Keshav Gopal, PhD: No financial relationships to disclose
Background: Obesity is a major risk factor for type 2 diabetes (T2D) and related cardiovascular diseases including diabetic cardiomyopathy (DbCM), which is often asymptomatic during the early stages of T2D. Increased cardiovascular risk is more prominent in women at the later stage of T2D, but an understanding of the pathology of DbCM in females is lacking, as most of the reported mechanistic studies have been performed in males. Therefore, our aim was to characterize a mouse model of DbCM predominantly used in males and elucidate whether its pathological features were reproduced in females.
METHODS AND RESULTS: Male and female (with or without ovariectomy surgery) C57BL/6J mice were subjected to experimental T2D (high-fat diet [60% kcal from lard] for 12-wks with streptozotocin [75 mg/kg] administered at 4-wks). Body weight, glucose homeostasis, and in vivo cardiac function were serially assessed throughout the protocol. At study completion, mice were euthanized, following which the heart and other tissues were extracted and evaluated for biochemical analysis. Both male and female mice subjected to experimental T2D exhibited increases in body weight, blood glucose levels, and glucose intolerance, though these increases were more prominent in males than females when compared to their lean counterparts. However, only male mice displayed the cardiac abnormalities present in DbCM, including diastolic dysfunction as reflected by a significant decrease in the tissue Doppler e’/a’ ratio and an increase in E/e’ ratio. Furthermore, we observed no changes in parameters of systolic function compared to the lean mice. Cardiac tissues from female mice with T2D demonstrated gene expression changes (higher expression of Acox1 and lower expression of Acc2) indicative of higher fatty acid oxidation with no change in glucose and ketone body oxidation when compared to hearts from male mice with T2D. Interestingly, ovariectomized T2D female mice exhibited a more pronounced phenotype, which included increases in body weight, blood glucose levels, glucose intolerance, and diastolic dysfunction that were now comparable to that observed in male mice with experimental T2D.
Conclusion: Our data suggest that the protection observed in female mice against experimental DbCM may be related to a higher capacity for myocardial fatty acid oxidation, and that the presence of ovarian hormones protects against cardiac abnormalities in the early stage of DbCM. Hence, future studies are needed to better define the potential contribution of ovarian hormones to cardiac energy metabolism in females with T2D.
