Small Extracellular Vesicles and Insulin Action (SEV)

Effect of Small Extracellular Vesicles From Adipose Tissue on Insulin Action

The goals of this research study are to: 1) understand why some people with obesity are protected from developing conditions such as type 2 diabetes and cardiovascular disease while others are more likely to develop obesity-related conditions; 2) assess the effect of small extracellular vesicles (sEVs also called exosomes), obtained from human participants, on metabolic function in cultured cells and in mice.

Study Overview

• Status: Recruiting
• Conditions: Obesity; Insulin Resistance; Obesity, Metabolically Benign; Metabolically Healthy Obesity
• Intervention / Treatment: Behavioral: People with Metabolically Unhealthy Obesity - Low Calorie Diet

Detailed Description

Insulin resistance is commonly associated with obesity and is a major contributor to the development of obesity-related metabolic diseases, including nonalcoholic fatty liver disease, the metabolic syndrome, and type 2 diabetes (T2D). Most persons with obesity are "metabolically unhealthy" (MUO), often defined by having insulin resistance and the metabolic syndrome. However, a subset of people with obesity are metabolically healthy (MHO) and protected from the adverse metabolic effects of excess adiposity. The mechanisms that determine the differences in metabolic health between people with MUO and MHO are not unclear. This project will examine the effects of plasma and adipose tissue small extracellular vesicles (sEVs) on multi-organ insulin action. The investigators will isolate sEVs from subcutaneous abdominal adipose tissue biopsies and blood samples obtained from human participants with MHO, MUO or who are metabolically healthy and lean (MHL) and examine the effects of these sEVs on insulin resistance in muscle, liver and fat cells in culture and on multi-organ insulin sensitivity in lean and obese mice. The investigators will also identify differences in the potential bioactive molecules, namely miRNA and bioactive lipids, that are carried by sEVs. The results from this study will help determine whether plasma or adipose tissue sEVs in people who are MHL, MHO, or MUO are involved in regulating liver, muscle and adipose tissue insulin sensitivity. These results could identify novel pathways that regulate metabolic health in people and provide the foundation for exploring the potential of sEVs as a therapeutic target to prevent and treat the metabolic complications of obesity.

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Beth Henk; Phone Number: 3143628250; Email: bhenk@wustl.edu
• Study Contact Backup: Name: Kyle Timmons; Phone Number: 3142731879; Email: nutritionresearch@wustl.edu

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Contact: Johanna Sonnenschein; Phone Number: 3142731879; Email: nutritionresearch@wustl.edu
      • Contact: Beth Henk; Phone Number: 3143628250; Email: bhenk@wustl.edu
      • Principal Investigator: Dmitri Samovski, PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Metabolically healthy lean subjects must have a BMI ≥18.5 and ≤24.9 kg/m²; Subjects with obesity must have a BMI ≥30.0 and ≤50.0 kg/m²
• Metabolically healthy lean and people with metabolically healthy obesity must have intrahepatic triglyceride (IHTG) content ≤5%; fasting plasma glucose concentration <100 mg/dl, 2-hr oral glucose tolerance plasma glucose concentration <140 mg/dl, hemoglobin A 1C (HbA1c) ≤5.6% and HOMA-IR <2.5.
• People with metabolically unhealthy obesity must have intrahepatic triglyceride (IHTG) content ≥5.6%; HOMA-IR ≥2.5, and HbA1c 5.7%-6.4%, or fasting plasma glucose concentration ≥100 mg/dl, or 2-hr oral glucose tolerance test (OGTT) plasma glucose concentration ≥140 mg/dl.

Exclusion Criteria:

• History of diabetes, liver disease other than NAFLD or other serious diseases,
• Consume excessive amounts of alcohol (>21 units/week for men and >14 units/week for women),
• Take medications that could affect the study outcome measures, engage in regular exercise (>120 min/week),
• Are pregnant or lactating

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Metabolically healthy lean - Baseline testing only; Metabolically healthy lean - Lean individuals that have good glucose (sugar) control (defined as normal fasting glucose, glucose tolerance and hemoglobin A1c), normal insulin sensitivity (defined as Homeostatic Model Assessment of Insulin Resistance [HOMA-IR] <2.5) and normal intrahepatic triglyceride (fat) levels. Dietary intervention - None.
No Intervention: People with Metabolically Healthy Obesity - Baseline testing only; People with Metabolically Healthy Obesity - Persons with obesity that have good glucose (sugar) control, normal insulin sensitivity and normal intrahepatic triglyceride (fat) levels. Dietary intervention - None.
Experimental: People with Metabolically Unhealthy Obesity - Low Calorie Diet; People with Metabolically Unhealthy Obesity - Persons with obesity with plasma glucose and intrahepatic triglyceride (fat) levels higher than recommended in combination with insulin resistance (defined as HOMA-IR ≥2.5). Dietary intervention - Low calorie diet.	Behavioral: People with Metabolically Unhealthy Obesity - Low Calorie Diet; Consumption of a low-calorie diet with caloric intake reduced by ~25% to achieve ~10% weight loss in about 4 to 5 months.; Other Names: Dietary weight loss

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of exosomes on insulin sensitivity in cultured cells	Exosomes obtained from the plasma and adipose tissue of metabolically healthy lean participants, and participants with metabolically healthy or metabolically unhealthy obesity will be tested in cultured cells and mice to determine their effect on insulin sensitivity.	Baseline only (cross-sectional comparison of metabolically healthy lean, and of people with metabolically healthy or metabolically unhealthy obesity).
Change in the effect of exosomes on insulin sensitivity	Exosomes obtained from the plasma and adipose tissue of participants with metabolically unhealthy obesity before and after 10% weight loss will be tested in cultured cells and mice to determine their effect on insulin sensitivity.	Before and after ~10% weight loss (~4-5 months) in people with metabolically abnormal obesity

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in the content of microRNAs within exosomes obtained from plasma and adipose tissue	Exosomes obtained from the plasma and adipose tissue of metabolically healthy lean participants, and participants with metabolically healthy or metabolically unhealthy obesity will be analyzed to determine their microRNA composition.	Baseline only (cross-sectional comparison of metabolically healthy lean, and of people with metabolically healthy or metabolically unhealthy obesity).
Differences in the content of lipids within exosomes obtained from plasma and adipose tissue	Exosomes obtained from the plasma and adipose tissue of metabolically healthy lean participants, and participants with metabolically healthy or metabolically unhealthy obesity will be analyzed to determine their lipid composition.	Baseline only (cross-sectional comparison of metabolically healthy lean, and of people with metabolically healthy or metabolically unhealthy obesity).
Changes in the content of microRNAs within exosomes obtained from plasma and adipose tissue	Exosomes obtained from the plasma and adipose tissue of metabolically unhealthy obesity before and after weight loss will be analyzed to determine changes in their microRNA content after weight loss.	Before and after ~10% weight loss (~4-5 months) in people with metabolically abnormal obesity
Changes in the content of lipids within exosomes obtained from plasma and adipose tissue	Exosomes obtained from the plasma and adipose tissue of metabolically unhealthy obesity before and after weight loss will be analyzed to determine changes in their lipid content after weight loss.	Before and after ~10% weight loss (~4-5 months) in people with metabolically abnormal obesity
Insulin sensitivity	Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure	Baseline only (cross-sectional comparison of metabolically healthy lean, and people with metabolically healthy or metabolically unhealthy obesity).
Change in insulin sensitivity	Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure	Before and after ~10% weight loss (~4-5 months) in people with metabolically abnormal obesity
Fat mass and fat free mass	Fat mass and fat free mass will be assessed using dual-energy x-ray absorptiometry (DXA)	Baseline only (cross-sectional comparison of metabolically healthy lean, and people with metabolically healthy or metabolically unhealthy obesity).
Change in fat mass and fat free mass	Fat mass and fat free mass will be assessed using dual-energy x-ray absorptiometry (DXA)	Before and after 10% weight loss (~4-5 months) in people with metabolically abnormal obesity
Abdominal adipose tissue volumes	Abdominal subcutaneous and intra-abdominal adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)	Baseline only (cross-sectional comparison of metabolically healthy lean, and people with metabolically healthy or metabolically unhealthy obesity).
Change in abdominal adipose tissue volumes	Abdominal subcutaneous and intra-abdominal adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)	Before and after ~10% weight loss (~4-5 months) in people with metabolically abnormal obesity
Intra-hepatic triglyceride content	Intra-hepatic triglyceride content will be assessed by magnetic resonance techniques	Baseline only (cross-sectional comparison of metabolically healthy lean, and people with metabolically healthy or metabolically unhealthy obesity).
Change in intra-hepatic triglyceride content	Intra-hepatic triglyceride content will be assessed by magnetic resonance techniques	Before and after ~10% weight loss (~4-5 months) in people with metabolically abnormal obesity

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Dmitri Samovski, PhD, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): June 8, 2023
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): September 1, 2029

Study Registration Dates

• First Submitted: June 27, 2023
• First Submitted That Met QC Criteria: June 27, 2023
• First Posted (Actual): July 6, 2023

Study Record Updates

• Last Update Posted (Actual): July 17, 2025
• Last Update Submitted That Met QC Criteria: July 14, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Obesity; Weight Loss; Exosomes; Extracellular vesicles
• Additional Relevant MeSH Terms: Nutrition Disorders; Metabolic Diseases; Overnutrition; Body Weight; Glucose Metabolism Disorders; Hyperinsulinism; Overweight; Obesity, Metabolically Benign; Obesity; Insulin Resistance
• Other Study ID Numbers: 202005117

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Currently there is no plan to share individual participant data.

Drug and device information, study documents

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