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

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

doi:10.3390/ijms22052576

Cited by 28 publications

(46 citation statements)

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“…Although is clear that obesity exacerbates the cardiometabolic complications in PCOS women [4], the mechanism by which hyperandrogenemia promotes white adipocytes (WAT) expansion remains unclear. We previously demonstrated that hyperandrogenemia in female rats recapitulates several of the cardiometabolic features observed in women with PCOS, including increased body weight, BMI, fat mass, IR, blood pressure, and albuminuria [13,14]. The expansion of WAT is present in both the subcutaneous (SAT) and visceral WAT (VAT) [13,15,16].…”

Section: Introductionmentioning

confidence: 96%

Mitochondrial function and oxidative stress in white adipose tissue in a rat model of PCOS: effect of SGLT2 inhibition

et al. 2022

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Background Polycystic ovary syndrome (PCOS), characterized by androgen excess and ovulatory dysfunction, is associated with a high prevalence of obesity and insulin resistance (IR) in women. We demonstrated that sodium–glucose cotransporter-2 inhibitor (SGLT2i) administration decreases fat mass without affecting IR in the PCOS model. In male models of IR, administration of SGLT2i decreases oxidative stress and improves mitochondrial function in white adipose tissue (WAT). Therefore, we hypothesized that SGLT2i reduces adiposity via improvement in mitochondrial function and oxidative stress in WAT in PCOS model. Methods Four-week-old female rats were treated with dihydrotestosterone for 90 days (PCOS model), and SGLT2i (empagliflozin) was co-administered during the last 3 weeks. Body composition was measured before and after SGLT2i treatment by EchoMRI. Subcutaneous (SAT) and visceral (VAT) WAT were collected for histological and molecular studies at the end of the study. Results PCOS model had an increase in food intake, body weight, body mass index, and fat mass/lean mass ratio compared to the control group. SGLT2i lowered fat mass/lean ratio in PCOS. Glucosuria was observed in both groups, but had a larger magnitude in controls. The net glucose balance was similar in both SGLT2i-treated groups. The PCOS SAT had a higher frequency of small adipocytes and a lower frequency of large adipocytes. In SAT of controls, SGLT2i increased frequencies of small and medium adipocytes while decreasing the frequency of large adipocytes, and this effect was blunted in PCOS. In VAT, PCOS had a lower frequency of small adipocytes while SGLT2i increased the frequency of small adipocytes in PCOS. PCOS model had decreased mitochondrial content in SAT and VAT without impacting oxidative stress in WAT or the circulation. SGLT2i did not modify mitochondrial function or oxidative stress in WAT in both treated groups. Conclusions Hyperandrogenemia in PCOS causes expansion of WAT, which is associated with decreases in mitochondrial content and function in SAT and VAT. SGLT2i increases the frequency of small adipocytes in VAT only without affecting mitochondrial dysfunction, oxidative stress, or IR in the PCOS model. SGLT2i decreases adiposity independently of adipose mitochondrial and oxidative stress mechanisms in the PCOS model.

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Section: Introductionmentioning

confidence: 96%

Mitochondrial function and oxidative stress in white adipose tissue in a rat model of PCOS: effect of SGLT2 inhibition

et al. 2022

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“…They potentially reduce plasma glucose levels by blocking glucose reabsorption in the renal proximal tubule of patients with diabetes 17–19. SGLT-2 inhibition has also shown positive effects on reducing body weight, blood pressure, cardiovascular and renal complications, attenuating beta-cells exhaustion and relieving oxidative damage and inflammation 20–23…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Currently, several reports have investigated the use of SGLT-2 inhibitors for PCOS, such as empagliflozin, licogliflozin and dapagliflozin 20 24–27. In PCOS mouse models displaying hyperandrogenism, empagliflozin was found to be beneficial in reducing blood pressure and the amount of fat 20. Tan et al found that 50 mg of licogliflozin three times per day for 2 weeks improved hyperinsulinaemia and hyperandrogenaemia compared with a placebo in obese patients with PCOS 24.…”

Section: Introductionmentioning

confidence: 99%

“…Marinkovic-Radosevic et al suggested that SGLT-2 inhibitors indirectly improved the metabolic status (eg, glucose and lipid homoeostasis) in patients with PCOS by inhibiting glucose and sodium reabsorption in the proximal tubule of the kidney and by reducing the liver fat and visceral adipose tissue 28. In another study, it is suggested that empagliflozin could reduce blood pressure in PCOS rats via amelioration of the androgen-induced increase in intrarenal ACE expression and activity 20. Li et al reported that the antioxidative effect of SGLT-2 inhibition might be partially mediated by sodium-hydrogen exchanger 1 and nicotinamide adenine dinucleotide phosphate oxidase inhibition,22 since chronic low-grade inflammation accompanies PCOS 29 30.…”

Section: Introductionmentioning

confidence: 99%

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Sodium-glucose cotransporter-2 inhibitors for improving endocrine and metabolic profiles in overweight and obese individuals with polycystic ovary syndrome: a meta-analysis protocol

Zhang

Xing

2022

BMJ Open

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IntroductionPolycystic ovary syndrome (PCOS) is a heterogeneous reproductive endocrine disorder. Several ongoing trials test sodium-glucose cotransporter-2 (SGLT-2) inhibitors for women with PCOS. However, their effectiveness has not been fully elucidated owing to the lack of high-confidence evidence. Our group agrees with the statement that SGLT-2 inhibition could treat PCOS as it is supported by reports demonstrating the benefits of SGLT-2 inhibition on metabolic status and weight control. Moreover, the functions of chronic inflammation amelioration and cardiovascular system protection make it a more attractive candidate for PCOS therapy. Therefore, to provide physicians with a reference, we intend to perform a meta-analysis on the efficacy and safety of SGLT-2 inhibitors on the endocrine and metabolic profiles of patients with PCOS.Methods and analysisWe will search for randomised controlled trials performed until September 2022 using PubMed, Web of Science, EMBASE, the Cochrane Library, Google Scholar, the PhRMA Clinical Study Results Database (www.clinicaltrials.gov), the China National Knowledge Infrastructure, the Wanfang, the Weipu and the Chinese biomedical literature databases. The outcomes will include androgen-associated outcomes, body fat, glucose and lipid homoeostasis, inflammatory outcomes and adverse events. In addition, two investigators will independently assess methodological quality using the revised Cochrane risk-of-bias tool 2. The analysis will be performed using RevMan V.5.3 software, and subgroup and sensitivity analyses and a meta-regression will be used to determine the heterogeneity source.Ethics and disseminationEthical approval is not required because this is a meta-analysis. We will disseminate these results by publishing them in a peer-reviewed journal.PROSPERO registration numberCRD42021281176.

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Cardiometabolic effects of SGLT2 inhibitors on polycystic ovary syndrome

Lempesis

Apple

Duarte

et al. 2023

Diabetes Metabolism Res

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Polycystic ovary syndrome (PCOS) is a complex endocrinopathy affecting many women of reproductive age. Although its physiology is poorly understood, hyperandrogenemia and insulin resistance play a pivotal role in this complex syndrome, predisposing patients to a variety of cardiovascular and metabolic modalities. Current therapeutic options, including lifestyle modifications and medications, often do not satisfactorily improve clinical outcomes. SGLT2 inhibitors (SGLT‐2i) are a novel option which can potentially improve many hormonal and metabolic parameters for patients with PCOS, though the net cardiovascular effects remain under investigation in this population of patients with PCOS. Overall, the use of SGLT‐2i may be associated with beneficial somatometric, metabolic and hormonal outcomes of PCOS. To date, all available studies have recorded body mass index, waist and hip circumference, and fat mass reductions, improved insulin and androgen levels, and reduced blood pressure. The aim of the present review is to summarise PCOS‐related manifestations and mechanisms leading to cardiovascular disease, to explore the cardiometabolic impact of SGLT2i on PCOS, and to critically analyse the cardiometabolic and hormonal outcomes of the recent studies on the use of SGLT2i in women with PCOS.

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

Cited by 28 publications

References 63 publications

Mitochondrial function and oxidative stress in white adipose tissue in a rat model of PCOS: effect of SGLT2 inhibition

Mitochondrial function and oxidative stress in white adipose tissue in a rat model of PCOS: effect of SGLT2 inhibition

Sodium-glucose cotransporter-2 inhibitors for improving endocrine and metabolic profiles in overweight and obese individuals with polycystic ovary syndrome: a meta-analysis protocol

Cardiometabolic effects of SGLT2 inhibitors on polycystic ovary syndrome

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