Role of NADPH Oxidase in Microvascular Dysfunction Following GDM

Anna Stanhewicz, PhD

Status and phase: Enrolling; Early Phase 1

Conditions: Gestational Diabetes; Oxidative Stress; Vascular Endothelial Function

Treatments: Drug: Acetylcholine; Drug: Insulin aspart

Study type: Interventional

Funder types: Other

Identifiers

NCT05946798

1R01HL169201-01 (U.S. NIH Grant/Contract)

202303158

Details and patient eligibility

About

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.

Full 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 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.

Enrollment: 40 estimated patients

Sex: Female

Ages: 18 to 50 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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40 participants in 4 patient groups, including a placebo group

local lactated Ringer's perfusion

Placebo Comparator group

Description:

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

Treatment:

Drug: Insulin aspart

Drug: Acetylcholine

local apocynin perfusion

Experimental group

Description:

local apocynin is perfused through the microdialysis fiber to serve as the NADPH oxidase inhibited experimental treatment

Treatment:

Drug: Insulin aspart

Drug: Acetylcholine

local L-NAME perfusion

Experimental group

Description:

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

Treatment:

Drug: Insulin aspart

Drug: Acetylcholine

local apocynin + L-NAME perfusion

Experimental group

Description:

local apocynin and L-NAME are perfused through the microdialysis fiber for dual inhibition of NADPH oxidase and nitric oxide synthase

Treatment:

Drug: Insulin aspart

Drug: Acetylcholine