Targeting immunometabolic pathways with AZD1656 alleviates inflammation and metabolic dysfunction in type 2 diabetic cardiomyopathy

Journal article

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.

Authors: Anderson, S; Karlstaedt, A; Young, M; Karatzia, L; Cullen, F

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature [academic journals on nature.com]
• Journal: Nature Cardiovascular Research
• Volume: 5
• Issue: 2
• Pages: 138-154
• Publication date: 2026-02-23
• Acceptance date: 2025-12-15
• DOI: 10.1038/s44161-025-00769-0
• EISSN: 2731-0590
• ISSN: 2731-0590
• Language: English
• Keywords: Inflammation; Diabetic cardiomyopathy; Cardiac dysfunction; Diabetes mellitus; Metabolic control analysis; Glycemic; Immune system; Cardiomyopathy; Glucokinase; Heart failure