Redox-driven blood-nerve barrier dysfunction framework proposed for diabetic neuropathy, highlighting incretin therapies as modulators

Diabetic peripheral neuropathy (DPN) is a major cause of disability in diabetes, with current treatments primarily addressing symptoms rather than underlying neurovascular-immune pathology. This gap leaves patients vulnerable to progressive nerve damage. The blood-nerve barrier (BNB), a critical component of the peripheral nerve neurovascular unit (PNVU), is increasingly recognized as central to DPN pathogenesis. Understanding its dysfunction, particularly due to redox imbalance, offers new avenues for intervention. Incretin-based therapies, known for metabolic and anti-inflammatory effects, are being explored for their potential to stabilize the BNB.

The authors synthesized clinical, redox, vascular, and immunological evidence to develop a peripheral nerve neurovascular unit (PNVU) and blood-nerve barrier (BNB)-centered framework for DPN. They outlined diagnostic and translational endpoints, reviewed BNB anatomy and function, and discussed how chronic hyperglycemia and dyslipidemia drive redox imbalance, inflammation, and junctional disassembly. Finally, they evaluated incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4is), as potential modulators of oxidative and inflammatory stress within this framework.

The review establishes that chronic hyperglycemia and dyslipidemia are primary drivers of DPN, leading to metabolic-to-vascular coupling, redox imbalance, and antioxidant defense failure. This cascade promotes advanced glycation end products (AGEs) formation, activates the RAGE and NF-κB signaling pathways, and induces endothelial activation and leukocyte recruitment. These processes culminate in macrophage polarization and tight-junction disassembly, significantly increasing blood-nerve barrier (BNB) permeability.

Increased BNB permeability exposes peripheral nerves to pro-inflammatory and neurotoxic mediators, directly contributing to DPN pathology. The authors highlight that current diagnostic tools, while useful, do not directly assess early BNB dysfunction. They propose that incretin-based therapies, such as semaglutide and other GLP-1RAs, along with DPP-4 inhibitors and emerging multi-agonists, hold mechanistic plausibility for modulating oxidative and inflammatory stress within this redox-driven framework. However, direct evidence for incretin-mediated BNB stabilization in human DPN remains limited, underscoring a critical area for future research.