Role of Adiposomes in Endothelial Dysfunction

Role of Adiposomes in Diabetes-Associated Endothelial Dysfunction and Restorative Effects of Exercise and Metabolic Surgery

The development of type II diabetes (T2D) is strongly associated with obesity and both are well-established risk factors for cardiovascular disease. Knowing that vascular dysfunction is an early event in the development of cardiovascular disease in obese diabetic (OB-T2D) patients, The investigators set their long-term goal to define molecular mechanisms of vascular dysfunction and corrective strategies that target these mechanisms such as physical activity and weight loss. The investigators recently discovered that human adipose tissues release extracellular vesicles (adiposomes) that are efficiently captured by endothelial cells. Adiposomes are known to carry bioactive cargos such as proteins and micro RNAs; however, their lipid content has not been studied nor has their ability to transfer their lipid cargo to endothelial cells. In the current application, the investigators propose to investigate the role of adiposomes in communicating the unhealthy milieu, mainly dysregulated lipids, to endothelial cells in OB-T2D subjects. On top of these lipid species that the investigators propose to be carried by adiposomes are glycosphingolipids (GSLs). These lipids originate from the glycosylation of ceramides, a chemical process that is upregulated in the presence of inflammation and high glucose levels. Preliminary findings showed that in endothelial cells, GSL-rich adiposomes disturb plasma membrane structure and subsequently induce endothelial dysfunction. Moreover, the investigators found that preconditioning endothelial cells with high shear stress (which is an exercise mimetic) protected endothelial cells from the detrimental effects induced by adiposomes. Therefore, the central hypothesis is that adipose tissues in OB-T2D patients release GSL-loaded adiposomes that induce vascular endothelial dysfunction. The researchers propose that exercise and weight loss interventions (bariatric surgery) will restore adipose tissue homeostasis, reduce GSL-loaded adiposomes, and subsequently alleviate vascular risk in OB-T2D patients. The investigators will test the hypotheses by pursuing the following aims: aim 1: Investigate the role of GSL-rich adiposomes in the pathogenesis of endothelial dysfunction in OB-T2D adults; aim 2: Test the effectiveness of exercise training in reducing adiposome-mediated effects on vascular function; and aim 3: Examine changes in adiposome/caveolae axis following metabolic surgery and their association with vascular function.

Study Overview

• Status: Recruiting
• Conditions: Cardiovascular Diseases; Obesity; Diabetes
• Intervention / Treatment: Other: Exercise training

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Abeer M Mohamed, MD, PhD; Phone Number: 312-355-8099; Email: amahmo4@uic.edu

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Recruiting
      • University of Illinois at Chicago
      • Contact: Abeer M Mohamed, MD, PhD; Phone Number: 312-355-8099; Email: amahmo4@uic.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• BMI ≥ 35 kg/m2
• Between ages 18-50 years
• Not pregnant
• Diabetic (Current use of diabetes medication or fasting glucose ≥126 mg/dL)
• Medical clearance to participate in a moderate-intensity exercise program

Exclusion Criteria:

• Pregnant women
• Current smokers
• Currently abusing alcohol or drugs
• Chronic heart, liver, or kidney diseases, autoimmune diseases, or cancer
• Non-English speakers
• History of allergic reactions to lidocaine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Exercise training; Aerobic exercise training for 12 weeks, 3 times per week, 60 minutes per session.	Other: Exercise training; Aerobic exercise training using a treadmill or a bike for 12 weeks, 3 times per week, 60 minutes per session.
No Intervention: Control (standards of care); This arm will receive brochures for healthy lifestyle recommendations. No intervention will be conducted.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brachial artery flow-mediated dilation (percent vasodilation) in 60 obese diabetic subjects	Brachial flow-mediated dilation will be measured using ultrasound Alpha 7. For recording, a linear probe will be positioned five centimeters above the left arm's antecubital fossa, and a 1-minute baseline imaging will be recorded. Then, a blood pressure cuff will be put around the right mid-forearm and inflated to 200 to 220 mmHg for 5 minutes. Following cuff deflation (reactive hyperemia), a video grabber will be used to record a 300-second video sequence at three frames per second for offline measurement. The greatest brachial artery diameter at baseline will be deducted from the largest mean values obtained following cuff deflation to determine relative flow mediated dilation	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glycosphingolipid content (ng/ml) in adiposomes from 60 obese diabetic subjects	Adiposomes isolated from adipose tissue samples will be examined for their glycosphingolipid content using mass spectrometry and the outcome will be in nanograms per milliliter (ng/ml)	4 years

Collaborators and Investigators

• Sponsor: University of Illinois at Chicago
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Abeer M Mohamed, MD, PhD, University of Illinois at Chicago

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2022
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: December 19, 2021
• First Submitted That Met QC Criteria: January 5, 2022
• First Posted (Actual): January 20, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 21, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases
• Other Study ID Numbers: 2021-1113; 1R01HL161386-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No