en Endocrine Physiology/Pharmacology Endocrine Physiology/Pharmacology Clinical research article Clinical research article <p><span style="font-size:12px;"><span style="font-family:Arial;"><span style="line-height:150%"><span style="line-height:150%"><span new="" roman="" times="">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.</span></span></span><br /> <span style="line-height:150%"><span style="line-height:150%"><span new="" roman="" times="">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.</span></span></span><br /> <span style="line-height:150%"><span style="line-height:150%"><span new="" roman="" times="">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-na&iuml;ve patients (n=42), GDF-15 yielded an AUC of 0.895 (95% CI 0.840&ndash;0.950) at a cutoff of 695 pg/mL. Metformin-treated patients had 28% higher GDF-15 than treatment-na&iuml;ve patients (p<0.001). Metformin use was the strongest independent correlate of GDF-15 (&beta;=0.412, p<0.001), exceeding HOMA-IR (&beta;=0.298) and eGFR (&beta;=&minus;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).</span></span></span><br /> <span style="line-height:150%"><span style="line-height:150%"><span new="" roman="" times="">Conclusions: GDF-15 discriminates T2DM with high accuracy, but metformin use &mdash; not glycaemia &mdash; 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.</span></span></span></span></span></p> GDF-15,type 2 diabetes mellitus,metformin,diagnostic biomarker,biomarker confounding 0 0 http://ppj.phypha.ir/browse.php?a_code=A-10-2728-1&slc_lang=en&sid=1 Athir Kadhim athir.kadhim@mtu.edu.iq Yes College of Health and Medical Techniques/Baghdad, Middle Technical University, Baghdad, Iraq