standard Deviation 3.369 |
| Non Carriers of G Allele | Change in Microvascular Blood Volume (MBV) During Insulin Infusion | 11.3 ml/kg | Standard Deviation 1.37 |
Primary
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).
Time frame: Baseline to 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G Allele Carriers | Change in Microvascular Blood Volume (MBV) During Insulin Infusion After 4 Weeks of Sildenafil Treatment in Both Groups | 12.93 ml/kg | Standard Deviation 2.31 |
| Non Carriers of G Allele | Change in Microvascular Blood Volume (MBV) During Insulin Infusion After 4 Weeks of Sildenafil Treatment in Both Groups | 8.4 ml/kg | Standard Deviation 0.63 |