Targeting immunometabolic pathways with an investigational glucokinase activator has shown potential for transforming the treatment of diabetic cardiomyopathy beyond glycaemic control in type 2 diabetes in recent preclinical research.

Conventional diabetes treatments primarily focus on controlling blood sugar levels but do not address the root cause of underlying cardiac dysfunction prevalent in type 2 diabetes.

The investigational drug AZD1656 was initially developed to lower blood glucose, but it was later found to possess immunomodulatory effects, leading investigations into its potential role in treating cardiac complications of type 2 diabetes.

The international study, published in the journal Nature Cardiovascular Research, used obese, hyperglycaemic db/db mice – a widely accepted murine model of type 2 diabetes.

Animals were treated with 30 mg/kg AZD1656 for six weeks, and group sizes ranged from five to 18 animals.

Untreated db/db mice exhibited hallmark features of diabetic cardiomyopathy, such as impaired diastolic function, metabolic inflexibility and systemic inflammation.

Diastolic dysfunction was confirmed by significant changes in isovolumetric relaxation time (P=0.0001), mitral valve deceleration time (P<0.0001), and E wave/A wave ratio (P=0.0003).

Improved cardiac function in diabetic cardiomyopathy

AZD1656 markedly enhanced cardiac performance in diabetic cardiomyopathy, including diastolic function and myocardial performance index, and facilitated recovery after ischaemia–reperfusion injury. Infarct size was smaller compared with untreated diabetic mice (P=0.005).

At a metabolic level, diabetic hearts exhibited significant disturbances, including depleted amino acids, disrupted tricarboxylic acid cycle intermediates and reduced energy reserves.

In vivo pyruvate dehydrogenase flux was reduced by 95%, indicating significantly impaired glucose oxidation. Diabetic cardiomyopathy treatment with AZD1656 largely normalised these abnormalities, restoring metabolomic profiles towards control levels and enhancing mitochondrial function.

Cardiac oxygen consumption was reduced by approximately 68% following treatment, indicating improved energetic efficiency. Lipidomic analyses showed partial normalisation of phosphatidylcholine composition, while transcriptomic data revealed a reversal of pro-inflammatory gene expression, including normalisation of Nlrp3 inflammasome signalling.

T-cell immunometabolism and mechanism of action

A key mechanistic discovery was that AZD1656 enhances glucokinase-dependent glycolysis in regulatory T cells (Tregs), improving their migratory capacity without triggering proliferation.

This metabolic reprogramming enables increased Treg infiltration into the myocardium, shifting the immune balance away from pro-inflammatory CD4⁺ T cell activity toward immune regulation.

In treated mice, this was reflected by reduced effector T-cell infiltration (P=0.002) and increased Treg recruitment (P=0.03).

These findings suggest that AZD1656 confers cardioprotection in diabetic cardiomyopathy by restoring immune homeostasis through targeted modulation of T-cell metabolism and trafficking.

However, limitations must be acknowledged when interpreting the results. The preclinical design meant that findings might not fully translate to humans. Sample sizes varied across experimental groups, and systemic metabolic parameters such as hyperglycaemia and obesity were not improved, suggesting that the observed benefits are likely driven by cardiac-specific effects rather than by overall metabolic correction, the authors noted.

Future implications for diabetic cardiomyopathy

Overall, the work indicates a potentially first-in-class approach to treating diabetic heart disease by targeting both immune dysregulation and metabolic impairment. This positions immunometabolic modulation as a promising therapeutic strategy not only in diabetic cardiomyopathy but also in other sterile inflammation pathologies.

Commenting on the findings, which stem from her earlier Wellcome Career Re-Entry Fellowship, Professor Dunja Aksentijevic, professor of cardiovascular physiology and metabolism at Queen Mary University of London, said: ‘This work establishes aberrant immunometabolic signalling as a promoter of cardiac remodelling in type 2 diabetes.

‘Targeting this axis by enhancing the migratory capacity of regulatory T cells improved diabetic cardiomyopathy, thus opening a new therapeutic direction for the treatment of hundreds of millions of people worldwide living with type 2 diabetes.’

Reference
Anderson S et al. Targeting immunometabolic pathways with AZD1656 alleviated inflammation and metabolic dysfunction in type 2 diabetic cardiomyopathy. Nat Cardiovasc Res 2026;5(2):138–54.