Distinct Roles of Mitochondrial DNA Copy Number, Fibroblast Growth Factor 21, and Growth Differentiation Factor 15 in Glycemic Control, Obesity, and Muscle Health in Type 2 Diabetes Mellitus

Background: Mitochondrial dysfunction and metabolic stress play critical roles in type 2 diabetes mellitus (T2DM). This cross-sectional study examines the associations of mitochondrial DNA copy number (mtDNA-CN), fibroblast growth factor 21 (FGF21), and growth differentiation factor 15 (GDF15) with metabolic parameters, body composition, and physical performance in T2DM patients. Methods: A total of 181 T2DM patients (mean age: 53.0 years; 98 males, 82 females) were included in the study. Metabolic markers (HbA1c, lipid profile), body composition indices (skeletal muscle index [SMI], body fat percentage [PBF], and physical performance measures (handgrip strength, gait speed) were assessed. Serum mtDNA-CN, FGF21, and GDF15 levels were quantified, and their associations with clinical parameters were analyzed using correlation, regression, and receiver operating characteristic analyses. Results: Higher mtDNA-CN was associated with better glycemic control, lower triglycerides (TAG), and higher SMI ( P < 0.001). Serum FGF21 correlated positively with PBF ( P < 0.001) and TAG ( P < 0.001), showing moderate predictive value for obesity. GDF15 was positively associated with BMI and PBF but had limited discriminatory power for glycemic control (area under the curve = 0.614). Both mtDNA-CN and GDF15 correlated with SMI, suggesting potential roles in muscle health. Conclusion: mtDNA-CN, FGF21, and GDF15 are linked to distinct aspects of metabolic and physical health in T2DM. mtDNA-CN reflects glycemic control and muscle health, FGF21 indicates metabolic disturbances in obesity, and GDF15 is associated with aging-related metabolic dysfunction. These biomarkers provide valuable insights into the interplay between mitochondrial function, metabolic health, and physical performance in T2DM.