Insulin resistance negatively impacts the diabetic heart in various ways, including impaired insulin-mediated glucose uptake and a reduction in intracellular signaling. The unique cardiac condition, termed diabetic cardiomyopathy, is independent of coronary artery disease and was described as a part of the clinical spectrum of familial lipodystrophy syndromes. Diabetic cardiomyopathy is characterized by extensive fibrotic changes, leading to increased myocardial stiffness and the development of diastolic dysfunction. The molecular mechanisms leading to myocyte injury, hypertrophy and dysfunction in the diabetic heart are triggered by the characteristic metabolic abnormalities and by abnormal energetics.
This study aimed to assess the metabolic changes associated with diabetes mellitus type 2 (DM2) and their effect on the development of cardiac hypertrophy.
Leptin resistant (db/db) mice were treated for 1 month with angiotensin II to induce severe cardiomyopathy and were compared to WT lean mice. Echocardiography, heart morphology and fibrosis, and biochemical markers were measured.
Biochemical markers indicated that the db/db mice suffer from diabetes compared to WT lean mice (86.7±20.8 mg/dL in lean mice vs. 510±210.7mg/dL glucose in db/db mice, p=0.025, n=3), and hyperlipidemia (53.34±5.77mg/dL vs 163.34±51.31 mg/dL cholesterol, p=0.021, n=3, respectively). Echocardiography revealed that hypertensive diabetic mice developed a unique cardiomyopathy which is different from the cardiomyopathy present in angiotensin-treated control (lean) mice. Hypertensive diabetic mice have preserved fractional shortening compared to hypertensive lean mice (33.6±7.2% vs. 17.7±5.7% , p=0.004, n=5). Left ventricle cavity is increased in hypertensive lean mice compared to non-hypertensive lean mice (3.7±0.5mm, n=5 vs. 2.7±0.3mm, n=9, p=0.003), while hypertension in diabetic mice leads to a smaller cavity (3.7±0.5mm, vs. 2.4±0.3mm, p<0.001, n=5). Histological staining revealed that hypertension triggers infiltration of immune cells and fibrosis which is more pronounced in hypertensive diabetic mice. This model reveals the contribution of diabetes and the associated metabolic syndrome to the development of cardiomyopathy.
