Targeting the Endothelial Glycocalyx to Enhance Vascular Function and Exercise-Induced Vascular Adaptations in Type 2 Diabetes
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Glygocalyx Integrity - Perfused Boundary Region
研究概览
简要总结
The prevalence of type 2 diabetes (T2D) continues to increase in the US, with 26.8 million adults carrying a diagnosis. Importantly, T2D is widespread in the Veteran population. This epidemic of T2D also contributes to the staggering rates of cardiovascular disease and cardiovascular mortality. Lifestyle modifications, including increased physical activity, are recommended as first-line therapy for the management of T2D. Unfortunately, patients with T2D exhibit diminished vascular adaptations to exercise. The proposed project will test the overall hypothesis that degradation of the endothelial glycocalyx, a characteristic feature of T2D, precludes shear stress mechanotransduction and consequent exercise-induced vascular adaptations. As such, the investigators pose that restoration of the endothelial glycocalyx via dietary supplementation of glycocalyx precursors will potentiate vascular adaptations to exercise in Veterans with T2D.
详细描述
The prevalence of type 2 diabetes (T2D) continues to increase in the US. Importantly, T2D is widespread among Veterans. This T2D epidemic also contributes to the staggering rates of cardiovascular disease (CVD) and cardiovascular mortality. Current standards of medical care for T2D emphasize prioritizing the use of therapies that decrease CVD risk. Lifestyle modifications, such as increased physical activity, are recommended as first-line therapy for the management of T2D. Unfortunately, the efficacy of these interventions for preventing CVD morbidity and mortality in patients with T2D remains questionable. Evidence indicates that exercise training in T2D subjects does not elicit optimal vascular adaptations, including improvements in endothelial function. It is likely that such lessened vascular adaptations explain why increased physical activity does not lead to a robust reduction in CVD morbidity and mortality in T2D. A better understanding of the mechanisms responsible for the deficit of vascular adaptations to exercise in T2D is required for identifying new adjuvant therapeutics aimed at maximizing the cardiovascular benefits of exercise.
The primary goal of this project is to establish the endothelial glycocalyx as a novel target organ for heightening exercise-induced vascular adaptations. To that end, a dietary supplement that contains glycocalyx precursors (glucosamine sulfate, fucoidan, superoxide dismutase, and high molecular weight hyaluronan) will be used as an innovative "tool" to restore the endothelial glycocalyx in T2D subjects. Demonstration that dietary supplementation of glycocalyx precursors (DSGP) is effective at enhancing endothelial glycocalyx integrity in patients with T2D will be accomplished in the Proof of Concept Clinical Trial Phase (or Aim 1) of this project. Subsequently, in the Expended Clinical Trial Phase (or Aim 2), the use of the DSGP will allow us to test the hypothesis that glycocalyx restoration re-sensitizes the endothelium to shear stress mechanotransduction and thus potentiates exercise-induced vascular adaptations. This project will be the first to determine if targeting the glycocalyx is a viable therapeutic strategy for boosting exercise-induced endothelial benefits in diabetes.
The overarching hypothesis is that endothelial glycocalyx degradation is a key factor that precludes shear stress mechanotransduction and consequent exercise-induced vascular adaptations in T2D. A corollary to this hypothesis is that restoration of the endothelial glycocalyx by DSGP will improve vascular adaptations to exercise in T2D.
Specific aims are as follows:
Aim 1 (Proof of Concept Clinical Trial Phase): Document that DSGP enhances endothelial glycocalyx integrity in Veterans with T2D. The effects of DSGP for eight weeks on glycocalyx integrity and endothelial function will be studied using a double-blinded randomized placebo control trial. Sample size = 24 subjects (12 per group) for Aim 1.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 45 Years 至 64 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •45-74 years of age at the time of enrollment
- •Diagnosis of T2D by a health care provider, confirmed by chart review
- •HbA1c <9% and fasting blood glucose <200 mg/dL at screening visit
- •Body mass index (BMI) 25-45 kg/m2
- •Women should be postmenopausal (absence of menses for at least 1 year)
- •Sedentary subjects (<2 days/week of vigorous exercise)
- •Willingness to follow up instructions provided by study team
排除标准
- •Evidence of cardiac arrhythmias, unstable angina (or other cardiac event), heart failure or stroke in the last 12 months
- •Evidence of chronic kidney disease stage IV or V (GFR <30 mL/min)
- •Evidence of uncontrolled hypertension, systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 110 mmHg on more than 2 occasions in the past 12 months or at screening visit
- •Diagnosis of chronic liver disease
- •Uncontrolled thyroid dysfunction (abnormal TSH within 3 months of study enrollment)
- •Active cancer
- •Current use of hormone replacement therapy
- •Excessive alcohol consumption (>14 drinks/week for men, >7 drinks/week for women)
- •Current pregnancy or intent to become pregnant during the course of the study
- •Inability to swallow capsules
- •Known allergies to any of the compounds in the supplement: glucosamine extract, fucoidan extract, olive extract, artichoke extract, red and white grapes extract, melon concentrate, hyaluronic acid
研究组 & 干预措施
Dietary supplementation of glycocalyx precursors (DSGP)
Participants will daily ingest 3,712mg (i.e., six capsules) of DSGP for eight weeks. DSGP, commercially available as Endocalyx (Microvascular Health Solutions LLC, Alpine, UT), include glucosamine sulfate, fucoidan, superoxide dismutase, and high molecular weight hyaluronan.
干预措施: Endocalyx (Drug)
Placebo
Participants will daily ingest 6 capsules daily of placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Glygocalyx Integrity - Perfused Boundary Region
时间窗: Change from baseline to eight weeks assessment
Glycocalyx integrity will be assessed non-invasively using the GlycoCheck. The Glycocheck video microscope instrument will be placed under the subject's tongue to assess red blood cell penetration of the glycocalyx lining. PBR (perfused boundary region) is a measure of distance (mcm) that red blood cells penetrate into the glycocalyx. An increase in PBR in indicative of lower glycocalyx integrity.
次要结局
- Brachial Artery Flow Mediated Dilation(Baseline and final assessment (Week 8))
- Insulin-stimulated Leg Blood Flow(Baseline and final assessment (Week 8))
- Femoral Artery Flow Mediated Dilation(Baseline and final assessment (Week 8))