Diabetes has recently been referred to as ?the epidemic of the 21st century? and contributes to a substantial economic burden on the United States public health. Cardiovascular disease (CVD) accounts for 80% of morbidity and mortality in diabetes, however, women with type 1 diabetes have a substantially greater risk for CVD compared to men with diabetes. A critical barrier to understanding this sexual dimorphism in CVD risk is the lack of knowledge regarding the role of estrogen (E2) on vascular health in diabetic women. Oxidative stress is a common phenotype in patients with diabetes and is routinley associated with hyperglycemia and diabetic complications. In addition, sirtuin1 (Sirt1) has been proposed to play a fundemental role in regulating nitric oxide (NO) bioavailability, and is lower in patients with diabetes. Accordingly, our central hypothesis is that an elevated concentration of E2 in women with type 1 diabetes contributes to a reduction in NO- bioavailability and vascular health through two separate pathways; an increase in oxidative stress and a decrease in circulating Sirt1. In support, compelling preliminary data indicate that the natural increase in vascular health from menses to the late follicular phase of the menstrual cycle is lost in the presence of type 1 diabetes. In addition, this loss is associated with increased oxidative stress and lower Sirt1. To investigate the impact of E2 on vascular health in women with diabetes, we propose to utilize the menstrual cycle as a natural and novel method to investigate changes in sex-steroid hormones. We will perform a comprehensive assessment of vascular health in men and at two different times during the menstrual cycle in premenopausal women with and without type 1 diabetes: 1) during the menses (low estrogen/low progesterone) and 2) late follicular (elevated estrogen/low progesterone) phases. In addition, we will employ two novel treatments that may mitigate future CVD risk in patients with diabetes. Findings will not only contribute to understanding the molecular mechanisms associated with sex disparities of CVD risk in diabetes, they may identify novel therapeutic approaches to decrease estrogen-mediated vascular dysfunction in women with diabetes. This proposal demonstrates the true model of translational research and represents a major shift in the approach to understanding the sexual dimorphism of CVD risk in patients with type 1 diabetes.
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