Extracellular Vesicles, Insulin Action, and Exercise

NCT ID: NCT06546085

Last Updated: 2026-01-23

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-02-10
• Study Completion Date: 2029-04-30

Brief Summary

Extracellular vesicles (EVs) play a role in obesity-induced insulin resistance and likely impact the development of cardiovascular disease. However, little is known on how EVs affect vascular insulin action in people. The purpose of this study is to understand how EVs play a role in type 2 diabetes related cardiovascular disease. This research will also study if exercise can change how EVs impact blood flow and metabolic health. This study will contribute to designing precision medicine to treat/prevent cardiovascular disease in type 2 diabetes.

Detailed Description

Insulin resistance is a key underlying factor promoting hyperglycemia and hypertension in people with type 2 diabetes (T2D), who have a 3-fold greater cardiovascular disease (CVD) risk when compared with healthy controls. Despite several therapeutic approaches that favor insulin sensitivity through a variety of purported mechanisms (e.g. weight loss, incretins, AMPK activation, reduction in bioactive lipids: DAG/ceramides, etc.), long-term progression of glucose deterioration occurs. This suggests adjunctive targets may be important to prevent/reverse T2D. Studies show that extracellular vesicles (EVs) obtained from plasma are involved in obesity-induced insulin resistance at levels of adipocytes, muscle, and liver. However, little is known how plasma EVs affect vascular insulin action in humans. This is of clinical relevance as EVs enhance the Framingham Risk Score, suggesting EVs are a unique factor promoting CVD. This proposal will fill this knowledge gap by conducting a translational study in 3 distinct groups of people separated by obesity and T2D. The investigators hypothesize that 1) insulin will promote EV uptake and modify insulin signaling in endothelial cells, 2) EVs from adults with T2D will impair vessel reactivity compared to controls; 3) insulin will alter circulating EV insulin signaling and cargo, and 4) exercise training will change EV uptake and cargo as well as EV mediated vascular reactivity to insulin as well as relate to improved vascular function in humans.

Conditions

Type 2 Diabetes; Obesity

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Lean with Normal Glucose Tolerance

Participants will not receive the study intervention and will be healthy controls.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Obesity with Normal Glucose Tolerance

Participants with obesity and normal glucose tolerance will participate in 3 supervised exercise training sessions at 85% VO2max that expends \~400 kcal for 16 weeks.

Group Type: EXPERIMENTAL

Exercise

Intervention Type: BEHAVIORAL

Supervised treadmill exercise at 85% VO2max, 3x/wk for 16 weeks. Exercise duration will be adjusted based on individual VO2-heart rate (HR) relationship so that \~400 kcals will be expended during each training session.

Obesity with Type 2 Diabetes

Participants with obesity and type 2 diabetes will participate in 3 supervised exercise training sessions at 85% VO2max that expends \~400 kcal for 16 weeks.

Group Type: EXPERIMENTAL

Exercise

Intervention Type: BEHAVIORAL

Supervised treadmill exercise at 85% VO2max, 3x/wk for 16 weeks. Exercise duration will be adjusted based on individual VO2-heart rate (HR) relationship so that \~400 kcals will be expended during each training session.

Interventions

Exercise

Supervised treadmill exercise at 85% VO2max, 3x/wk for 16 weeks. Exercise duration will be adjusted based on individual VO2-heart rate (HR) relationship so that \~400 kcals will be expended during each training session.

Intervention Type: BEHAVIORAL

Eligibility Criteria

Inclusion Criteria

• Male or female 30 - 80 years old.
• HbA1c <5.7% and fasting glucose <100mg/dl to be considered NGT
• T2D diagnosis or confirmation HbA1c ≥6.5% and fasting glucose ≥126 mg/dl
• Prescribed metformin, GLP-1 agonists (oral/injectable), TZDs, DPP-IV inhibitors, Acarbose, SGLT-2 inhibitors ≥6 year.
• Has a body mass index of 20-24.99 or 25.0-45 kg/m2.
• Not diagnosed with Type 1 diabetes.
• Not currently engaged in >150 min/wk of exercise.

Exclusion Criteria

• Participants with morbid obesity (BMI >45 kg/m2) and underweight patients (BMI: ≤18 kg/m2).
• Intolerance to insulin
• Evidence of type 1 diabetes and diabetics requiring insulin therapy.
• Participants who have not been weight stable (≥2 kg weight change in past 6 months)
• Participants who have been recently active in past 6 months via health screening questions (≥150 min of moderate/high intensity exercise)
• T2D with HbA1c ≥10.0%
• Participants who are smokers or who have quit smoking ≤2 years ago
• Participants prescribed metformin, GLP-1 agonists (oral/injectable), TZDs, DPP-IV inhibitors, Acarbose, SGLT-2 inhibitors within 6 year.
• Hypertriglyceridemic (≥400 mg/dl) and hypercholesterolemic (≥260 mg/dl) participants as determined from LabCorp samples.
• Kidney dysfunction as determined from LabCorp biochemical outcomes (e.g. creatinine (≥1.0 mg/dl), eGFR (≤59 ml/min/1.73), BUN (≥24 mg/dl) as derived from comprehensive metabolic panels).
• Hypertensive (≥160/100 mmHg) at time of screening.
• Abnormal liver function (reflective from comprehensive panel liver enzymes Alk (≥121 IU/L), AST (≥40 IU/L) and ALT (≥32 IU/L) via LabCorp).
• History of significant metabolic, cardiac, cerebrovascular, hematological, pulmonary, gastrointestinal, liver, renal, or endocrine disease or cancer that in the investigator's opinion would interfere with or alter the outcome measures, or impact subject safety.
• Pregnant (as evidenced by positive pregnancy test) or nursing women
• Participants with contraindications to participation in an exercise training program
• Known hypersensitivity to perflutren (contained in Definity).
• Anemic as confirmed by hematocrit (HCT) (women ≤36%, Men ≤38%) at time of screening.
• Suggested infections at time of screening as confirmed by WBC (≥10.8 x10E3/uL) and/or platelets (≥450 x10E3/uL).

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

University of Virginia

OTHER

Sponsor Role: collaborator

Rutgers, The State University of New Jersey

OTHER

Sponsor Role: lead

Responsible Party

Steven K Malin, PhD

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Steven K Malin, PhD

Role: PRINCIPAL_INVESTIGATOR

Rutgers University - New Brunswick

Locations

Institute for Food, Nutrition, and Health

New Brunswick, New Jersey, United States

Site Status: RECRUITING

Robert Wood Johnson University Hospital Clinical Research Center

New Brunswick, New Jersey, United States

Site Status: RECRUITING

Rutgers University Loree Gymnasium

New Brunswick, New Jersey, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Steven K Malin, PhD

Role: CONTACT

steven.malin@rutgers.edu

848-932-7540

Emily M Heiston, PhD

Role: CONTACT

emily.heiston@rutgers.edu

848-932-7540

Facility Contacts

Sue Shapses, PhD

Role: primary

shapses@rutgers.edu

848-932-9403

Fei Chen

Role: primary

chenf2@rwjms.rutgers.edu

732-235-5966

Steven K Malin, PhD

Role: primary

steven.malin@rutgers.edu

848-932-7540

References

Heiston EM, Ballantyne A, La Salvia S, Musante L, Erdbrugger U, Malin SK. Acute exercise decreases insulin-stimulated extracellular vesicles in conjunction with augmentation index in adults with obesity. J Physiol. 2023 Nov;601(22):5033-5050. doi: 10.1113/JP282274. Epub 2022 Feb 16.

Reference Type: BACKGROUND

PMID: 35081660 (View on PubMed)

Eichner NZM, Gilbertson NM, Heiston EM, Musante L, LA Salvia S, Weltman A, Erdbrugger U, Malin SK. Interval Exercise Lowers Circulating CD105 Extracellular Vesicles in Prediabetes. Med Sci Sports Exerc. 2020 Mar;52(3):729-735. doi: 10.1249/MSS.0000000000002185.

Reference Type: BACKGROUND

PMID: 31609300 (View on PubMed)

Zhang M, Wang L, Chen Z. Research progress of extracellular vesicles in type 2 diabetes and its complications. Diabet Med. 2022 Sep;39(9):e14865. doi: 10.1111/dme.14865. Epub 2022 May 20.

Reference Type: BACKGROUND

PMID: 35509124 (View on PubMed)

Nozaki T, Sugiyama S, Koga H, Sugamura K, Ohba K, Matsuzawa Y, Sumida H, Matsui K, Jinnouchi H, Ogawa H. Significance of a multiple biomarkers strategy including endothelial dysfunction to improve risk stratification for cardiovascular events in patients at high risk for coronary heart disease. J Am Coll Cardiol. 2009 Aug 11;54(7):601-8. doi: 10.1016/j.jacc.2009.05.022.

Reference Type: BACKGROUND

PMID: 19660689 (View on PubMed)

Ragland TJ, Heiston EM, Ballantyne A, Stewart NR, La Salvia S, Musante L, Luse MA, Isakson BE, Erdbrugger U, Malin SK. Extracellular vesicles and insulin-mediated vascular function in metabolic syndrome. Physiol Rep. 2023 Jan;11(1):e15530. doi: 10.14814/phy2.15530.

Reference Type: BACKGROUND

PMID: 36597186 (View on PubMed)

Heiston EM, Ballantyne A, Stewart NR, La Salvia S, Musante L, Lanningan J, Erdbrugger U, Malin SK. Insulin infusion decreases medium-sized extracellular vesicles in adults with metabolic syndrome. Am J Physiol Endocrinol Metab. 2022 Oct 1;323(4):E378-E388. doi: 10.1152/ajpendo.00022.2022. Epub 2022 Jul 20.

Reference Type: BACKGROUND

PMID: 35858245 (View on PubMed)

Hallmark R, Patrie JT, Liu Z, Gaesser GA, Barrett EJ, Weltman A. The effect of exercise intensity on endothelial function in physically inactive lean and obese adults. PLoS One. 2014 Jan 20;9(1):e85450. doi: 10.1371/journal.pone.0085450. eCollection 2014.

Reference Type: BACKGROUND

PMID: 24465565 (View on PubMed)

Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest. 1996 Jun 1;97(11):2601-10. doi: 10.1172/JCI118709.

Reference Type: BACKGROUND

PMID: 8647954 (View on PubMed)

Solomon TP, Malin SK, Karstoft K, Haus JM, Kirwan JP. The influence of hyperglycemia on the therapeutic effect of exercise on glycemic control in patients with type 2 diabetes mellitus. JAMA Intern Med. 2013 Oct 28;173(19):1834-6. doi: 10.1001/jamainternmed.2013.7783. No abstract available.

Reference Type: BACKGROUND

PMID: 23817567 (View on PubMed)

Other Identifiers

R01DK133598-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

Pro2024000230

Identifier Type: -

Identifier Source: org_study_id