Clinical trial NCT06546085: Extracellular Vesicles, Insulin Action, and Exercise
Official title: Extracellular Vesicles, Insulin Action, and Exercise on Vascular Function in Type 2 Diabetes
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Type 2 Diabetes
Obesity
Lead sponsor: Rutgers, The State University of New Jersey
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: University of Virginia
First posted: 2024-08-09
Enrollment: 60
Sex: ALL
Minimum age (years): 40
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a between-within clinical trial study design. Groups (lean, obese/normal glucose tolerance, type 2 diabetes) will be matched on age and sex while those with obesity and normal glucose tolerance (NGT) will have matched BMI to type 2 diabetes (T2D) for cross-sectional comparisons. People with obesity and NGT as well as obesity with T2D will undergo exercise training for 16 weeks to determine EV changes in comparison to lean controls.
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: Inclusion Criteria:

* Male or female 40 - 70 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 ≥1 year.
* Has a body mass index of 20-25 or 30-45 kg/m2.
* Not diagnosed with Type 1 diabetes.
* Not currently engaged in \>90 min/wk of exercise.

Exclusion Criteria:

* Participants with morbid obesity (BMI \>45 kg/m2) and under-/overweight patients (BMI: ≤18 or 25-30 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 (≥90 min of moderate/high intensity exercise)
* T2D with HbA1c ≥8.0%
* Participants who are smokers or who have quit smoking ≤5 years ago
* Participants prescribed metformin, GLP-1 agonists (oral/injectable), TZDs, DPP-IV inhibitors, Acarbose, SGLT-2 inhibitors within 1 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).
* Participants taking vasoactive medications (i.e. angiotensin converting enzyme inhibitors, angiotensin receptor blockers, nitrates, alpha- or beta-blockers).
* 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).

Primary outcomes:
measure: Change in Extracellular Vesicles during insulin infusion
timeFrame: From enrollment to the end of treatment at 16 weeks.
Secondary outcomes:
measure: Change in Metabolic Insulin Sensitivity by the Isoglycemic Clamp
timeFrame: From enrollment to the end of treatment at 16 weeks.
measure: Change in Contrast Enhanced Ultrasound
timeFrame: From enrollment to the end of treatment at 16 weeks.
measure: Change in Flow Mediated Dilation of the brachial artery
timeFrame: From enrollment to the end of treatment at 16 weeks.
measure: Change in Pulse Wave Velocity
timeFrame: From enrollment to the end of treatment at 16 weeks.
measure: Change in Augmentation Index
timeFrame: From enrollment to the end of treatment at 16 weeks.
measure: Change in Post Ischemic Flow Velocity in the brachial artery
timeFrame: From enrollment to the end of treatment at 16 weeks.
Other outcomes:
Locations:
city: New Brunswick
country: United States
facility: Institute for Food, Nutrition, and Health
state: New Jersey
city: New Brunswick
country: United States
facility: Robert Wood Johnson University Hospital Clinical Research Center
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers University Loree Gymnasium
state: New Jersey
Study officials:
affiliation: Rutgers University - New Brunswick
name: Steven K Malin, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.