miR ‐27a‐3p Upregulation and Netrin‐1 Deficiency Drive Inflammatory Responses and Nerve Degeneration in Patients With Diabetes

Background Inflammation is increasingly recognized in the pathogenesis of diabetic neuropathy (DN). Circulating miR‐27a‐3p levels are closely related to inflammation and increased in patients with diabetic nephropathy and retinopathy. miR‐27a‐3p has a predicted binding site in the 3 UTR of Netrin‐1 mRNA, an anti‐inflammatory nerve growth factor whose levels correlate with small nerve fiber loss in patients with DN. Methods Eighty‐two participants with (DN+) and without (DN‐) small nerve fiber damage and 45 healthy controls underwent measurement of plasma miR‐27a‐3p, PBMC levels of NF‐kB and NLRP3, serum Netrin‐1, TNFα, IL‐1β, and IL‐10 levels. Results Corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) were significantly lower in the DN‐ and DN+ groups compared to controls ( p < 0.001). Plasma miR‐27a‐3p and PBMC NF‐kB and NLRP3 expression were significantly higher in the DN+ group, and miR‐27a‐3p identified DN+ with an area under the curve (AUC) of 89%. Serum Netrin‐1 and IL‐10 levels were lower, while TNFα and IL‐1β levels were higher in the DN+ group. miR‐27a‐3p levels correlated negatively with CNFL and Netrin‐1 and positively with NF‐kB and NLRP3. Conclusion miR‐27a‐3p levels are elevated in subjects with DN and correlate with markers of inflammation, Netrin‐1, and corneal nerve loss. miR‐27a‐3p could be a biomarker for DN, and miR‐27a‐3p/Netrin‐1 crosstalk may be a promising therapeutic target for DN.