Rethinking diabetic retinopathy: Homeostatic mechanisms for retinal clearance

Diabetic retinopathy (DR) is a sight-threatening consequence of diabetes. DR disrupts cell-to-cell communication in the retinal neurovascular unit (NVU), impairing blood flow which leads to vascular complications. Here, we propose an integrated framework of DR pathogenesis in which impaired clearance mechanisms and accumulation of extracellular metabolic waste act in concert to drive NVU dysfunction. By integrating evidence across cellular and molecular domains, we aim to highlight how these early events set the stage for later complications, including diabetic macular oedema.

We have examined and summarised the literature, synthesising evidence and providing a narrative review of the impact of diabetes on retinal clearance homeostasis. PubMed database was used to search for terms including diabetic retinopathy, neurovascular unit, clearance and extracellular waste.

Diabetes disrupts blood-retinal barrier integrity, alters retinal waste production and fluid homeostasis, and promotes the accumulation of misfolded and glycated proteins. However, these processes, despite being interdependent, have largely been considered in isolation. This review integrates the available evidence to identify impaired retinal clearance as a convergent mechanistic link between barrier dysfunction, altered fluid dynamics and extracellular waste accumulation in DR. It also highlights how the specific clearance pathways may contribute to disease progression and represent potential therapeutic targets.

Failure of tissue homeostasis may represent a critical but underappreciated driver of progressive retinal NVU dysfunction during DR. In this context, extracellular waste accumulation is not merely a downstream consequence of retinopathic progression, but a potential initiating factor that links metabolic dysregulation to the breakdown of the blood-retinal barrier and disrupts retinal architecture.