AZD1656 treatment reduced cardiac oxygen consumption by 68% and attenuated diastolic dysfunction and infarct size in mice with type 2 diabetic cardiomyopathy.
Does the glucokinase activator AZD1656 improve cardiac function and metabolic remodeling in a mouse model of type 2 diabetic cardiomyopathy?
AZD1656 improves cardiac diastolic function, reduces infarct size, and restores metabolic flexibility in diabetic cardiomyopathy by modulating the cardiac immune landscape, independent of systemic glycemic control.
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 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.
Anderson et al. (Mon,) conducted a other in Type 2 diabetic cardiomyopathy (n=60). AZD1656 vs. Untreated db/db mice was evaluated on Cardiac oxygen consumption. AZD1656 treatment reduced cardiac oxygen consumption by 68% and attenuated diastolic dysfunction and infarct size in mice with type 2 diabetic cardiomyopathy.