byNature Publishing Group

A hypothetical mechanism of the glycophagy role in physiology and pathology involvement in diabetic heart disease. Credit:Nature Cardiovascular Research(2025). DOI: 10.1038/s44161-025-00726-x

Scientists have reversed diabetic heart failure with a genetic therapy in mice and miniature human "hearts" grown from stem cells. The new gene therapy may be a promising treatment for diabetic heart disease, in which the heart can't relax properly between beats.

A team of NZ, Australian, and international researchers found that diabetic hearts don't have enough of a protein they need to break down an energy source called glycogen into sugar. When the researchers used a modified virus to put this protein into the hearts ofdiabetic miceand into the mini human diabetic "hearts," they started beating properly again.

While more work is needed, the researchers hope their findings may eventually help to treat the hearts of patients withdiabetesdirectly, rather than just managing the symptoms. The work ispublishedin the journalNature Cardiovascular Research.

"Diabetes often leads to problems with the heart's ability to relax properly between beats, known as diastolic dysfunction," says co-lead researcher Associate Professor Kim Mellor, head of Cellular and Molecular Cardiology at Waipapa Taumata Rau, University of Auckland.

Together with Professor Lea Delbridge, head of the Cardiac Phenomics Laboratory at the University of Melbourne, Mellor has discovered a process, called "glycophagy," used by cells to break down excess glycogen inheart cells. In diabetes, this process becomes disrupted, leading todiastolic dysfunction, where the heart becomes stiff and struggles to relax and fill properly.

"Before now, it has not been understood how the heart can store and mobilize sugar to create energy," says Mellor. "The heart needs a lot of energy to pump and we have shown this isn't working well in the diabetic heart. If we can understand that process, we can treat it."

The group, which included a large network of international researchers, also found that a protein called GABARAPL1 is key to glycophagy and is deficient in diabetic heart disease.

In diabetic mice, the group successfully trialed using a virus to deliver genes to the heart to boost thiskey protein, GABARAPL1, and restore the breakdown of glycogen in the heart. The treatment reduced glycogen buildup and improved heart function, without affecting blood sugar levels or body weight.

"We've shown that fixing this energy recycling system in heart cells can reverse the damage caused by diabetes," says Mellor. "It's a completely new way of thinking about how to treat diabetic heart disease."

Thegenetic therapyalso worked in miniature human hearts grown from humanstem cells, improving their ability to relax after each beat, a key sign of healthy heart function.

"This discovery could lead to a new class of treatments that target the heart directly, rather than just managing diabetes symptoms," says Delbridge.

"It is significant to find an intervention that can benefit the heart's relaxation," says Mellor. "That's the way the heart fills with blood and there aren't many medicines that can improve how the heart fills, rather than how it contracts."

The researchers plan to explore clinical applications and investigate how sex differences may influence treatment response. Early findings suggest the therapy may be especially effective in female hearts, which show stronger glycophagy responses.

More information: K. M. Mellor et al, Targeted glycophagy ATG8 therapy reverses diabetic heart disease in mice and in human engineered cardiac tissues, Nature Cardiovascular Research (2025). DOI: 10.1038/s44161-025-00726-x Journal information: Nature Cardiovascular Research

Provided by Nature Publishing Group