The researchers examined heart tissue from transplant recipients and healthy donors.
The study discovered that diabetes is not just a co-morbidity for heart disease – it actively worsens heart failure by disrupting key biological processes and reshapes the heart muscle at a microscopic level.
“The metabolic effect of diabetes in the heart is not fully understood in humans,” said Dr Hunter.
“Under healthy conditions, the heart primarily uses fats but also glucose and ketones as fuel for energy. It has previously been described that glucose uptake is increased in heart failure, however, diabetes reduces the insulin sensitivity of glucose transporters – proteins that move glucose in and out of cells – in heart muscle cells.
“We observed that diabetes worsens the molecular characteristics of heart failure in patients with advanced heart disease and increases the stress on mitochondria – the powerhouse of the cell which produces energy.”
The researchers also observed reduced production of structural proteins critical for heart muscle contraction and calcium handling in people with diabetes and ischaemic heart disease, along with a build-up of tough, fibrous heart tissue that further affects the heart’s ability to pump blood.
“RNA sequencing confirmed that many of these protein changes were also reflected at the gene transcription level, particularly in pathways related to energy metabolism and tissue structure, which reinforces our other observations,” said Dr Hunter.
“And once we had these clues at the molecular level, we were able to confirm these structural changes using confocal microscopy.”
Associate Professor Lal said the discovery of mitochondrial dysfunction and fibrotic pathways could help guide future therapies.
“Now that we’ve linked diabetes and heart disease at the molecular level and observed how it changes energy production in the heart while also changing its structure, we can begin to explore new treatment avenues,” said Associate Professor Lal.
“Our findings could also be used to inform diagnosis criteria and disease management strategies across cardiology and endocrinology, improving care for millions of patients.”
Reference: Hunter B, Zhang Y, Harney D, et al. Left ventricular myocardial molecular profile of human diabetic ischaemic cardiomyopathy. EMBO Mol Med. 2025:1-42. doi: 10.1038/s44321-025-00281-9
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