3058-LB: Semaglutide-Induced Modulation of Multiomic Profiles and Oral Minimal Model-Derived Metrics in Mexican-Americans with Prediabetes: A Preliminary Analysis

Introduction and Objective: Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, have revolutionized obesity, diabetes, and CV disease management. Although major clinical trials (STEP1, STEP2) have linked fasting circulating proteomic signatures to semaglutide’s benefits, specific molecular pathways underlying responses remain unknown. Here, we link circulating multi-omic profiles and oral minimal model (OMM)-derived indices to semaglutide therapy in a community-based Mexican-American cohort. Methods: In this prospective longitudinal study, we analyzed circulating transcriptomic and proteomic (fasting and prandial) profiles in adults with prediabetes (n=101) before and after 12 weeks of semaglutide therapy. Participants underwent serial blood sampling over 4 hours following a standardized meal to derive OMM metabolic indices. Individuals with pre-existing diabetes, recent use of antidiabetic or glucotoxic agents, severe organ dysfunction, or pregnancy were excluded. Results: Transcriptomic analysis revealed 71 significant differentially expressed genes (pFDR< 0.05), primarily enriched in pathways governing lipid metabolism and transport, immunoinflammatory responses, and cell structure/signaling. Proteomic profiling identified 13 fasting-state and 4 prandial-state significant proteins (pFDR < 0.05), which mapped to pancreatic function, digestive enzyme regulation, and immunoinflammatory modulation. Regarding OMM data, significant increases (p < 0.05) were seen in insulin sensitivity (Si) and total disposition index (DItotal), with nonsignificant increases in dynamic and static insulin release (φd, φs). Conclusion: Semaglutide significantly alters metabolic and molecular signatures in Mexican-Americans with prediabetes. Further integration of these multi-omic profiles with OMM data will elucidate the pathways driving personalized therapeutic outcomes in this high-risk population. Disclosure A.D. Gutierrez: None. R. Roshani: None. H.M. Highland: None. D. Bian: None. E. Frankel: None. J.E. Below: None. Funding National Institutes of Health (R01DK127084)