Clinical trial NCT05933707: Small Extracellular Vesicles and Insulin Action
Official title: Effect of Small Extracellular Vesicles From Adipose Tissue on Insulin Action
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Obesity
Insulin Resistance
Metabolically Healthy Obesity
Obesity, Metabolically Benign
Keywords: Obesity
Weight Loss
Exosomes
Extracellular vesicles
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2023-07-06
Enrollment: 72
Sex: ALL
Minimum age (years): 25
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Effect of exosomes on insulin sensitivity in cultured cells
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, and of people with metabolically healthy or metabolically unhealthy obesity).
measure: Change in the effect of exosomes on insulin sensitivity
timeFrame: Before and after ~10% weight loss (~4-5 months) in people with metabolically abnormal obesity
Secondary outcomes:
measure: Differences in the content of microRNAs within exosomes obtained from plasma and adipose tissue
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, and of people with metabolically healthy or metabolically unhealthy obesity).
measure: Differences in the content of lipids within exosomes obtained from plasma and adipose tissue
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, and of people with metabolically healthy or metabolically unhealthy obesity).
measure: Changes in the content of microRNAs within exosomes obtained from plasma and adipose tissue
timeFrame: Before and after ~10% weight loss (~4-5 months) in people with metabolically abnormal obesity
measure: Changes in the content of lipids within exosomes obtained from plasma and adipose tissue
timeFrame: Before and after ~10% weight loss (~4-5 months) in people with metabolically abnormal obesity
measure: Insulin sensitivity
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, and people with metabolically healthy or metabolically unhealthy obesity).
measure: Change in insulin sensitivity
timeFrame: Before and after ~10% weight loss (~4-5 months) in people with metabolically abnormal obesity
measure: Fat mass and fat free mass
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, and people with metabolically healthy or metabolically unhealthy obesity).
measure: Change in fat mass and fat free mass
timeFrame: Before and after 10% weight loss (~4-5 months) in people with metabolically abnormal obesity
measure: Abdominal adipose tissue volumes
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, and people with metabolically healthy or metabolically unhealthy obesity).
measure: Change in abdominal adipose tissue volumes
timeFrame: Before and after ~10% weight loss (~4-5 months) in people with metabolically abnormal obesity
measure: Intra-hepatic triglyceride content
timeFrame: Baseline only (cross-sectional comparison of metabolically healthy lean, and people with metabolically healthy or metabolically unhealthy obesity).
measure: Change in intra-hepatic triglyceride content
timeFrame: Before and after ~10% weight loss (~4-5 months) in people with metabolically abnormal obesity
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Dmitri Samovski, PhD
role: PRINCIPAL_INVESTIGATOR
References: