Background: Growth differentiation factor-15 (GDF-15) is a stress-inducible cytokine elevated in type 2 diabetes mellitus (T2DM), but metformin independently raises circulating GDF-15 through distinct transcriptional pathways, complicating its interpretation as a diagnostic biomarker. No adequately powered study has previously examined GDF-15 as a T2DM diagnostic marker in an Iraqi population.
Methods: We enrolled 100 patients with newly confirmed T2DM (WHO criteria, diagnosed within six months) and 100 age- and sex-matched controls. Serum GDF-15 and peripheral blood mononuclear cell (PBMC) GDF-15 mRNA were measured by MIQE-compliant RT-qPCR, with GAPDH as reference gene. Metformin use, dose, and duration were recorded for all participants.
Results: Serum GDF-15 was markedly higher in T2DM patients than controls (median 1231 vs. 441 pg/mL; p<0.001), with 2.74-fold PBMC mRNA upregulation (p<0.001). In treatment-naïve patients (n=42), GDF-15 yielded an AUC of 0.895 (95% CI 0.840–0.950) at a cutoff of 695 pg/mL. Metformin-treated patients had 28% higher GDF-15 than treatment-naïve patients (p<0.001). Metformin use was the strongest independent correlate of GDF-15 (β=0.412, p<0.001), exceeding HOMA-IR (β=0.298) and eGFR (β=−0.187). A combined diagnostic model reached AUC 0.934, modestly exceeding HbA1c alone (AUC 0.908; p=0.034), with significant net reclassification improvement (NRI 0.14, p=0.012).
Conclusions: GDF-15 discriminates T2DM with high accuracy, but metformin use — not glycaemia — is its dominant correlate. The diagnostic gain over HbA1c is statistically real but clinically modest. Clinical use requires metformin-stratified reference intervals and cost-effectiveness validation before adoption.