The Role of Circulating Secreted Frizzled-Related Protein 4 (SFRP4) in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis

Secreted frizzled-related protein 4 (SFRP4), an extracellular regulator of Wnt signaling, has been implicated in insulin resistance, β-cell dysfunction, and inflammation associated with type 2 diabetes mellitus (T2DM). This systematic review and meta-analysis evaluated the association between circulating SFRP4 levels and T2DM. A systematic literature search was conducted across multiple databases following PRISMA guidelines. Observational studies evaluating circulating SFRP4 levels in adults with T2DM and healthy controls were included. Methodological quality was assessed using the Newcastle-Ottawa Scale and Joanna Briggs Institute checklist. Meta-analysis was performed using a random-effects model, with heterogeneity, subgroup, sensitivity, publication bias, and univariate meta-regression analyses conducted using R software. Twelve studies were included in the systematic review, while nine studies comprising 631 individuals with T2DM and 467 controls were included in the meta-analysis. Circulating SFRP4 levels were significantly higher in T2DM than in controls (SMD = 1.70, 95% CI: 0.47-2.94; p = 0.0131), with substantial heterogeneity (I2 = 96.7%). Sensitivity analyses supported the robustness of the findings. Elevated circulating SFRP4 levels are associated with T2DM and may represent a promising researchbiomarker. However, substantial heterogeneity limits precision, and prospective studies are needed to determine its predictive value beyond established glycemic biomarkers.