Role of NADPH Oxidase in Microvascular Dysfunction Following GDM

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.

Study Overview

• Status: Recruiting
• Conditions: Oxidative Stress; Gestational Diabetes; Vascular Endothelial Function
• Intervention / Treatment: Drug: Acetylcholine; Drug: Insulin aspart

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 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.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Anna Reid-Stanhewicz, PHD; Phone Number: 319-467-1732; Email: anna-stanhewicz@uiowa.edu

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • University of Iowa
      • Contact: Anna Stanhewicz, PhD; Phone Number: 319-467-1732; Email: anna-stanhewicz@uiowa.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / 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 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
Experimental: local apocynin perfusion; local apocynin is perfused through the microdialysis fiber to serve as the NADPH oxidase inhibited 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 apocynin + L-NAME perfusion; local apocynin and L-NAME are perfused through the microdialysis fiber for dual inhibition of NADPH oxidase and 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Anna Stanhewicz, PhD

Study record dates

Study Major Dates

• Study Start (Actual): August 30, 2023
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: June 29, 2023
• First Submitted That Met QC Criteria: July 7, 2023
• First Posted (Actual): July 14, 2023

Study Record Updates

• Last Update Posted (Actual): May 13, 2025
• Last Update Submitted That Met QC Criteria: May 7, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: postpartum; gestational diabetes; vascular
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Female Urogenital Diseases and Pregnancy Complications; Metabolic Diseases; Pregnancy Complications; Glucose Metabolism Disorders; Diabetes Mellitus; Diabetes, Gestational; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Neurotransmitter Agents; Vasodilator Agents; Cholinergic Agents; Cholinergic Agonists; Acetylcholine; Insulin Aspart
• Other Study ID Numbers: 202303158; 1R01HL169201-01 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No