Diabetes Mellitus, Type 2
Conditions
Keywords
Endothelial function, Glycocalyx, Diabetes
Brief summary
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.
Detailed description
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).
Interventions
DRUGEndocalyx
3,712mg (six capsules) of DSGP for eight weeks.
DRUGPlacebo
Ingredients per capsule (6 capsules per day) Nu-Mag Nat 10.00mg Rice Flour White 830 mg Magnesium Stearate 10.00mg
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Dietary supplement vs placebo
Eligibility
Sex/Gender
ALL
Age
45 Years to 64 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glygocalyx Integrity - Perfused Boundary Region | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Brachial Artery Flow Mediated Dilation | Baseline and final assessment (Week 8) | Arterial measurements will be performed by imaging the brachial artery artery longitudinally using high-resolution duplex ultrasonography. Arterial vasodilatory responses to hyperemia (flow-mediated dilation; FMD) will be examined by inflating a cuff up to 250 mmHg for five minutes. Before, during and after rapid release of the cuff, brachial artery blood flow velocity and diameter will be continuously measured. This is a measurement of endothelial function. When assessing FMD, the cuff will squeeze the arm tightly; however, any discomfort will be alleviated as soon as the pressure in the cuff is released. |
| Insulin-stimulated Leg Blood Flow | Baseline and final assessment (Week 8) | Insulin-stimulated leg blood flow will be assessed via Doppler and contrast-enhanced ultrasound during an insulin-dextrose clamp. After a minimum of 20 minutes in supine rest, baseline cardiovascular measurements will be collected, including Doppler and contrast-enhanced ultrasound-based measures, blood samples obtained and then the insulin clamp will start. Briefly, insulin (Humulin R U-100) will be infused via IV at a constant rate of 80mU/m2 body surface area/min for the three-hour period. Blood glucose will be measured at five-minute intervals and maintained at fasting levels; this will be achieved by variable IV infusion rates of a 20% dextrose solution. The measurements described will allow for the assessment of the insulin stimulated leg blood flow |
| Femoral Artery Flow Mediated Dilation | Baseline and final assessment (Week 8) | Arterial measurements will be performed by imaging the femoral artery longitudinally using high-resolution duplex ultrasonography. Arterial vasodilatory responses to hyperemia (flow-mediated dilation; FMD) will be examined by inflating a cuff up to 250 mmHg for five minutes. Before, during and after rapid release of the cuff, femoral artery blood flow velocity and diameter will be continuously measured (these are used to calculate the FMD). This is a measurement of endothelial function. When assessing FMD, the cuff will squeeze the leg tightly; however, any discomfort will be alleviated as soon as the pressure in the cuff is released. |
Countries
United States
Participant flow
Pre-assignment details
This clinical trial is a proof of concept clinical trial phase that corresponds to Aim 1 of a larger project. The participants assigned to intervention in this trial completed either the DSGP supplementation or placebo arms. No aim 2/clinical trial phase 2 will be enacted for the larger project.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Endocalyx: 3,712mg (six capsules) of DSGP for eight weeks. | 12 |
| Placebo Participants will daily ingest 6 capsules daily of placebo for eight weeks.
Placebo: Ingredients per capsule (6 capsules per day) Nu-Mag Nat 10.00mg Rice Flour White 830 mg Magnesium Stearate 10.00mg | 12 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Dietary Supplementation of Glycocalyx Precursors (DSGP) | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 4 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 8 Participants | 11 Participants |
| Age, Continuous | 67.1 years STANDARD_DEVIATION 7 | 60.6 years STANDARD_DEVIATION 8.4 | 63.8 years STANDARD_DEVIATION 8.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 12 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 12 Participants | 24 Participants |
| Region of Enrollment United States | 12 Participants | 12 Participants | 24 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 12 Participants | 11 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 4 / 12 | 3 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Glygocalyx Integrity - Perfused Boundary Region
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.
Time frame: Change from baseline to eight weeks assessment
Population: participants that completed full study intervention with baseline and eight week assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dietary Supplementation of Glycocalyx Precursors (DSGP) | Glygocalyx Integrity - Perfused Boundary Region | 0.11 Delta micrometers (mcm) | Standard Error 0.17 |
| Placebo | Glygocalyx Integrity - Perfused Boundary Region | -0.16 Delta micrometers (mcm) | Standard Error 0.15 |
Secondary
Brachial Artery Flow Mediated Dilation
Arterial measurements will be performed by imaging the brachial artery artery longitudinally using high-resolution duplex ultrasonography. Arterial vasodilatory responses to hyperemia (flow-mediated dilation; FMD) will be examined by inflating a cuff up to 250 mmHg for five minutes. Before, during and after rapid release of the cuff, brachial artery blood flow velocity and diameter will be continuously measured. This is a measurement of endothelial function. When assessing FMD, the cuff will squeeze the arm tightly; however, any discomfort will be alleviated as soon as the pressure in the cuff is released.
Time frame: Baseline and final assessment (Week 8)
Population: participants that completed full study intervention with baseline and eight week assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dietary Supplementation of Glycocalyx Precursors (DSGP) | Brachial Artery Flow Mediated Dilation | Baseline | 2.93 FMD % | Standard Error 0.39 |
| Dietary Supplementation of Glycocalyx Precursors (DSGP) | Brachial Artery Flow Mediated Dilation | Final | 3.20 FMD % | Standard Error 0.47 |
| Placebo | Brachial Artery Flow Mediated Dilation | Final | 1.87 FMD % | Standard Error 0.34 |
| Placebo | Brachial Artery Flow Mediated Dilation | Baseline | 2.14 FMD % | Standard Error 0.27 |
Secondary
Femoral Artery Flow Mediated Dilation
Arterial measurements will be performed by imaging the femoral artery longitudinally using high-resolution duplex ultrasonography. Arterial vasodilatory responses to hyperemia (flow-mediated dilation; FMD) will be examined by inflating a cuff up to 250 mmHg for five minutes. Before, during and after rapid release of the cuff, femoral artery blood flow velocity and diameter will be continuously measured (these are used to calculate the FMD). This is a measurement of endothelial function. When assessing FMD, the cuff will squeeze the leg tightly; however, any discomfort will be alleviated as soon as the pressure in the cuff is released.
Time frame: Baseline and final assessment (Week 8)
Population: participants that completed full study intervention with baseline and eight week assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dietary Supplementation of Glycocalyx Precursors (DSGP) | Femoral Artery Flow Mediated Dilation | Baseline | 2.93 FMD % | Standard Error 0.39 |
| Dietary Supplementation of Glycocalyx Precursors (DSGP) | Femoral Artery Flow Mediated Dilation | Final | 3.20 FMD % | Standard Error 0.47 |
| Placebo | Femoral Artery Flow Mediated Dilation | Baseline | 2.14 FMD % | Standard Error 0.27 |
| Placebo | Femoral Artery Flow Mediated Dilation | Final | 1.87 FMD % | Standard Error 0.34 |
Secondary
Insulin-stimulated Leg Blood Flow
Insulin-stimulated leg blood flow will be assessed via Doppler and contrast-enhanced ultrasound during an insulin-dextrose clamp. After a minimum of 20 minutes in supine rest, baseline cardiovascular measurements will be collected, including Doppler and contrast-enhanced ultrasound-based measures, blood samples obtained and then the insulin clamp will start. Briefly, insulin (Humulin R U-100) will be infused via IV at a constant rate of 80mU/m2 body surface area/min for the three-hour period. Blood glucose will be measured at five-minute intervals and maintained at fasting levels; this will be achieved by variable IV infusion rates of a 20% dextrose solution. The measurements described will allow for the assessment of the insulin stimulated leg blood flow
Time frame: Baseline and final assessment (Week 8)
Population: participants that completed full study intervention with baseline and eight week assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dietary Supplementation of Glycocalyx Precursors (DSGP) | Insulin-stimulated Leg Blood Flow | Baseline | 5.98 mL/min | Standard Error 11.92 |
| Dietary Supplementation of Glycocalyx Precursors (DSGP) | Insulin-stimulated Leg Blood Flow | Final | 2.97 mL/min | Standard Error 12.14 |
| Placebo | Insulin-stimulated Leg Blood Flow | Baseline | 16.93 mL/min | Standard Error 15.38 |
| Placebo | Insulin-stimulated Leg Blood Flow | Final | 9.55 mL/min | Standard Error 9.03 |