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The study, published in Nature Cardiovascular Research, was led by Professor Dunja Aksentijevic and her team at Queen Mary University of London, in collaboration with Dr Stephanie Anderson, Dr Andrew Lewis and Professor Damian Tyler at the Radcliffe Department of Medicine (RDM), University of Oxford.
The research focuses on diabetic cardiomyopathy - a condition in which the heart becomes stiff and metabolically inefficient in people with type 2 diabetes, even in the absence of blocked arteries.
The condition increases the risk of heart failure, yet there are currently no therapies that directly target the underlying metabolic and inflammatory changes in the heart.
Looking beyond blood sugar
The drug studied, AZD1656, was originally designed to activate an enzyme called glucokinase to improve glucose control. However, earlier clinical trials showed that its effects on blood sugar were short-lived.
Subsequent research suggested the drug may also influence the immune system, particularly a type of immune cell known as regulatory T cells (Tregs), which help control inflammation. The researchers therefore investigated whether the drug could benefit the heart in diabetes by altering immune activity and metabolism, rather than by lowering glucose.
Improved heart relaxation and resistance to injury
Using a well-established mouse model of type 2 diabetes, the team found that untreated diabetic animals developed features resembling early diabetic heart disease. Their hearts showed impaired relaxation (a hallmark of diabetic cardiomyopathy), signs of inflammation and abnormal energy use.
After six weeks of treatment with AZD1656, heart relaxation improved and overall cardiac performance was better compared with untreated diabetic mice. When the researchers simulated a heart attack in isolated hearts, treated animals showed smaller areas of damage and improved recovery.
Dr Stephanie Anderson, postdoctoral researcher in the Radcliffe Department of Medicine and co-author of the study, said: 'Importantly, these improvements occurred without meaningful changes in body weight, blood glucose or insulin levels, suggesting that the cardiac benefits were not simply due to better diabetes control.'
Restoring the heart's energy balance
In diabetes, the heart becomes less flexible in how it generates energy. It relies heavily on fat as fuel and becomes less efficient at using glucose. This metabolic imbalance increases oxygen demand and may contribute to long-term damage.
Detailed metabolic analyses showed that AZD1656 largely restored a more balanced pattern of energy use in diabetic hearts. The treated hearts used glucose more effectively and consumed less oxygen for the same workload, indicating improved metabolic efficiency.
The drug also partially corrected abnormalities in the composition of heart lipids, which are important for cell membrane integrity and mitochondrial function.
Reducing harmful inflammation in the heart
The researchers also examined immune cells within the heart. Untreated diabetic mice had increased infiltration of inflammatory T cells and greater fibrosis (scarring). Genes associated with inflammatory pathways were also upregulated.
Treatment shifted this balance. The number of inflammatory T cells fell, while regulatory T cells - which act to suppress excessive immune responses - increased in the heart. Fibrosis was reduced and many inflammation-related genes returned towards normal levels.
Together, these findings suggest that modifying immune cell behaviour may help restore metabolic health in the diabetic heart.
What does this mean?
This work strengthens the idea that inflammation and altered energy metabolism are closely linked in diabetic heart disease. Rather than focusing solely on blood sugar levels, the findings point to immune–metabolic pathways as a potential therapeutic target.
Further clinical studies will be needed to determine whether targeting immune cell metabolism can meaningfully improve heart outcomes in people living with diabetes.