Immunomodulation by AZD1656 reverses cardiac dysfunction, metabolic remodelling and reduces infarct size in type 2 diabetic cardiomyopathy
Anderson, S.; Karlstaedt, A.; Chen, J.; O'Riordan, C.; Barnes, M.; Staka, Z.; Albee, L.; Garrod-Ketchley, C.; Vithanachchi, S.; Prag, H.; Cvetko, F.; Thiemermann, C.; Lewis, A. J.; Murphy, M. P.; Smith, D. M.; Henson, S.; Tyler, D.; Aksentijevic, D.
Show abstract
Type 2 diabetes (T2D) precipitates diabetic cardiomyopathy (dbCM), a condition characterized by chronic inflammation, metabolic dysregulation and impaired cardiac performance. Here we show that the glucokinase activator AZD1656, originally developed for glycaemic control but later identified to have immunomodulatory effects, reverses cardiac dysfunction and metabolic remodelling in dbCM. In obese, hyperglycaemic db/db mice with diastolic dysfunction, six weeks of AZD1656 treatment improved myocardial performance, reduced infarct size and enhanced post-ischaemic recovery. Integrated metabolic, functional and histological analyses revealed restoration of mitochondrial metabolism and attenuation of fibrosis. Mechanistically, AZD1656 remodelled the cardiac immune landscape by promoting regulatory T-cell infiltration. These findings demonstrate a link between cardiac inflammation and metabolic remodelling in dbCM and highlight that modulation of immune cells and metabolism can protect the diabetic heart. Targeting immunometabolic pathways may therefore offer a therapeutic strategy to alleviate cardiac dysfunction and reduce infarct vulnerability in T2D
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