Investigating the Role of GDF-15 in Diabetes and Obesity: A Comprehensive Analysis of a Cohort from the KDEP Study

<b>Background:</b> Growth differentiation factor 15 (GDF-15), a member of the transforming growth factor-β (TGF-β) superfamily, is upregulated under cellular stress conditions and has emerged as a potential biomarker for metabolic disorders. However, its expression in relation to diabetes and obesity across different demographic groups remains understudied. This study investigated the association between plasma GDF-15 levels, diabetes mellitus, and obesity in individuals of varying ages, ethnicities, and genders. <b>Methods:</b> In a cross-sectional study, plasma GDF-15 concentrations were measured in 2083 participants enrolled in the Kuwait Diabetes Epidemiology Program (KDEP). The dataset included anthropometric, clinical, biochemical, and glycemic markers. Multivariate regression analysis was used to examine associations between GDF-15 levels and metabolic phenotypes. <b>Results:</b> Mean plasma GDF-15 levels were significantly higher in males than females (580.6 vs. 519.3 ng/L, <i>p</i> < 0.001), and in participants >50 years compared to those <50 years (781.4 vs. 563.4 ng/L, <i>p</i> < 0.001). Arab participants had higher GDF-15 levels than South and Southeast Asians (597.0 vs. 514.9 and 509.9 ng/L, respectively; <i>p</i> < 0.001). Positive correlations were found with BMI, waist and hip circumferences, blood pressure, insulin, and triglycerides; negative correlations were observed with HDL cholesterol. Median regression indicated that elevated GDF-15 levels were independently and significantly associated with male gender, older age, obesity, diabetes, and insulin resistance. Adjusted median regression indicated that male gender (β = 30.1, 95%CI: 11.7, 48.5), older age (β = 9.4, 95%CI: 8.0, 10.7), and insulin resistance (β = 7.73, 95%CI: 1.47, 14.0) indicated a significant positive association with GDF-15. South Asian participants (β= -41.7, 95%CI: -67.2, -16.2) had significantly but Southeast Asian participants (β= -23.3, 95%CI: -49.2, 2.56) had marginally significantly lower GDF-15 levels compared to participants of Arab ethnicity. <b>Conclusions:</b> Higher GDF-15 levels are associated with age, male gender, Arab ethnicity, obesity, and diabetic traits. These findings support the potential role of GDF-15 as a biomarker for metabolic disorders, particularly in high-risk demographic subgroups.