Stephanie A. Anderson, Anja Karlstaedt, Megan Young, Loucia Karatzia, Fenn Cullen, J C Chen, Caroline E. O’Riordan, Michael R. Barnes, Zorana Staka, Lauren J. Albee, Conor Garrod-Ketchley, Sanushi Dambure, Hiran A Prag, Filip Cvetko, Jack J. Miller, Christoph Thiemermann, Andrew J. M. Lewis, Michael P. Murphy, D. M. Smith, Siân M. Henson, D Tyler, Dunja Aksentijević
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 glycemic control but later identified to have immunomodulatory effects, reverses cardiac dysfunction and metabolic remodeling in dbCM. In obese, hyperglycemic db/db mice with diastolic dysfunction, 6 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 remodeled the cardiac immune landscape by promoting infiltration of regulatory T cells. These findings demonstrate a link between cardiac inflammation and metabolic remodeling 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.