Modelling diabetes-associated metabolic stress in human multicellular cardiac microtissues

Type 2 diabetes is a global health crisis, closely associated with an increased risk of heart failure due to the development of diabetic cardiomyopathy. Progress in understanding the underlying mechanisms and identifying effective treatments has been limited by the lack of robust preclinical models that accurately mimic human cardiac physiology. Human induced pluripotent stem cells (iPSCs) offer the unique ability to generate large quantities of both cardiomyocytes and non-myocytes, enabling the development of advanced models for cardiovascular research. In this study, we present engineered 3D multicellular cardiac microtissues, comprising human iPSC-derived cardiomyocytes, endothelial cells, autonomic neurons, and cardiac fibroblasts, designed to provide a more physiologically relevant platform for investigating the effects of diabetogenic conditions on human heart tissue. Under diabetogenic conditions, these multicellular cardiac microtissues exhibited reduced viability, fibrotic marker expression, and prolonged systolic and diastolic phases, closely mirroring the contractile dysfunction observed in late-stage diabetic cardiomyopathy, outcomes not replicated in traditional 2D culture of cardiomyocytes or cardiomyocyte-only microtissues. Metformin treatment prevented the manifestation of diastolic dysfunction induced by diabetogenic conditions, demonstrating the utility of multicellular cardiac microtissues for drug assessment. Our findings emphasize the critical role of non-myocytes in the progression of cardiac dysfunction induced by hyperglycaemia and hyperlipidaemia, underscoring their importance in disease modelling. These iPSC-derived multicellular cardiac microtissues represent a significant advancement in preclinical models for diabetic cardiomyopathy, providing a more accurate platform for mechanistic studies and drug discovery.