Ovariectomy abolishes cardioprotection against diastolic dysfunction and impairs cardiac glucose oxidation in female mice with type 2 diabetes

Type 2 diabetes (T2D) increases the risk for diabetic cardiomyopathy (DbCM), which is often characterized by diastolic dysfunction. Pre-menopausal women have a reduced incidence of both T2D and DbCM, but this disappears following menopause. Our goal was to evaluate the potential role for ovarian hormones in mediating these differences. The effect of ovariectomy (OVX) was investigated in female mice with experimental T2D following high-fat diet feeding for 12-weeks in combination with a low-dose treatment of streptozotocin at week 4. Body weight and body composition, glucose homeostasis, cardiac structure/function via ultrasound echocardiography, and myocardial substrate metabolism via isolated working heart perfusions were assessed. Sham and OVX female mice with T2D exhibited increases in body weight and fat mass, as well as impaired glucose homeostasis, though these parameters were more prominent in OVX than sham females when compared to their lean counterparts. However, only OVX female mice with T2D developed diastolic dysfunction as reflected by a significant decrease in the mitral E/A and tissue Doppler e'/a' ratios, as well as an increase in the E/e' ratio. Isolated working hearts from both sham and OVX female mice with T2D exhibited a reduction in glucose oxidation, though this was more pronounced in the latter. Lastly, only OVX female mice with T2D demonstrated cardiomyocyte hypertrophy. Our data illustrate key roles for ovarian hormones in impacting how T2D impacts the progression of DbCM in females, which may have relevance to women living with T2D as they transition to menopause.