<scp>miR</scp> ‐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.