The incidence of diabetes and its association with increased
cardiovascular disease risk represents a major health issue worldwide. Diabetes-induced
hyperglycemia is implicated as a central driver of responses in the diabetic heart such as cardiomyocyte
hypertrophy,
fibrosis, and oxidative stress, termed
diabetic cardiomyopathy. The onset of these responses in the setting of diabetes has not been studied to date. This study aimed to determine the time course of development of
diabetic cardiomyopathy in a model of
type 1 diabetes (T1D) in vivo. Diabetes was induced in 6-week-old male FVB/N mice via
streptozotocin (55 mg/kg i.p. for 5 days; controls received
citrate vehicle). At 2, 4, 8, 12, and 16 weeks of untreated diabetes, left ventricular (LV) function was assessed by echocardiography before post-mortem quantification of markers of LV cardiomyocyte
hypertrophy,
collagen deposition, DNA fragmentation, and changes in components of the
hexosamine biosynthesis pathway (HBP) were assessed.
Blood glucose and HbA1c levels were elevated by 2 weeks of diabetes. LV and muscle (gastrocnemius) weights were reduced from 8 weeks, whereas liver and kidney weights were increased from 2 and 4 weeks of diabetes, respectively. LV diastolic function declined with diabetes progression, demonstrated by a reduction in E/A ratio from 4 weeks of diabetes, and an increase in peak A-wave amplitude, deceleration time, and isovolumic relaxation time (IVRT) from 4-8 weeks of diabetes. Systemic and local
inflammation (TNFα, IL-1β, CD68) were increased with diabetes. The cardiomyocyte hypertrophic marker
Nppa was increased from 8 weeks of diabetes while β-
myosin heavy chain was increased earlier, from 2 weeks of diabetes. LV
fibrosis (
picrosirius red; Ctgf and Tgf-β gene expression) and DNA fragmentation (a marker of cardiomyocyte apoptosis) increased with diabetes progression. LV Nox2 and Cd36 expression were elevated after 16 weeks of diabetes. Markers of the LV HBP (Ogt, Oga, Gfat1/2 gene expression), and
protein abundance of OGT and total O-GlcNAcylation, were increased by 16 weeks of diabetes. This is the first study to define the progression of cardiac markers contributing to the development of
diabetic cardiomyopathy in a mouse model of T1D, confirming multiple pathways contribute to
disease progression at various time points.