Deep phenotyping of a modified diabetic cardiomyopathy mouse model which reflects clinical disease progression
Abstract Diabetic cardiomyopathy (DbCM) is a progressive disease and common complication of metabolic diabetes. It is characterised by onset of cardiac structural and functional impairments and can lead to direct development of clinical heart failure (HF) or predispose to hypertensive/ischaemic stre...
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BMC
2025-08-01
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| Series: | Diabetology & Metabolic Syndrome |
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| Online Access: | https://doi.org/10.1186/s13098-025-01913-3 |
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| author | Narainrit Karuna Lauren Kerrigan Kevin Edgar Oisin Cappa David Simpson Claire Tonry David J. Grieve Chris J. Watson |
| author_facet | Narainrit Karuna Lauren Kerrigan Kevin Edgar Oisin Cappa David Simpson Claire Tonry David J. Grieve Chris J. Watson |
| author_sort | Narainrit Karuna |
| collection | DOAJ |
| description | Abstract Diabetic cardiomyopathy (DbCM) is a progressive disease and common complication of metabolic diabetes. It is characterised by onset of cardiac structural and functional impairments and can lead to direct development of clinical heart failure (HF) or predispose to hypertensive/ischaemic stress. DbCM is a complex disease which involves several metabolic and pathogenic factors. We characterised an established high-fat diet/streptozotocin (HFD/STZ)-induced DbCM model incorporating typical features of human disease to determine its suitability for preclinical evaluation of novel therapeutics prior to advancement to human trials. Male C57BL/6J mice were randomised to HFD and single-dose STZ (100 mg/kg) or control diet (CD) and vehicle. HFD/STZ mice developed type 2 diabetes mellitus (T2DM), reflected by high fasting blood glucose and HbA1c levels, reduced β-cell function, and increased insulin resistance without systolic blood pressure alteration. Furthermore, HFD/STZ mice displayed progressive diastolic dysfunction, evidenced by decreased MV E/A ratio, together with elevated chronic left ventricular (LV) filling pressure parameters, measured by left atrial (LA) area and LA volume, compared to controls, in parallel with LV hypertrophy and fibrosis. Monocyte trafficking into diabetic hearts was identified by single-nuclei RNA sequencing analysis, which revealed an interferon-α response in DbCM mice, whilst plasma proteomics confirmed the involvement of inflammatory processes with elevated plasma C-reactive protein in DbCM progression. Taken together, our HFD/STZ-induced DbCM model exhibits a unique DbCM pre-clinical phenotype reflecting a "triple-hit" of human DbCM features comprising (1) T2DM with insulin resistance, (2) progressive diastolic dysfunction and LV remodelling, and (3) metabolic inflammation. This improved HFD/STZ-induced DbCM model supports clinically relevant research on DbCM progression from early stages to cardiac dysfunction and remodelling as the basis for translational investigation. |
| format | Article |
| id | doaj-art-109f1629fc5f4641ad3b710e76e5b06d |
| institution | Kabale University |
| issn | 1758-5996 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Diabetology & Metabolic Syndrome |
| spelling | doaj-art-109f1629fc5f4641ad3b710e76e5b06d2025-08-20T03:42:52ZengBMCDiabetology & Metabolic Syndrome1758-59962025-08-0117111610.1186/s13098-025-01913-3Deep phenotyping of a modified diabetic cardiomyopathy mouse model which reflects clinical disease progressionNarainrit Karuna0Lauren Kerrigan1Kevin Edgar2Oisin Cappa3David Simpson4Claire Tonry5David J. Grieve6Chris J. Watson7Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University BelfastWellcome-Wolfson Institute for Experimental Medicine, Queen’s University BelfastWellcome-Wolfson Institute for Experimental Medicine, Queen’s University BelfastWellcome-Wolfson Institute for Experimental Medicine, Queen’s University BelfastWellcome-Wolfson Institute for Experimental Medicine, Queen’s University BelfastWellcome-Wolfson Institute for Experimental Medicine, Queen’s University BelfastWellcome-Wolfson Institute for Experimental Medicine, Queen’s University BelfastWellcome-Wolfson Institute for Experimental Medicine, Queen’s University BelfastAbstract Diabetic cardiomyopathy (DbCM) is a progressive disease and common complication of metabolic diabetes. It is characterised by onset of cardiac structural and functional impairments and can lead to direct development of clinical heart failure (HF) or predispose to hypertensive/ischaemic stress. DbCM is a complex disease which involves several metabolic and pathogenic factors. We characterised an established high-fat diet/streptozotocin (HFD/STZ)-induced DbCM model incorporating typical features of human disease to determine its suitability for preclinical evaluation of novel therapeutics prior to advancement to human trials. Male C57BL/6J mice were randomised to HFD and single-dose STZ (100 mg/kg) or control diet (CD) and vehicle. HFD/STZ mice developed type 2 diabetes mellitus (T2DM), reflected by high fasting blood glucose and HbA1c levels, reduced β-cell function, and increased insulin resistance without systolic blood pressure alteration. Furthermore, HFD/STZ mice displayed progressive diastolic dysfunction, evidenced by decreased MV E/A ratio, together with elevated chronic left ventricular (LV) filling pressure parameters, measured by left atrial (LA) area and LA volume, compared to controls, in parallel with LV hypertrophy and fibrosis. Monocyte trafficking into diabetic hearts was identified by single-nuclei RNA sequencing analysis, which revealed an interferon-α response in DbCM mice, whilst plasma proteomics confirmed the involvement of inflammatory processes with elevated plasma C-reactive protein in DbCM progression. Taken together, our HFD/STZ-induced DbCM model exhibits a unique DbCM pre-clinical phenotype reflecting a "triple-hit" of human DbCM features comprising (1) T2DM with insulin resistance, (2) progressive diastolic dysfunction and LV remodelling, and (3) metabolic inflammation. This improved HFD/STZ-induced DbCM model supports clinically relevant research on DbCM progression from early stages to cardiac dysfunction and remodelling as the basis for translational investigation.https://doi.org/10.1186/s13098-025-01913-3Diabetic cardiomyopathyMetabolic syndromeDiastolic dysfunctionHeart failureCardiac fibrosis |
| spellingShingle | Narainrit Karuna Lauren Kerrigan Kevin Edgar Oisin Cappa David Simpson Claire Tonry David J. Grieve Chris J. Watson Deep phenotyping of a modified diabetic cardiomyopathy mouse model which reflects clinical disease progression Diabetology & Metabolic Syndrome Diabetic cardiomyopathy Metabolic syndrome Diastolic dysfunction Heart failure Cardiac fibrosis |
| title | Deep phenotyping of a modified diabetic cardiomyopathy mouse model which reflects clinical disease progression |
| title_full | Deep phenotyping of a modified diabetic cardiomyopathy mouse model which reflects clinical disease progression |
| title_fullStr | Deep phenotyping of a modified diabetic cardiomyopathy mouse model which reflects clinical disease progression |
| title_full_unstemmed | Deep phenotyping of a modified diabetic cardiomyopathy mouse model which reflects clinical disease progression |
| title_short | Deep phenotyping of a modified diabetic cardiomyopathy mouse model which reflects clinical disease progression |
| title_sort | deep phenotyping of a modified diabetic cardiomyopathy mouse model which reflects clinical disease progression |
| topic | Diabetic cardiomyopathy Metabolic syndrome Diastolic dysfunction Heart failure Cardiac fibrosis |
| url | https://doi.org/10.1186/s13098-025-01913-3 |
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