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.

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.

Aim 2 (Expanded Clinical Trial Phase): Demonstrate the permissive role of the endothelial glycocalyx for exercise-induced vascular adaptations in Veterans with T2D. Having shown that endothelial glycocalyx restoration via DSGP in T2D subjects is feasible, will now investigate whether such supplementation potentiates exercise training-induced improvements in endothelial function. This will be accomplished with a factorial balanced design in which T2D subjects will be randomized to DSGP or placebo with and without concurrent exercise training for eight weeks. Sample size = 72 subjects (18 per group).

Inclusion Criteria:

1. 45-74 years of age at the time of enrollment
2. Diagnosis of T2D by a health care provider, confirmed by chart review
3. HbA1c <9% and fasting blood glucose <200 mg/dL at screening visit
4. Body mass index (BMI) 25-45 kg/m2
5. Women should be postmenopausal (absence of menses for at least 1 year)
6. Sedentary subjects (<2 days/week of vigorous exercise)
7. Willingness to follow up instructions provided by study team

Exclusion Criteria:

Exclusion:

1. Evidence of cardiac arrhythmias, unstable angina (or other cardiac event), heart failure or stroke in the last 12 months
2. Evidence of chronic kidney disease stage IV or V (GFR <30 mL/min)
3. 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
4. Diagnosis of chronic liver disease
5. Uncontrolled thyroid dysfunction (abnormal TSH within 3 months of study enrollment)
6. Active cancer
7. Current use of hormone replacement therapy
8. Excessive alcohol consumption (>14 drinks/week for men, >7 drinks/week for women)
9. Current pregnancy or intent to become pregnant during the course of the study
10. Inability to swallow capsules
11. 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

Details of research products in this project will be in text, table, plots and images that will be disseminated in peer reviewed journals and/or conference proceedings. Datasets that underlie these research products will be made available upon reasonable written request and review with the ACOS/R&D and the ISSO within a reasonable time

Upon completion of data analysis

Screening visit until final assessment (week 8 assessment)