Serum FGF21 and GDF15 as Indicators of Mitochondrial Stress and Their Association with Insulin Resistance and Oxidative Stress a Comparative Study in Adults Diagnosed with Metabolic Syndrome

Abstract

Background: Metabolic syndrome is characterized by central adiposity, dyslipidemia, elevated blood pressure, and impaired glucose regulation, and is strongly linked to insulin resistance, oxidative stress, and mitochondrial perturbation. Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are stress-responsive endocrine proteins increasingly recognized as markers of metabolic and mitochondrial stress. Objective: This study evaluated circulating FGF21 and GDF15 in adults with metabolic syndrome and examined their relationships with insulin resistance and oxidative stress. Methods: A comparative cross-sectional design included 120 adults, comprising 60 participants with metabolic syndrome and 60 metabolically healthy controls. Fasting glucose, insulin, lipid profile, FGF21, GDF15, malondialdehyde (MDA), superoxide dismutase (SOD), and total antioxidant capacity (TAC) were assessed. HOMA-IR was calculated from fasting glucose and insulin. Between-group comparisons, Spearman correlation, multiple linear regression, and receiver operating characteristic analysis were performed. Results: Participants with metabolic syndrome had higher BMI, waist circumference, fasting glucose, insulin, HOMA-IR, triglycerides, MDA, FGF21, and GDF15, whereas HDL-C, SOD, and TAC were lower (all major metabolic comparisons p<0.001). Mean FGF21 was 237.8±63.3 pg/mL in metabolic syndrome versus 127.5±65.3 pg/mL in controls, and GDF15 was 685.2±125.0 versus 495.1±125.2 pg/mL. FGF21 correlated with HOMA-IR (ρ=0.866) and MDA (ρ=0.834), while GDF15 correlated with HOMA-IR (ρ=0.851) and MDA (ρ=0.811), all p<0.001. In multivariable analysis, MDA, BMI, and GDF15 remained independently associated with HOMA-IR. The AUCs for discriminating metabolic syndrome were 0.883 for FGF21 and 0.856 for GDF15. Conclusion: Elevated FGF21 and GDF15 were strongly associated with insulin resistance and an unfavorable oxidative-stress profile, supporting their potential value as integrated biochemical indicators of metabolic stress.