Retatrutide, a novel triple-GIP/GLP-1/glucagon receptor agonist, has emerged as a promising therapeutic agent for type 2 diabetes mellitus (T2DM). This in silico study investigated the molecular mechanisms underlying Retatrutide's effects on insulin resistance pathways through comprehensive bioinformatics analysis. Using molecular docking simulations and protein–ligand interaction studies, we examined Retatrutide's binding affinities to GIP, GLP-1, and glucagon receptors, revealing high-affinity interactions with all three target receptors, demonstrating particularly strong binding to the GLP-1 receptor's extracellular domain.
Our pathway enrichment analysis revealed significant modulation of key insulin signaling cascades, particularly the PI3K/AKT and MAPK pathways. A network analysis identified 47 differentially expressed genes in insulin-responsive tissues, with notable upregulation of glucose transporter GLUT4 and insulin receptor substrate proteins. The analysis also revealed significant changes in genes that are involved in mitochondrial function and lipid metabolism, suggesting broader metabolic effects beyond glucose homeostasis.
Protein–protein interaction networks, constructed using the STRING database, highlighted the central role of AKT2 and AMPK as downstream effectors of Retatrutide's triple-receptor activation. Our gene ontology analysis demonstrated enrichment in biological processes related to glucose homeostasis, insulin sensitivity, and energy metabolism, with particular emphasis on pathways that are involved in β-cell preservation and adipose tissue remodeling.
Molecular dynamics simulations over 100ns revealed stable binding conformations of Retatrutide with all three target receptors, suggesting sustained activation of complementary metabolic pathways. The simulations also identified the key residues that are involved in receptor activation and signal transduction. The systems biology analysis indicated synergistic effects of triple-receptor agonism, leading to enhanced insulin sensitivity through multiple mechanisms, including improved β-cell function, reduced glucagon secretion, and enhanced glucose uptake in peripheral tissues.
These findings provide novel insights into Retatrutide's molecular mechanism of action and support its therapeutic potential in T2DM treatment through comprehensive modulation of insulin resistance pathways. Further experimental validation is warranted to confirm these in silico predictions.
