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Left ventricular (LV) dysfunction is an early, clinically detectable sign of cardiomyopathy in type 2 diabetes mellitus (T2DM) that precedes the development of symptomatic heart failure. Preclinical models of diabetic cardiomyopathy are essential to develop therapies that may prevent or delay the progression of heart failure. This study examined the molecular, structural, and functional cardiac phenotype of two rat models of T2DM induced by a high-fat diet (HFD) with a moderate- or high-sucrose content (containing 88.9 or 346 g/kg sucrose, respectively), plus administration of low-dose streptozotocin (STZ). At 8 wk of age, male Sprague-Dawley rats commenced a moderate- or high-sucrose HFD. Two weeks later, rats received low-dose STZ (35 mg/kg ip for 2 days) and remained on their respective diets. LV function was assessed by echocardiography 1 wk before end point. At 22 wk of age, blood and tissues were collected postmortem. Relative to chow-fed sham rats, diabetic rats on a moderate- or high-sucrose HFD displayed cardiac reactive oxygen species dysregulation, perivascular fibrosis, and impaired LV diastolic function. The diabetes-induced impact on LV adverse remodeling and diastolic dysfunction was more apparent when a high-sucrose HFD was superimposed on STZ. In conclusion, a high-sucrose HFD in combination with low-dose STZ produced a cardiac phenotype that more closely resembled T2DM-induced cardiomyopathy than STZ diabetic rats subjected to a moderate-sucrose HFD. NEW & NOTEWORTHY Left ventricular dysfunction and adverse remodeling were more pronounced in diabetic rats that received low-dose streptozotocin (STZ) and a high-sucrose high-fat diet (HFD) compared with those on a moderate-sucrose HFD in combination with STZ. Our findings highlight the importance of sucrose content in diet composition, particularly in preclinical studies of diabetic cardiomyopathy, and demonstrate that low-dose STZ combined with a high-sucrose HFD is an appropriate rodent model of cardiomyopathy in type 2 diabetes.

Aims: The glucose-driven enzymatic modification of myocardial proteins by the sugar moiety, β-N-acetylglucosamine (O-GlcNAc), is increased in pre-clinical models of diabetes, implicating protein O-GlcNAc modification in diabetes-induced heart failure. Our aim was to specifically examine cardiac manipulation of the two regulatory enzymes of this process on the cardiac phenotype, in the presence and absence of diabetes, utilising cardiac-targeted recombinant-adeno-associated viral-vector-6 (rAAV6)-mediated gene delivery., Methods and Results: In human myocardium, total protein O-GlcNAc modification was elevated in diabetic relative to non-diabetic patients, and correlated with left ventricular (LV) dysfunction. The impact of rAAV6-delivered O-GlcNAc transferase (rAAV6-OGT, facilitating protein O-GlcNAcylation), O-GlcNAcase (rAAV6-OGA, facilitating de-O-GlcNAcylation), and empty vector (null) were determined in non-diabetic and diabetic mice. In non-diabetic mice, rAAV6-OGT was sufficient to impair LV diastolic function and induce maladaptive cardiac remodelling, including cardiac fibrosis and increased Myh-7 and Nppa pro-hypertrophic gene expression, recapitulating characteristics of diabetic cardiomyopathy. In contrast, rAAV6-OGA (but not rAAV6-OGT) rescued LV diastolic function and adverse cardiac remodelling in diabetic mice. Molecular insights implicated impaired cardiac PI3K(p110α)-Akt signalling as a potential contributing mechanism to the detrimental consequences of rAAV6-OGT in vivo. In contrast, rAAV6-OGA preserved PI3K(p110α)-Akt signalling in diabetic mouse myocardium in vivo and prevented high glucose-induced impairments in mitochondrial respiration in human cardiomyocytes in vitro., Conclusion: Maladaptive protein O-GlcNAc modification is evident in human diabetic myocardium, and is a critical regulator of the diabetic heart phenotype. Selective targeting of cardiac protein O-GlcNAcylation to restore physiological O-GlcNAc balance may represent a novel therapeutic approach for diabetes-induced heart failure., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: Diabetes is associated with a significantly elevated risk of cardiovascular disease and its specific pathophysiology remains unclear. Recent studies have changed our understanding of cardiac cellularity, with cellular changes accompanying diabetes yet to be examined in detail. This study aims to characterise the changes in the cardiac cellular landscape in murine diabetes to identify potential cellular protagonists in the diabetic heart., Methods: Diabetes was induced in male FVB/N mice by low-dose streptozotocin and a high-fat diet for 26-weeks. Cardiac function was measured by echocardiography at endpoint. Flow cytometry was performed on cardiac ventricles as well as blood, spleen, and bone-marrow at endpoint from non-diabetic and diabetic mice. To validate flow cytometry results, immunofluorescence staining was conducted on left-ventricles of age-matched mice., Results: Mice with diabetes exhibited hyperglycaemia and impaired glucose tolerance at endpoint. Echocardiography revealed reduced E:A and e':a' ratios in diabetic mice indicating diastolic dysfunction. Systolic function was not different between the experimental groups. Detailed examination of cardiac cellularity found resident mesenchymal cells (RMCs) were elevated as a result of diabetes, due to a marked increase in cardiac fibroblasts, while smooth muscle cells were reduced in proportion. Moreover, we found increased levels of Ly6C hi monocytes in both the heart and in the blood. Consistent with this, the proportion of bone-marrow haematopoietic stem cells were increased in diabetic mice., Conclusions: Murine diabetes results in distinct changes in cardiac cellularity. These changes-in particular increased levels of fibroblasts-offer a framework for understanding how cardiac cellularity changes in diabetes. The results also point to new cellular mechanisms in this context, which may further aid in development of pharmacotherapies to allay the progression of cardiomyopathy associated with diabetes.