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

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.

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Publication Details

Journal
Nature Cardiovascular Research
Published
2026-02-23
DOI
https://doi.org/10.1038/s44161-025-00769-0
Citations
1
Primary Topic
Cardiovascular Function and Risk Factors
Type
article
Field-Weighted Citation Impact
30.07

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article

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

Fenn Cullen, Jack J. Miller, J C Chen, Loucia Karatzia et al.
1 citations
Nature Cardiovascular Research
Cardiovascular Function and Risk Factors
30.07
article

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

Fenn Cullen, Jack J. Miller, J C Chen, Loucia Karatzia, Dunja Aksentijević, Lauren J. Albee, D Tyler, Stephanie A. Anderson, Anja Karlstaedt, D. M. Smith, Zorana Staka, Hiran A Prag, Siân M. Henson, Megan Young, Andrew J. M. Lewis, Michael R. Barnes, Sanushi Dambure, Christoph Thiemermann, Filip Cvetko, Michael P. Murphy, Caroline E. O’Riordan, Conor Garrod-Ketchley
article en
1 citations

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.

Nature Cardiovascular ResearchVol. 5(2)
AstraZeneca (United Kingdom) (GB), Leiden University (NL), Cedars-Sinai Medical Center (US), St Thomas' Hospital (GB), Queen Mary University of London (GB), University of East Sarajevo (BA), Aarhus University (DK), University of Cambridge (GB), Aarhus University Hospital (DK), University of Oxford (GB), King's College Hospital NHS Foundation Trust (GB), AstraZeneca (Singapore) (SG), Cedars-Sinai Smidt Heart Institute (US), William Harvey Research Institute (GB), AstraZeneca (Germany) (DE), MRC Mitochondrial Biology Unit (GB)
AstraZeneca, Queen Mary University of London, Wellcome Trust, Somerville College, University of Oxford, Cedars-Sinai Medical Center, National Institute for Health and Care Research, British Heart Foundation, Diabetes UK, King's College London, University of Oxford, Novo Nordisk Fonden, Versus Arthritis, National Institutes of Health, Medical Research Council, Barts and The London School of Medicine and Dentistry
Good health and well-being
Openalex Percentile: Top 1%
Cardiovascular Function and Risk Factors
30.07
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