SUN-704 Exploring the Role of Fibroblast Growth Factor-21 as a Predictor of Insulin Resistance and Metabolic Syndrome

Abstract Disclosure: A. Mathew: None. D. Almansour: None. B. Seyoum: None. Introduction: Fibroblast growth factor-21 (FGF 21) is a hormone secreted by hepatic cells and adipose tissue. It binds to a subset of specific receptors and klotho receptors causing metabolic rearrangement mostly related to glucose and lipid metabolism. Its levels increase in obese and in patients with diabetes. We examined the correlation of FGF 21 serum levels with metabolic parameters. In this study, we are reporting that FGF 21 is a potential marker for metabolic syndrome and insulin resistance. Methodology: We determined plasma FGF 21 levels in healthy volunteers who underwent a hyperinsulinemic-euglycemic clamp study. FGF 21 was determined using ELISA test before and after the clamp study. A total of 60 participants were analyzed using R-commander. The M-value, which is calculated based on the hyperinsulinemic-euglycemic clamp study, is the gold standard to determine insulin sensitivity. Higher M-values are associated with higher insulin sensitivity and vice-versa. Results: FGF-21 values before and after clamp values have a statistically significant negative correlation with M-value; suggesting that higher FGF values are associated with lower M-values and thus associated with insulin resistance (p-value <0.05). The negative correlation was replicated in lean individuals (BMI<30) (correlation coeff -0.33, p-value 0.02). Insulin-resistant participants exhibited nearly double the mean FGF-21 levels before and after the clamp compared to insulin-sensitive individuals (p = 0.04 and p = 0.01, respectively). Participants meeting metabolic syndrome criteria had significantly higher FGF-21 levels than those without metabolic syndrome (p = 0.001 before clamp, p = 0.01 after clamp). Discussion: FGF-21 has been implicated in glucose and lipid metabolism, with therapeutic potential for obesity and diabetes management. Despite its insulin-sensitizing effects, paradoxically elevated FGF-21 levels in insulin-resistant states suggest FGF-21 resistance, which could likely be due to downregulation of the β-Klotho co-receptor or proteolytic cleavage. Our study reinforces previous findings that FGF-21 is elevated in obesity and metabolic syndrome, with significant associations with markers of adiposity and triglycerides. Increased FGF-21 expression in adipose tissue may represent a compensatory response to metabolic stress. Conclusion: Our findings suggest that FGF-21 is a promising biomarker for insulin resistance and metabolic syndrome. Elevated FGF-21 levels, particularly in lean individuals with insulin resistance, highlight its potential for early detection before conventional glucose markers become abnormal. Future research should explore the mechanistic pathways of FGF-21 resistance and its therapeutic applications in metabolic disorders. Presentation: Sunday, July 13, 2025