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Principal Investigator: Camila Margarita Manrique Acevedo
Organization: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
Fiscal Year: 2024
Funding agency: Veterans Affairs
PROJECT SUMMARY/ABSTRACT
Cardiovascular disease (CVD) is the leading cause of death in Veterans with type 2 diabetes (T2D).
Lifestyle modifications, including increased physical activity, are recommended as first-line therapy for the
management of T2D. Unfortunately, the efficacy of these lifestyle interventions for preventing CVD morbidity
and mortality in patients with T2D is not well-established. Available evidence from our group and others
indicates that vascular adaptations to exercise training are impaired in subjects with T2D. We propose that
diminished vascular adaptations explain why increased physical activity does not lead to a robust reduction in
CVD morbidity and mortality in T2D. However, the mechanisms responsible for this deficit in vascular
adaptations to exercise in T2D remain unknown. This is a major limitation for identifying new adjuvant
therapeutics to maximize the cardiovascular benefits of exercise in the diabetic population. Exercise exerts
direct effects on the vasculature via repetitive exposure to hemodynamic stimuli or shear stress. The
increased blood flow and luminal shear stress attendant to each bout of exercise are primary mechanisms
contributing to vascular adaptations. Shear stress is detected by mechanosensitive endothelial luminal
structures, such as the glycocalyx, that convert mechanical forces into biochemical signals via
mechanotransduction. As such, we propose that an intact endothelial glycocalyx is required for the
mechanotransduction of increased shear stress and the subsequent chronic vascular adaptations associated
with exercise to occur. Notably, glycocalyx degradation is a classic feature of T2D. Accordingly, our
overarching hypothesis is that endothelial glycocalyx degradation is a key factor precluding shear stress
mechanotransduction and consequent exercise-induced vascular adaptations in T2D. The corollary to this
hypothesis is that restoration of the endothelial glycocalyx by dietary supplementation of glycocalyx precursors
(DSGP) will improve vascular adaptations to exercise in T2D. Specifically, in Aim 1 (Proof of Concept Clinical
Trial Phase), we will document that DSGP enhances endothelial glycocalyx integrity in patients with T2D.
Although we provide preliminary evidence that DSGP can increase glycocalyx thickness and endothelial
function in a mouse model of T2D, this will be the first study to demonstrate these effects in T2D subjects. The
effects of DSGP for eight weeks will be studied using a double-blinded randomized placebo control trial.
Subsequently, in Aim 2 (Expended Clinical Trial Phase), we will demonstrate the permissive role of the
endothelial glycocalyx in exercise-induced vascular adaptations in patients with T2D. Having shown that
restoration of the endothelial glycocalyx via DSGP is feasible in T2D subjects, we will now investigate whether
such supplementation will potentiate exercise training-induced improvements in endothelial function. This will
be accomplished in a factorial balanced design in which T2D subjects will be randomized to DSGP or placebo
with and without concurrent exercise training for eight weeks. Our team is poised to move cardiovascular and
diabetes research forward with a translational project that will exert a sustained, powerful impact across a
number of levels of inquiry that are novel conceptually, methodologically, and therapeutically. Indeed,
targeting the glycocalyx holds extraordinary promise for achieving optimal exercise-induced vascular
adaptations in Veterans with T2D, thus maximizing the cardiovascular benefits of exercise.
Terms: <21+ years old><Adjuvant><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Arteries><Biochemical><Blood Vessels><Blood flow><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Caring><Cause of Death><Cell Coat><Cell Communication and Signaling><Cell Signaling><Cellular Mechanotransduction><Characteristics><Charge><Chronic><Clinical Trials><Diabetes Mellitus><Diagnosis><Dietary Supplementation><Double-Blind Method><Double-Blind Study><Double-Blinded><Double-Masked Method><Double-Masked Study><Endothelium><Epidemic><Erythrocuprein><Exercise><Exhibits><Exposure to><Glucosamine Sulfate><Glycocalyx><Glycoproteins><Heart Vascular><Hemocuprein><Hyaluronan><Impairment><Individual><Inflammation><Intracellular Communication and Signaling><Ketosis-Resistant Diabetes Mellitus><Left><Life Style Modification><Maturity-Onset Diabetes Mellitus><Mechanical Signal Transduction><Mechanosensory Transduction><Mediating><Methodology><Mice><Mice Mammals><Molecular Weight><Morbidity><Morbidity - disease rate><Murine><Mus><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Patients><Phase><Physical activity><Placebos><Population><Prevalence><Proteoglycan><Randomized><Recommendation><Research><Role><Sham Treatment><Side><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Stimulus><Structure><Superoxide Dismutase><Supplementation><T2 DM><T2D><T2DM><Testing><Therapeutic><Thick><Thickness><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Veterans><adult onset diabetes><adulthood><biological signal transduction><cardiovascular disorder><circulatory system><cytocuprein><db/db mouse><design><designing><diabetes><diabetic><diet supplementation><exercise training><fucan sulfate><fucoidan><fucoidin><hemodynamics><improved><ketosis resistant diabetes><life style intervention><lifestyle intervention><lifestyle modification><maturity onset diabetes><mechanical force><mechanosensing><mechanotransduction><military veteran><mortality><mouse model><murine model><novel><permissiveness><prevent><preventing><prospective><randomisation><randomization><randomized placebo control trial><randomized placebo controlled trial><randomly assigned><restoration><sham therapy><shear stress><social role><type 2 DM><type II DM><type two diabetes><vascular><veteran population>