Systems Biology and Functional Assessments of Human iPSC-Cardiomyocyte Models of Insulin Resistance Capture Key Hallmarks of Diabetic Cardiomyopathy

Human-centric models of diabetic cardiomyopathy (DbCM) are needed to provide mechanistic insights and translationally relevant therapeutic targets for patients with diabetes. A systems biology approach using insulin resistant (IR) two-dimensional (2D) human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) and threedimensional (3D) engineered heart tissue (EHT) provides a comprehensive evaluation of dysregulated pathways and determines suitability as a translationally relevant model of DbCM. Culturing hiPSC-CMs in 2D or 3D EHT in IR media induced insulin resistance and activated multiple pathways implicated in DbCM, including metabolic remodeling, mitochondrial dysfunction, extracellular matrix remodeling, endoplasmic reticulum stress, and blunted response to hypoxia, as assessed using transcriptomics and proteomics. Metabolic flux measurements in both IR 2D and 3D platforms demonstrated increased fatty acid oxidation and lipid storage, whereas glucose metabolism was downregulated. Modeling DbCM in 3D EHTs conferred additional metabolic and functional advantages over the 2D hiPSC-CM, demonstrating impaired contractility and muscle architecture. Metformin treatment improved both contractility and metabolic function, demonstrating the utility of IR EHT for drug assessment. In conclusion, IR 2D and 3D hiPSC-CM models effectively capture key DbCM features. However, 3D EHT provides additional insights into physiological and structural modifications. This highlights the potential of IR EHT for both mechanistic studies and drug screening in DbCM.