How type 2 diabetes physically alters the heart and drives failure

A new human heart study shows type 2 diabetes does not just raise cardiac risk but physically alters heart muscle, energy use and structure, helping explain why heart failure is so common in diabetes

Researchers from the University of Sydney have found that type 2 diabetes physically changes the human heart, disrupting how heart cells generate energy, weakening their ability to contract, and accelerating the build-up of stiff, fibrous tissue.

 

The study, titled Left ventricular myocardial molecular profile of human diabetic ischaemic cardiomyopathy, published in the journal EMBO Molecular Medicine, analysed donated human hearts and observed that when diabetes and ischaemic heart disease, when there is a lack of blood flow and oxygen, coexist, the damage is deeper, more complex, and more severe.

What did the researchers study?

Instead of relying on animal models or indirect markers, the researchers examined actual human heart tissue taken from people undergoing heart transplants in Sydney. They compared four groups:

• people with ischaemic cardiomyopathy and diabetes,
• those with ischaemic cardiomyopathy without diabetes,
• people with non-ischaemic cardiomyopathy, and
• healthy donor hearts.

Using advanced “multi-omics” tools such as proteomics, metabolomics, lipidomics and RNA sequencing, the team mapped thousands of molecular changes inside the left ventricle, the heart’s main pumping chamber.

How does diabetes disrupt the heart’s energy supply?

A healthy heart is an energy guzzler that burns fats, glucose and ketones continuously to keep beating. The study found that in diabetic hearts, this system begins to unravel.

 

Key proteins involved in fatty acid transport and oxidation were significantly reduced. At the same time, mitochondria, the cell’s energy factories, showed signs of stress and impaired function. This means heart cells struggle to produce the molecule that powers contraction.

 

Diabetes also blunted insulin-sensitive glucose transport in heart cells, making it harder for the heart to switch fuel sources when under stress. The result is an energy-starved muscle trying to do the hardest job in the body.

What happens to the heart muscle itself?

The researchers also saw structural damage at the microscopic level. They found that the proteins responsible for contraction and calcium handling, which is essential for the heart’s squeeze-and-relax cycle, were reduced in diabetic ischaemic hearts. This weakens pumping efficiency and slows relaxation between beats.

 

At the same time, there was a marked increase in fibrosis, the build-up of collagen and other stiff connective tissue. Fibrosis makes the heart less flexible, more rigid, and harder to fill with blood, which is an early step towards heart failure with preserved or reduced ejection fraction.

 

Moreover, once heart muscle is replaced with fibrous material, it cannot contract.

 

The study showed that diabetes amplifies fibrosis-related pathways, accelerating this stiffening process. This helps explain why people with diabetes often develop heart failure even when blockages in the arteries seem modest.

 

People with type 2 diabetes are already known to have a much higher risk of heart failure, but the reasons have often been unclear. This study provides an explanation. It shows that diabetes:

• drains the heart’s energy systems,
• weakens its contractile machinery, and
• accelerates fibrotic stiffening.

In effect, diabetes prepares the heart for failure by changing its internal architecture. 

 

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