Signaling complexity in diabetic neuropathy: a multitargeted perspective on pathogenesis and therapy.
Level 5 - mechanism / opinion, no new human data
Narrative review synthesizing molecular mechanisms and therapeutic targets without primary human data or systematic review methodology.
PubMed 41422384 · doi:10.1080/10799893.2025.2603983
What was done
This narrative review synthesized the molecular signaling pathways contributing to diabetic neuropathy pathogenesis and evaluated recent therapeutic strategies targeting these mechanisms, based on existing literature from metabolic, inflammatory, mitochondrial, and insulin signaling domains.
What was found
The abstract reports no numerical data. It describes the interplay among multiple metabolic pathways (polyol, advanced glycation end-products, protein kinase C, hexosamine), inflammatory cascades (NF-κB, MAPK, NLRP3 inflammasome, cytokine/chemokine signaling), mitochondrial/oxidative stress axes (AMPK/SIRT/PGC-1α and Nrf2 impairment), and disrupted insulin signaling (Akt and RAC1 pathways). It notes that while targeted agents (such as aldose reductase inhibitors, RAGE antagonists, PKC inhibitors, AMPK activators, and Nrf2 inducers) show preclinical promise, their clinical translation remains limited.
Why it matters
It highlights that single-target approaches frequently fail in clinical trials because diabetic neuropathy involves a complex, self-propagating network of multiple signaling pathways, supporting the development of multi-targeted therapies.
Limits
The abstract provides no quantitative effect sizes, systematic search methodology, risk of bias assessment, or human clinical trial data, reflecting primarily conceptual and preclinical mechanistic literature.
Cited by
- supports Activation of the polyol pathway by glucose, along with elevated sodium and hypoxia, contributes to acquired mitochondrial dysfunction.