Impact of SGLT-2 Inhibition on Cardiometabolic Abnormalities in a Rat Model of Polycystic Ovary Syndrome.

Jacob E Pruett,Licy L Yanes Cardozo,Steven J Everman,Stephanie A Ye,Edgar D Torres Fernandez,Kacey Davenport,Ruth M Vinson,Damian G Romero,Madelyn K Logan

doi:10.3390/ijms22052576

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have a high prevalence of obesity, insulin resistance (IR), increased blood pressure (BP), and activation of the renin angiotensin system (RAS). Effective evidence-based therapeutics to ameliorate the cardiometabolic complications in PCOS are lacking. The sodium-glucose cotransporter-2 (SGLT2) inhibitor Empagliflozin (EMPA) reduces BP and hyperglycemia in type 2 diabetes mellitus. We hypothesized that hyperandrogenemia upregulates renal SGLT2 expression and that EMPA ameliorates cardiometabolic complications in a hyperandrogenemic PCOS model. Four-week-old female Sprague Dawley rats were treated with dihydrotestosterone (DHT) for 90 days, and EMPA was co-administered for the last three weeks. DHT upregulated renal SGLT2, SGLT4, and GLUT2, but downregulated SGLT3 mRNA expression. EMPA decreased DHT-mediated increases in fat mass, plasma leptin, and BP, but failed to decrease plasma insulin, HbA1c, or albuminuria. EMPA decreased DHT-mediated increase in renal angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), and angiotensin II type 1 receptor (AGT1R) mRNA and protein expression. In summary, SGLT2 inhibition proved beneficial in adiposity and BP reduction in a hyperandrogenemic PCOS model; however, additional therapies may be needed to improve IR and renal injury.

Highlights

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women, affecting between 5–20% of women in this demographic [1,2,3].PCOS is characterized by androgen excess, ovulatory dysfunction, and polycystic appearance of the ovaries [4]
We showed that the hyperandrogenemic rat model of PCOS recapitulates several cardiometabolic features observed in women with PCOS, including increased body mass index (BMI), insulin resistance (IR), blood pressure (BP), hyperleptinemia, albuminuria, and activation of the intrarenal renin angiotensin system (RAS) [25,29,30]
Women with PCOS have a high prevalence of cardiometabolic risk factors; effective evidence-based therapeutic agents to ameliorate those cardiometabolic risk factors are lacking

Summary

Introduction

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women, affecting between 5–20% of women in this demographic [1,2,3]. PCOS is characterized by androgen excess, ovulatory dysfunction, and polycystic appearance of the ovaries [4]. The etiology of PCOS is currently unknown. The sources of excess androgens in PCOS are the ovaries, the adrenals, and peripheral tissues, such as the adipose tissue, which convert pro-androgens into active metabolites [5,6,7,8]. Patients with PCOS currently have very few effective evidence-based pharmacological agents for treating their cardiometabolic complications [13,14]

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Results

Conclusion