Impact of SGLT-2 Inhibition on the Cardiometabolic Profile of PCOS

点击翻译按钮获取中文摘要

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age, afflicting between 5-20% of women worldwide. It is characterized by hyperandrogenemia and oligo- ovulation. PCOS is highly co-prevalent with several cardiovascular risk factors such as obesity, hypertension, insulin resistance, and dyslipidemia. Mitochondrial dysfunction in women with PCOS is also apparent which could lead to the unhealthy expansion of white adipose tissue (WAT) seen in PCOS. While the exact etiology of PCOS is unknown, hyperandrogenemia appears to be a major mediator of the cardiometabolic profile of PCOS. With these knowledge gaps, it is unsurprising that there are limited options for women with PCOS to reduce their cardiovascular risk factors. As cardiovascular disease is the number one killer of women in the United States, women with PCOS desperately need more treatment options. Treatments such as metformin and angiotensin II receptor blockers have shown some promise, but they only treat part of the disease. Among these new potential treatments are sodium-glucose co-transporter 2 inhibitors (SGLT2i), an exciting class of therapeutic tools that reduces BP and cardiovascular mortality in patients with type 2 diabetes. Recently, SGLT2i reduced the body weight of women with PCOS. Additionally, in mice with insulin resistance, SGLT2i increased markers of fatty acid oxidation and decreased urinary 8-isoprostane, a marker of oxidative stress. Therefore, SGLT2i need to be investigated for treatment of PCOS as they may reduce obesity, BP, dyslipidemia, and renal injury in this disease. To study SGLT2i in PCOS, our laboratory has previously characterized a Sprague Dawley female rat model of PCOS via implantation of a dihydrotestosterone pellet at four weeks of age. Our hyperandrogenemic female (HAF) rats mimic many of the same features of PCOS women such as oligo-ovulation accompanied by increased adiposity, BP, insulin resistance, and renal injury. We have exciting preliminary data that SGLT2i decreases adiposity in our model, with evidence of functional improvement of WAT from a marked decreased in plasma leptin. We also found reduced expression of renal angiotensin-converting enzyme mRNA. This project will test the central hypothesis that pharmacological administration of SGLT2i in HAF rats will ameliorate both the increase in BP by downregulating the intrarenal renin-angiotensin system (RAS) and obesity by improving mitochondrial function in WAT. This hypothesis will be tested in the following specific aims: 1) To test the hypothesis that in HAF rats, androgens increase SGLT2 that leads to activation of the RAS leading to increased BP and reduced renal function, and administration of an SGLT2i will decrease BP and improve renal hemodynamics, and 2) To test the hypothesis that in HAF rats, androgens cause mitochondrial dysfunction in WAT and that SGLT2i will attenuate androgen-induced mitochondrial dysfunction leading to improvement in WAT activity. Therefore, this project has a critical clinical and translational value in improving the health of a large but underserved population of women.