Diabetes: 20 papers
Peer-reviewed work on the endothelial glycocalyx, microvascular health and the ingredients in our formulas, newest first. Abstracts are indexed here and every paper links to the journal.
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Published paper
Early impairment of skeletal muscle endothelial glycocalyx barrier properties in diet-induced obesity in mice.
This mouse study examined whether the endothelial glycocalyx in skeletal muscle microvessels is damaged early in the course of diet-induced obesity. Using intravital measurement of glycocalyx barrier properties (accessibility of the glycocalyx to circulating tracers/red blood cells) in mice fed a high-fat diet, the authors found loss of glycocalyx barrier function before or alongside the development of overt metabolic disease. The findings suggest the glycocalyx is an early target of obesogenic diet rather than a late consequence of established obesity.
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Published paper
Rapid insulin-mediated increase in microvascular glycocalyx accessibility in skeletal muscle may contribute to insulin-mediated glucose disposal in rats.
In rats, systemic insulin infusion rapidly increased the accessible (perfused) volume of the endothelial glycocalyx in skeletal muscle microvessels, measured as increased distribution volume of a glycocalyx-permeable tracer. Enzymatic degradation of the glycocalyx with hyaluronidase blunted both this insulin-induced increase in glycocalyx accessibility and insulin-mediated glucose disposal. The authors conclude that insulin-driven changes in glycocalyx accessibility may contribute to how insulin promotes glucose uptake by muscle.
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Published paper
Impact of dietary supplementation of glycocalyx precursors on vascular function in type 2 diabetes
This combined preclinical and clinical study tested whether a dietary mixture of glycocalyx precursors (glucosamine sulfate, fucoidan, superoxide dismutase, and high molecular weight hyaluronan) could restore the endothelial glycocalyx and improve vascular function in type 2 diabetes. In diabetic db/db mice, four weeks of supplementation restored glycocalyx length and improved flow-mediated dilation and arterial stiffness, and the same mixture promoted glycocalyx growth in cultured endothelial cells. However, in a pilot double-blind randomized placebo-controlled trial of 22 Veterans with type 2 diabetes, eight weeks of supplementation did not improve glycocalyx integrity or vascular function compared with placebo.
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Published paper
Erythrocyte Glycocalyx Reports Glomerular Endothelial Glycocalyx Damage in Disease and Predicts Glomerular Albumin Permeability
This paper, published in the Journal of the American Society of Nephrology, reports that the glycocalyx layer on red blood cells reflects damage to the glycocalyx of glomerular endothelial cells in the kidney. The authors propose the erythrocyte glycocalyx as an accessible marker that also predicts glomerular permeability to albumin. Only the title and citation were available, so the methods, population, and numerical results cannot be verified here.
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Published paper
Associations Between Adipose Tissue Glycocalyx Quality, Nox Activity, and Microvascular Blood Flow
This undergraduate honors thesis reports a small within-subject human physiology experiment in which sublingual microvascular measures (GlycoCheck perfused boundary region, capillary density, red blood cell velocity) were compared under fasting conditions and during a hyperinsulinemic-euglycemic clamp, alongside adipose tissue microdialysis measures of lipolysis (glycerol), reactive oxygen species and blood flow. Insulin infusion was associated with a small but statistically significant increase in perfused boundary region (suggesting thinner/less dense glycocalyx) and decreases in red blood cell velocity and some vessel-diameter-specific densities, while microdialysis measures did not change significantly. The work is descriptive and exploratory, with only 6-8 participants analyzed per outcome.
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Published paper
Role of dietary interventions on microvascular health in South-Asian Surinamese people with type 2 diabetes in the Netherlands; a randomized controlled trial
This three-arm randomized, placebo-controlled trial tested a monthly 5-day fasting-mimicking diet (Prolon) versus a glycocalyx-mimetic supplement (Endocalyx, containing fucoidan, glucosamine sulfate and hyaluronic acid) versus placebo for 3 months in 56 South-Asian Surinamese patients with type 2 diabetes, with follow-up at 6 months. Sublingual microvascular measures were made with SDF imaging and GlycoCheck software. The fasting-mimicking diet lowered BMI and HbA1c temporarily but was associated with worsening of the dynamic perfused boundary region, while the supplement group showed improved dynamic PBR and microvascular health score and lower urinary MCP-1 relative to placebo.
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Published paper
Sex-related differences in arterial stiffness in type 2 diabetics: role of uric acid
This is a clinical trial protocol/registration document (NCT03648996) rather than a report of results. It describes a planned study testing whether a low-fructose diet (isocaloric or hypocaloric) or the xanthine oxidase inhibitor allopurinol changes arterial stiffness in people with type 2 diabetes, with attention to sex-related differences and the role of uric acid. No outcome data are presented in the provided text.
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Published paper
Ways and Means of Cellular Reconditioning for Kidney Regeneration
This narrative review proposes 'cellular reconditioning' — repairing individual damaged cell components to trigger broader recovery — as an addition to regenerative nephrology. It catalogs mitochondrial, lysosomal/autophagy, and peroxisomal dysfunction alongside loss of endothelial glycocalyx integrity as interconnected contributors to acute and chronic kidney disease, and reviews the enzymes (metalloproteinases, heparanase-1, hyaluronidases) that shed the glycocalyx. It also summarizes clinical glycocalyx biomarkers and imaging methods, plus reported preventive and restorative interventions.
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Published paper
Association of Gestational Diabetes With Subclinical Cardiovascular Disease on Echocardiogram and Endothelial Function Testing (Abstract 12986)
This conference abstract reports a cross-sectional analysis of 217 women assessed roughly nine years after pregnancy, 53 of whom had a history of gestational diabetes. Women with prior gestational diabetes showed greater left ventricular wall thickness, worse diastolic function, and worse endothelial and glycocalyx measures (EndoPAT reactive hyperemia index and GlycoCheck parameters). Some hypertrophy differences were explained by BMI, hypertension, and diabetes, but the diastolic and vascular findings persisted after adjustment.
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Published paper
Microvascular Differences in Individuals With Obesity At Risk of Developing Cardiovascular Disease
In a cross-sectional analysis of 813 middle-aged adults with overweight/obesity, sublingual microcirculation was imaged using sidestream dark-field video microscopy with new GlycoCheck software that adds red blood cell velocity analysis. Participants at high 10-year cardiovascular risk (Framingham) had fewer perfused small capillaries and faster red cell velocity than low-risk participants, whereas velocity-corrected perfused boundary region (a glycocalyx index) did not differ between risk groups.
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Published paper
Effects of Glucagon Like Peptide 1 Receptor Agonists, Sodium Glucose Cotransporter 2 Inhibitors, and Their Combination on Endothelial Glycocalyx, Arterial Function, and Myocardial Work Index in Patients With Type 2 Diabetes Mellitus After 12 Month Treatme
In this 12-month randomized trial, 160 patients with type 2 diabetes were assigned to add-on insulin, liraglutide (GLP-1RA), empagliflozin (SGLT-2i), or the GLP-1RA/SGLT-2i combination. Despite similar HbA1c reductions across groups, the newer agents and especially the combination produced greater improvements in sublingual glycocalyx thickness (perfused boundary region), arterial stiffness, central blood pressure, and echocardiographic myocardial strain and work indices than insulin.
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Published paper
Effects of Different Antidiabetic Medications on Endothelial Glycocalyx, Myocardial Function, and Vascular Function in Type 2 Diabetic Patients: One Year Follow-Up Study
One hundred people with poorly controlled type 2 diabetes were assessed before and 12 months after intensifying their antidiabetic treatment, with measurements of arterial stiffness, brachial artery flow-mediated dilation, sublingual endothelial glycocalyx (perfused boundary region by GlycoCheck), heart muscle deformation on echocardiography, and blood markers of oxidative stress. Average HbA1c fell from 8.9% to 7.1%, and this was accompanied by lower arterial stiffness, a smaller perfused boundary region (suggesting a thicker/less penetrable glycocalyx), better endothelial and left ventricular function, and lower oxidative stress markers. In multivariable analysis, incretin-based drugs (GLP-1 receptor agonists and DPP-4 inhibitors) were associated with these improvements over and above the fall in HbA1c.
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Published paper
Sublingual endothelial glycocalyx and atherosclerosis. A cross-sectional study
In the largest study of its kind, sublingual perfused boundary region (PBR, an indirect index of endothelial glycocalyx thickness) was measured once in 6,169 multi-ethnic adults and related to classical cardiovascular risk factors and self-reported cardiovascular disease. The smallest glycocalyx size (highest PBR quartile) was independently associated with female sex, older age, and diabetes, but not with prevalent cardiovascular disease, coronary heart disease/revascularization, or stroke. The authors conclude that PBR-estimated glycocalyx size does not track a high cardiovascular risk profile in a general population.
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Published paper
HDL cholesterol levels and endothelial glycocalyx integrity in treated hypertensive patients
This cross-sectional study measured sublingual perfused boundary region (PBR 5-9 µm) with GlycoCheck sidestream dark-field imaging in 120 treated hypertensive patients over 50 and compared results across HDL-cholesterol tertiles. Patients in the highest HDL-C tertile (71-101 mg/dL) had a modestly lower PBR (thicker glycocalyx) than those with lower HDL-C. However, in multivariable analysis only BMI, not HDL-C, independently predicted PBR.
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Published paper
Early detection of left ventricular dysfunction in first-degree relatives of diabetic patients by myocardial deformation imaging: The role of endothelial glycocalyx damage
Researchers compared 40 first-degree relatives of people with type 2 diabetes (normal glucose tolerance), 40 people with abnormal glucose tolerance, and 20 normoglycemic controls without a family history, measuring sublingual glycocalyx thickness (perfused boundary region) and left ventricular deformation by speckle-tracking echocardiography before and 120 minutes after an oral glucose load. Both relatives and dysglycemic subjects had thinner glycocalyx (higher PBR), lower insulin sensitivity, and impaired longitudinal strain and twisting compared with controls. Greater glycocalyx damage tracked with worse myocardial deformation both at baseline and after glucose loading.
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Published paper
Improvement of arterial stiffness and myocardial deformation in patients with poorly controlled diabetes mellitus type 2 after optimization of antidiabetic medication
This study compared arterial stiffness, heart muscle deformation, endothelial function, and sublingual microvascular glycocalyx thickness in 50 patients with poorly controlled type 2 diabetes versus 25 healthy controls, then reassessed the diabetic patients 6 months after their antidiabetic medication was optimized. At baseline, diabetic patients had stiffer arteries, worse left ventricular strain and diastolic indices, and a higher perfusion boundary region (indicating a thinner endothelial glycocalyx). After achieving glycemic control, carotid-femoral pulse wave velocity fell and untwisting velocity and flow-mediated dilatation improved.
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Published paper
P673 Improvement of arterial stiffness and myocardial deformation in patients with poorly controlled diabetes mellitus type 2 after optimization of antidiabetic medication
This conference abstract compared 50 adults with poorly controlled type 2 diabetes with 25 healthy controls using arterial stiffness measures, speckle-tracking echocardiography, sublingual microvascular imaging (GlycoCheck perfused boundary region), and brachial flow-mediated dilation. Diabetic patients had stiffer arteries, worse left ventricular deformation, and a higher PBR (indicating a thinner endothelial glycocalyx). After six months of optimized antidiabetic medication and achieved glycemic control, carotid-femoral pulse wave velocity fell and untwisting velocity and endothelial function improved.
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Published paper
Skeletal muscle capillary density and microvascular function are compromised with aging and type 2 diabetes
This cross-sectional comparison measured muscle capillary density (from biopsies), whole-body insulin sensitivity, and sublingual microvascular measures in 15 young men, 15 older men, and 15 older men with type 2 diabetes. Both aging and type 2 diabetes were associated with fewer capillary contacts per muscle fiber and lower insulin sensitivity. Men with type 2 diabetes also showed a thicker erythrocyte-perfused boundary region on sidestream dark-field imaging, consistent with impaired endothelial glycocalyx function.
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Published paper
Methods for evaluating endothelial function: a position statement from the European Society of Cardiology Working Group on Peripheral Circulation
This European Society of Cardiology Working Group position statement reviews the available in-vivo and ex-vivo methods for assessing endothelial function, from invasive coronary angiography with acetylcholine to flow-mediated dilatation, pulse wave analysis, peripheral arterial tonometry, laser Doppler flowmetry, biochemical markers, endothelial microparticles, progenitor cells, and glycocalyx imaging. For each technique it outlines the physiological rationale, methodology, reproducibility, and clinical applications. The authors conclude that no single method is superior and that endothelial function testing may aid risk stratification but needs further validation before routine clinical use.
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Published paper
Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus
This small open-label study compared endothelial glycocalyx thickness in the sublingual and retinal microcirculation of 10 men with type 2 diabetes and 10 healthy age-matched men, then measured both groups again after 8 weeks of oral sulodexide (200 mg/day), a glycosaminoglycan mixture of heparan and dermatan sulfate. Men with diabetes had thinner glycocalyx in both vascular beds, higher albumin leakage from capillaries, and higher markers of hyaluronan breakdown. After sulodexide, glycocalyx dimensions increased in the diabetes group, with a non-significant trend toward normalized albumin leakage.
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