The inflammatory-miRNA axis in diabetic microvascular complications: a meta-analysis highlighting synergistic effects...

To compare peripheral blood levels of TNF-α, IL-6, hsCRP/CRP, miR-126, and miR-29b in patients with diabetic retinopathy (DR), diabetic nephropathy (DN), or the concurrent occurrence of DR and DN, and to explore the evidence for a shared biomarker axis and synergistic effects in dual complications.

We systematically searched PubMed, Web of Science, Embase, the Cochrane Library, for studies reporting these biomarkers in DR, DN, or both. Study quality was assessed using the Newcastle-Ottawa Scale. Meta-analyses were performed using Review Manager, assessing heterogeneity, publication bias (Egger's test), and sensitivity. Subgroup analyses explored the influence of various factors.

Twenty-six studies were included. Inflammatory markers were significantly elevated across groups: TNF-α (DR: SMD = 1.04, 95%CI[0.56,1.51], P < 0.001; DN: SMD = 1.50, 95%CI[1.19,1.80], P < 0.001; DR + DN: SMD = 1.60, 95%CI[0.41,2.78], P = 0.008), IL-6 (DR: SMD = 0.52, 95%CI[0.06,0.98], P = 0.03; DN: SMD = 0.89, 95%CI[0.43,1.35], P = 0.0002; DR + DN: SMD = 0.53, 95%CI[0.21,0.84], P = 0.001), and hsCRP/CRP (DR: SMD = 0.50, 95%CI[0.15,0.85], P = 0.005; DN: SMD = 0.25, 95%CI[0.10,0.39], P = 0.0007; DR + DN: SMD = 0.57, 95%CI[0.08,1.05], P = 0.02). Notably, the SMD for TNF-α in the DR + DN group was higher than in DR or DN alone. Conversely, miR-126 (DR: SMD=-1.87, 95%CI[-3.56,-0.18], P = 0.03; DN: SMD=-0.36, 95%CI[-0.54,-0.18], P = 0.0001) and miR-29b (DR: SMD=-0.47, 95%CI[-0.51,-0.43], P < 0.0001) were downregulated. Subgroup analyses (by complication type [NPDR, PDR] and control groups [T1DM/T2DM without complications or healthy]) showed high heterogeneity (I²=65%-96%, P < 0.05). Sensitivity analyses confirmed result stability; Egger's test indicated no significant publication bias (P > 0.05).

The analysis reveals that the investigated inflammatory markers and microRNAs collectively constitute a dysregulated pathway in diabetic microvascular disease. Critically, the inflammatory response was markedly amplified in patients with concurrent DR and DN, indicative of a synergistic pathogenic relationship between these conditions. These findings highlight the considerable promise of leveraging a combination of these biomarkers to enhance the early detection and risk stratification of interconnected microvascular complications in diabetes.

The online version contains supplementary material available at 10.1007/s40200-025-01809-z.