797-P: Multiomic Comparison of GLP1R Analogues Interaction Networks

GLP1R agonists are drugs increasingly used in clinical practice in patients with type 2 diabetes, and obesity. Subsequent clinical trials indicate their beneficial effects, including cardioprotection, but the exact mechanisms of those actions are still not known. We performed integrative analysis of four GLP1R interaction networks and associated metabolomic and lipidomic datastes. Interactomics revealed 130 common genes among semaglutide, exenatide, tirzapeptide, and retatrutide, primarily associated with diabetes-related processes, including obesity and hyperglycemia. Noteworthy findings encompassed ontological terms related to cardiovascular diseases (CVDs), such as hypertension, calcium regulation in cardiac cells, and amino acid accumulation-induced mTOR activation. Additionally, enrichment in gene sets linked to longevity, less recognized terms like fatty liver disease, chemokine signaling, and sirtuin interactome, were observed.Specific processes for tirzapeptide included behavior-related terms and hydrochloric acid secretion, while retatrutide exhibited associations with fibrosarcoma, thinking and speaking disturbances, and adipogenesis signaling. Shared processes like primary ciliary dyskinesia differed in implicated genes. Metabolomics identified shared metabolites associated with diverse pathways, including galactose metabolism and nitric oxide-related pathways. Lipidomics highlighted enriched phenotypes and pathways, such as arachidonic acid metabolism and cholesterol biosynthesis. Integration of interaction networks with metabolomic and lipidomic data revealed top interactors and impacted metabolites, shedding light on the intricate molecular landscape of GLP1R. These findings contribute valuable insights into the potential therapeutic implications and broader health considerations of GLP1R agonists.