Extracellular Vesicles, Insulin Action, and Exercise on Vascular Function in Type 2 Diabetes
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 60
- 试验地点
- 3
- 主要终点
- Change in Extracellular Vesicles during insulin infusion
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 30 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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/m
- •Not diagnosed with Type 1 diabetes.
- •Not currently engaged in >150 min/wk of exercise.
排除标准
- •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).
研究组 & 干预措施
Lean with Normal Glucose Tolerance
Participants will not receive the study intervention and will be healthy controls.
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.
干预措施: Exercise (Behavioral)
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.
干预措施: Exercise (Behavioral)
结局指标
主要结局
Change in Extracellular Vesicles during insulin infusion
时间窗: From enrollment to the end of treatment at 16 weeks.
Extracellular vesicles (CD41 -CD31+, CD45, Tx, CD31, CD105) will be isolated from plasma before and during insulin stimulation.
次要结局
- Change in Contrast Enhanced Ultrasound(From enrollment to the end of treatment at 16 weeks.)
- Change in Flow Mediated Dilation of the brachial artery(From enrollment to the end of treatment at 16 weeks.)
- Change in Metabolic Insulin Sensitivity by the Isoglycemic Clamp(From enrollment to the end of treatment at 16 weeks.)
- Change in Pulse Wave Velocity(From enrollment to the end of treatment at 16 weeks.)
- Change in Augmentation Index(From enrollment to the end of treatment at 16 weeks.)
- Change in Post Ischemic Flow Velocity in the brachial artery(From enrollment to the end of treatment at 16 weeks.)
研究者
Steven K Malin, PhD
Associate Professor
Rutgers, The State University of New Jersey