Proteomic profiling of patient-derived blood vessel organoids (BVOs) exposed to diabetic media revealed robust upregulation of IGFBP7 — insulin-like growth factor binding protein 7 — which replicated microvascular pathology seen in clinical diabetic specimens. UK Biobank association analyses confirmed IGFBP7's link to microangiopathy, while downstream effectors LGALS1 and LGALS3 (galectin-1 and galectin-3) showed strong associations with diabetic nephropathy and retinopathy. The All of Us cohort independently validated genetic variants in this diabetic microangiopathy signature, connecting them to diabetes diagnosis and cardiometabolic outcomes.
Diabetic microangiopathy — capillary basement membrane thickening, pericyte loss, endothelial dysfunction — remains effectively untreatable despite affecting hundreds of millions globally. This work is notable for triangulating three independent evidence streams: an organoid disease model, a population biobank, and a genetic cohort. Galectin-3 has already attracted drug development interest in fibrosis and heart failure, making the LGALS3 finding particularly actionable. However, several cautions apply: organoids, while human-derived, cannot fully recapitulate in vivo hemodynamic and metabolic complexity; biobank associations are observational and cannot confirm causality without intervention data; and cohort ancestry diversity remains unclear. Most critically, this is a preprint posted on medRxiv and has not yet undergone peer review — findings, statistical interpretations, and conclusions remain subject to revision. If validated, targeting the IGFBP7–galectin axis could represent a genuinely novel therapeutic entry point for one of diabetes's most burdensome complications.
