Role of NADPH Oxidase in Microvascular Dysfunction Following GDM

Study Overview
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Brief Summary
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The purpose of this investigation is to examine NADPH oxidase as a source of reactive oxygen species contributing to aberrant microvascular function in otherwise healthy women with a history of GDM.

Detailed Description
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Women with a history of gestational diabetes mellitus (GDM) are at a 2-fold greater risk for the development of overt cardiovascular disease (CVD) following the effected pregnancy. While subsequent development of type II diabetes elevates this risk, prior GDM is an independent risk factor for CVD morbidity, particularly within the first decade postpartum. GDM is associated with impaired endothelial function during pregnancy and decrements in macro- and microvascular function persist postpartum, despite the remission of insulin resistance following delivery. Collectively, while the association between GDM and elevated lifetime CVD risk is clear, and available evidence demonstrates a link between GDM and vascular dysfunction in the decade following pregnancy, the mechanisms mediating this persistent dysfunction remain unexamined. The purpose of this investigation is to examine NADPH oxidase as a source of reactive oxygen species contributing to aberrant microvascular function in otherwise healthy women with a history of GDM. In this study, the investigators use the blood vessels in the skin as a representative vascular bed for examining mechanisms of microvascular dysfunction in humans. Using a minimally invasive technique (intradermal microdialysis for the local delivery of pharmaceutical agents) they examine the blood vessels in a dime-sized area of the skin in women who have had GDM. As a compliment to these measures, the investigators also collect endothelial cells from an antecubital vein and measure NADPH oxidase expression and markers of oxidative stress in these cells.

Official Title
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Role of NADPH Oxidase in Microvascular Dysfunction Following GDM

Conditions
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Gestational Diabetes, Oxidative Stress, Vascular Endothelial Function

Intervention / Treatment
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* Drug: Acetylcholine
* Drug: Insulin aspart


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: 18 years or older pregnant within 5 years of the study visit had gestational diabetes diagnosed by their obstetrician and confirmed according to the American College of Obstetricians and Gynecologists criteria for gestational diabetes. or without a history of gestational diabetes EXCLUSION CRITERIA: skin diseases current tobacco or electronic cigarette/vape pen use, diagnosed or suspected hepatic or metabolic disease including diabetes, statin or other cholesterol-lowering medication, current antihypertensive medication, history of preeclampsia or gestational hypertension, current pregnancy, body mass index <18.5 kg/m2, allergy to materials used during the experiment.(e.g. latex), known allergies to study drugs

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

Sexes Eligible for Study
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Female

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: local lactated Ringer's perfusion<br>lactated Ringer's is perfused through the microdialysis fiber to serve as the vehicle control | Drug: Acetylcholine<br>* acetylcholine is perfused at 10 ascending concentrations (10^-10M - 10^-1 M) for 5 minutes each<br>Drug: Insulin aspart<br>* insulin aspart is perfused at 5 ascending concentrations (10^-8M - 10^-4 M) for 10 minutes each<br>|
| Experimental: local apocynin perfusion<br>local apocynin is perfused through the microdialysis fiber to serve as the NADPH oxidase inhibited experimental treatment | Drug: Acetylcholine<br>* acetylcholine is perfused at 10 ascending concentrations (10^-10M - 10^-1 M) for 5 minutes each<br>Drug: Insulin aspart<br>* insulin aspart is perfused at 5 ascending concentrations (10^-8M - 10^-4 M) for 10 minutes each<br>|
| Experimental: local L-NAME perfusion<br>local L-NAME is perfused through the microdialysis fiber to inhibit nitric oxide synthase | Drug: Acetylcholine<br>* acetylcholine is perfused at 10 ascending concentrations (10^-10M - 10^-1 M) for 5 minutes each<br>Drug: Insulin aspart<br>* insulin aspart is perfused at 5 ascending concentrations (10^-8M - 10^-4 M) for 10 minutes each<br>|
| Experimental: local apocynin + L-NAME perfusion<br>local apocynin and L-NAME are perfused through the microdialysis fiber for dual inhibition of NADPH oxidase and nitric oxide synthase | Drug: Acetylcholine<br>* acetylcholine is perfused at 10 ascending concentrations (10^-10M - 10^-1 M) for 5 minutes each<br>Drug: Insulin aspart<br>* insulin aspart is perfused at 5 ascending concentrations (10^-8M - 10^-4 M) for 10 minutes each<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| microvascular acetylcholine-mediated dilation | cutaneous vascular vasodilator responses to acetylcholine perfusion in lactated Ringer's, apocynin, L-NAME, and apocynin+L-NAME treated microdialysis sites | at the study visit, an average of 4 hours | 
| microvascular insulin-mediated dilation | cutaneous vascular vasodilator responses to insulin perfusion in lactated Ringer's, apocynin, L-NAME, and apocynin+L-NAME treated microdialysis sites | at the study visit, an average of 4 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| endothelial cell NADPH oxidase expression | NADPH oxidase expression in biopsied endothelial cells | at the study visit, an average of 4 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gestational diabetes, postpartum, vascular