Abstract
People affected by diabetes are at an increased risk of developing heart failure than their non-diabetic counterparts, attributed in part to a distinct cardiac pathology termed diabetic cardiomyopathy. Mitochondrial dysfunction and excess reactive oxygen species (ROS) have been implicated in a range of diabetic complications and are a common feature of the diabetic heart. In this study, we sought to characterise impairments in mitochondrial structure and function in a recently described experimental mouse model of diabetic cardiomyopathy. Diabetes was induced in 6-week-old male FVB/N mice by the combination of three consecutive-daily injections of low-dose streptozotocin (STZ, each 55 mg/kg i.p.) and high-fat diet (42% fat from lipids) for 26 weeks. At study end, diabetic mice exhibited elevated blood glucose levels and impaired glucose tolerance, together with increases in both body weight gain and fat mass, replicating several aspects of human type 2 diabetes. The myocardial phenotype of diabetic mice included increased myocardial fibrosis and left ventricular (LV) diastolic dysfunction. Elevated LV superoxide levels were also evident. Diabetic mice exhibited a spectrum of LV mitochondrial changes, including decreased mitochondria area, increased levels of mitochondrial complex-III and complex-V protein abundance, and reduced complex-II oxygen consumption. In conclusion, these data suggest that the low-dose STZ-high fat experimental model replicates some of the mitochondrial changes seen in diabetes, and as such, this model may be useful to study treatments that target the mitochondria in diabetes.
Highlights
The global prevalence of diabetes mellitus in adults has increased from an estimated 108 million in 1980, to 422 million by 2014, and is projected to reach 693 million by 2045 (Cho et al, 2018)
Diabetic mice exhibited a significant increase in blood glucose levels by the 2-week timepoint, and this remained elevated for the duration of the study (Figure 1D)
This study builds upon previous reports from our laboratory describing an experimental model of diabetic cardiomyopathy that recapitulates several of the clinical features of human disease, including robust diastolic dysfunction and myocardial structure changes
Summary
The global prevalence of diabetes mellitus in adults has increased from an estimated 108 million in 1980, to 422 million by 2014, and is projected to reach 693 million by 2045 (Cho et al, 2018). Type 2 diabetes is the predominant type, accounting for approximately 90% of cases in adults (Zhou et al, 2016). Diabetes patients have considerably worse clinical outcomes associated with heart failure, in contrast to those without diabetes (Jia et al, 2018). This is in part explained by a distinct form of heart failure that can manifest in diabetes patients, termed diabetic cardiomyopathy. Despite our progress in understanding this disease process, there are currently no effective treatments that target the underlying pathogenesis contributing to diabetic cardiomyopathy (Marwick et al, 2018)
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