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Human-centric models of DbCM are needed to provide mechanistic insights and therapeutic targets in a translationally relevant setting. We hypothesised that culturing human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in an “insulin resistance” (IR) media, and assessing this using a systems biology approach, would offer a comprehensive evaluation of dysregulated pathways, establishing their suitability as a model of DbCM. Culturing 2D hiPSC-CMs in IR media induced insulin resistance and activated pathways implicated in DbCM, including metabolic remodelling, mitochondrial dysfunction, and endoplasmic reticulum stress. Adaptation to hypoxia, a key component of post-ischaemic remodelling, was blunted in the 2D IR hiPSC-CMs, highlighting impaired cellular responses to low oxygen conditions. Proteomic and transcriptomic analyses revealed significant enrichment of DbCM-related pathways, particularly those involved in metabolic dysregulation. In conclusion, 2D hiPSC-CMs cultured in IR media recapitulate key features of DbCM, including impaired adaptation to hypoxia, providing a valuable model for studying diabetic cardiomyopathy. Overall design: RNA-seq profiling of control of insulin-resistant hiPSC-CMs in normoxia or hypoxia.ENAfalseHuman iPSC-cardiomyocyte models of insulin resistance demonstrate metabolic and contractile dysfunction that recapitulates diabetic cardiomyopathyHuman iPSC-cardiomyocyte models of insulin resistance demonstrate metabolic and contractile dysfunction that recapitulates diabetic cardiomyopathy2025-09-242025-06-19PRJNA1219113GSE288708960640357580