Extracellular Vesicles, Insulin Action, and Exercise

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.

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).