A new study published in Cardiovascular Diabetology by researchers from the Li Group and collaborators sheds light on the precise subcellular mechanisms driving diabetic cardiomyopathy (DCM), offering hope for early therapeutic intervention. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in both 2D cultures and 3D bio-printed cardiac microtissues, the team identified a compartment-specific breakdown of cyclic adenosine monophosphate (cAMP) signalling.
The researchers discovered that while cytosolic cAMP pools suffer a blunted response to stress, mitochondrial pools exhibit both pathologically low resting cAMP levels and impaired stress responsiveness. This dual-compartment defect is driven by the downregulation of the cAMP-producing enzyme ADCY2 alongside the upregulation of the scaffold protein PDE4DIP, which accelerates local cAMP breakdown around mitochondria. High-speed optical mapping in 3D microtissues confirmed these signalling disruptions cause severe calcium handling and conduction defects mirroring those seen in clinical diabetic heart disease.
Treating the diabetic models with Fibroblast Growth Factor 1 (FGF1) successfully normalised PDE4DIP expression, restored cytosolic and mitochondrial cAMP signalling, and improved calcium transient amplitude in 3D microtissues. Targeting these exact subcellular microdomains with early FGF1 intervention could be key to preventing heart failure progression before irreversible structural tissue damage sets in.
The research was led by Associate Professor Dan Li, with Dr Kun Liu and DPhil student Kazuki Osuka contributing equally to the work, alongside collaborators in the UK, China, Taiwan and Sweden.
The full paper 'Compartment-specific cAMP dysfunction in diabetic cardiomyopathy in hiPSC-derived cardiomyocytes: therapeutic potential of fibroblast growth factor 1', is published in Cardiovascular Diabetology (DOI: 10.1186/s12933-026-03288-9).