Progression of Markers Contributing to Cardiomyopathy in a Mouse Model of Type 1 Diabetes

The increasing incidence of diabetes and its association with cardiovascular disease represents a major health issue. Hyperglycaemia is implicated as a central driver of responses seen in the diabetic heart such as hypertrophy, fibrosis, and oxidative stress, together termed diabetic cardiomyopathy. The timing of onset of each of these responses in diabetes is unknown; therefore, we determined the time course of characteristics of diabetic cardiomyopathy in a mouse model of type 1 diabetes 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). After 2, 4, 8, 12, or 16 weeks of diabetes, left ventricular function via Doppler echocardiography was determined, prior to cull and subsequent measurement of markers of cardiomyocyte hypertrophy, fibrosis, DNA fragmentation, and markers of the hexosamine biosynthesis pathway. Blood glucose and HbA1c were elevated from 2 weeks of diabetes. LV and muscle weights were reduced from 8 weeks, liver and kidney weights were increased from 2 and 4 weeks, respectively. Left ventricular diastolic function worsened with diabetes indicated by a progressive decrease in E/A ratio from 4 weeks, and increased deceleration time, IVRT, and A wave amplitude from 8 weeks of diabetes. Cardiac hypertrophy (cardiomyocyte size) was evident from 8 weeks, with gene expression of the hypertrophic marker β-myosin heavy chain and systemic inflammation (plasma tumour necrosis factor-α) being increased earlier, from 2 weeks of diabetes. Cardiac fibrosis (% collagen, CTGF expression) and DNA fragmentation were increased from 4 weeks of diabetes. Markers of hexosamine biosynthesis pathway machinery (LFGlutamine fructose-6-phosphate amidotransferase (GFAT) 1 and 2, O-GlcNAc-ase (OGA), O-GlcNAc transferase (OGT) = Low Frequency) were increased by 16 weeks of diabetes.