Oxidative Stress in Microvascular Dysfunction Following Gestational Diabetes

Sponsor

Anna Stanhewicz, PhD (Other)

Overall Status

Recruiting

CT.gov ID

NCT05946785

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this investigation is to examine the role of oxidative stress in aberrant microvascular function in otherwise healthy women with a history of GDM.

Condition or Disease	Intervention/Treatment	Phase
Gestational Diabetes Vascular Endothelial Function	Drug: Acetylcholine Drug: insulin aspart	Early Phase 1

Detailed Description

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 the role of oxidative stress in mediating vascular dysfunction in women who have had gestational diabetes.

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 markers of oxidative stress and insulin-mediated eNOS phosphorylation in these cells.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

Role of Oxidative Stress in Microvascular Dysfunction Following Gestational Diabetes

Actual Study Start Date :

Feb 1, 2021

Anticipated Primary Completion Date :

Aug 1, 2023

Anticipated Study Completion Date :

Feb 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: local lactated Ringer's perfusion lactated Ringer's is perfused through the microdialysis fiber to serve as the vehicle control	Drug: Acetylcholine acetylcholine is perfused at 10 ascending concentrations (10^-10M - 10^-1 M) for 5 minutes each Drug: insulin aspart insulin aspart is perfused at 5 ascending concentrations (10^-8M - 10^-4 M) for 10 minutes each
Experimental: local ascorbate perfusion local ascorbate is perfused through the microdialysis fiber to serve as the antioxidant experimental treatment	Drug: Acetylcholine acetylcholine is perfused at 10 ascending concentrations (10^-10M - 10^-1 M) for 5 minutes each Drug: insulin aspart insulin aspart is perfused at 5 ascending concentrations (10^-8M - 10^-4 M) for 10 minutes each
Experimental: local L-NAME perfusion local L-NAME is perfused through the microdialysis fiber to inhibit nitric oxide synthase	Drug: Acetylcholine acetylcholine is perfused at 10 ascending concentrations (10^-10M - 10^-1 M) for 5 minutes each Drug: insulin aspart insulin aspart is perfused at 5 ascending concentrations (10^-8M - 10^-4 M) for 10 minutes each

Arm

Intervention/Treatment

Placebo Comparator: local lactated Ringer's perfusion

lactated Ringer's is perfused through the microdialysis fiber to serve as the vehicle control

Drug: Acetylcholine

acetylcholine is perfused at 10 ascending concentrations (10^-10M - 10^-1 M) for 5 minutes each

Drug: insulin aspart

insulin aspart is perfused at 5 ascending concentrations (10^-8M - 10^-4 M) for 10 minutes each

Experimental: local ascorbate perfusion

local ascorbate is perfused through the microdialysis fiber to serve as the antioxidant experimental treatment

Drug: Acetylcholine

acetylcholine is perfused at 10 ascending concentrations (10^-10M - 10^-1 M) for 5 minutes each

Drug: insulin aspart

insulin aspart is perfused at 5 ascending concentrations (10^-8M - 10^-4 M) for 10 minutes each

Experimental: local L-NAME perfusion

local L-NAME is perfused through the microdialysis fiber to inhibit nitric oxide synthase

Drug: Acetylcholine

acetylcholine is perfused at 10 ascending concentrations (10^-10M - 10^-1 M) for 5 minutes each

Drug: insulin aspart

insulin aspart is perfused at 5 ascending concentrations (10^-8M - 10^-4 M) for 10 minutes each

Outcome Measures

Primary Outcome Measures

microvascular acetylcholine-mediated dilation [at the study visit, an average of 4 hours]
cutaneous vascular vasodilator responses to acetylcholine perfusion in lactated Ringer's, ascorbate, and L-NAME treated microdialysis sites
microvascular insulin-mediated dilation [at the study visit, an average of 4 hours]
cutaneous vascular vasodilator responses to insulin perfusion in lactated Ringer's, ascorbate, and L-NAME treated microdialysis sites

Secondary Outcome Measures

endothelial cell markers of oxidative stress [at the study visit, an average of 4 hours]
nitrotyrosine, MnSOD and NADPH oxidase expression in biopsied endothelial cells
endothelial cell insulin-stimulated eNOS phosphorylation [at the study visit, an average of 4 hours]
eNOS phosphorylation response to incubation with insulin in biopsied endothelial cells

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 50 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

INCLUSION CRITERIA:

female sex
18 -50 years old
pregnancy history 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/e-cigarette 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.