Immunomodulation by AZD1656 reverses cardiac dysfunction, metabolic remodelling and reduces infarct size in type 2 diabetic cardiomyopathy

Type 2 Diabetes (T2D) can lead to diabetic cardiomyopathy (dbCM), which is characterised by chronic, systemic inflammation, disrupted metabolism and impaired cardiac function. However, whether cardiac inflammation is present in dbCM and causally linked to metabolic remodelling remains unknown. AZD1656 (AZD), an activator of glucokinase, was postulated to provide glycaemic control in T2D by acting on in the pancreas and liver. However, AZD failed to control hyperglycaemia in clinical trials. Nevertheless, testing of the drug in COVID-19 T2D patients as part of the ARCADIA trial indicated an immunomodulatory effect. Therefore, we used the db/db mouse model of dbCM and an integrated in vivo and ex vivo experimental approach to examine the effects of AZD on cardiac functional and metabolic disturbances and inflammation. 20-week db/db mice displaying the features of human dbCM (obesity, hyperglycaemia and diastolic dysfunction) treated for six weeks with AZD showed improved metabolic remodelling, attenuated diastolic dysfunction, reduced infarct size and improved functional post-ischemic recovery compared to untreated dbCM, alongside an improved cardiac immunophenotype, including reduced T cell-mediated fibrosis and B cell infiltration. Therefore, targeting of immunometabolism may offer a new therapeutic approach to treat cardiac dysfunction and metabolic dysregulation and reduce infarct size in dbCM.