Glycocalyx Failure Across The Diabetic Gut-Kidney-Brain Axis: A Three-Barrier Model of Albuminuria and Cognitive Vulnerability

Abstract

Diabetes injures multiple biological interfaces, yet intestinal permeability, albuminuria and neurovascular dysfunction are usually interpreted as separate complications. This review develops a three-barrier glycocalyx framework linking the intestinal mucus-epithelial surface, the glomerular endothelial glycocalyx and the brain endothelial glycocalyx without assuming that a continuous causal pathway has already been demonstrated in humans. Across these interfaces, carbohydrate-rich surface layers regulate steric and charge exclusion, mechanotransduction, leukocyte adhesion and access of circulating or luminal molecules to the underlying cells. Hyperglycaemia, oxidative and inflammatory stress, abnormal shear and glycocalyx-degrading enzymes can perturb these functions. Human evidence is strongest for intestinal barrier abnormalities in diabetes, systemic endothelial glycocalyx loss and the association of glycocalyx shedding with albuminuria. Brain-endothelial glycocalyx data are mechanistically compelling but remain dominated by experimental and disease-adjacent studies. Albuminuria is associated with cognitive and neuroimaging outcomes, but it is not an organ-specific readout of cerebral glycocalyx injury. We therefore propose a falsifiable programme combining direct or validated measures of each barrier, circulating shedding products, renal phenotyping, blood-brain barrier imaging and domain-level cognition in longitudinal cohorts. Glycocalyx preservation is a promising pharmacological concept, but target engagement at one vascular bed cannot be presumed to restore another. The framework converts parallel observations into testable cross-barrier hypotheses while preserving the boundaries of current evidence.