The Impact of SGLT‐2 Inhibition on Obesity and the Metabolic Profile in a PCOS Rat Model

Abstract

Polycystic Ovary Syndrome (PCOS), the most common endocrine disorder in young women, is characterized by hyperandrogenemia, and is associated with obesity and insulin resistance. It is suggested that hyperandrogenemia is the cause of these metabolic complications. Current treatment for obesity in PCOS is lackluster, which is why new therapies are being investigated. Sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors such as Empagliflozin (EMPA) have been shown in diabetics to reduce body fat and insulin resistance. We have previously reported that exposure of female rats to dihydrotestosterone (DHT) before puberty resembles many characteristics found in PCOS: increase in food intake (FI), body weight (BW), fat/lean mass, blood pressure, and renal injury. We want to test the hypothesis that EMPA improves obesity and metabolic complications in a PCOS‐like rat model. Methods Forty four‐week old female SD rats were randomized to either placebo (PBO) or DHT exposure (7.5mg/90 days). Body weight was measured weekly. Body composition was analyzed monthly by EchoMRI. Fasting plasma was analyzed monthly for glucose and insulin. A 24‐hour urine was collected in metabolic cages monthly to assess the concentration of urinary glucose. After 10 wks of DHT, rats were randomized to receive drinking water alone or with EMPA (10mg/kg/day) for another 3 wks. FI was measured daily. At the end of the treatment, body composition, fasting plasma, and glucosuria were assessed. Morning plasma was collected for leptin and adiponectin after 3 wks of EMPA treatment. Results In PCOS rats, EMPA decreased fat mass (21.1 ± 2.7 g vs 12.2 ± 0.8 g, p=0.0019), leptin (0.86 ± 0.16 ng/mL vs 0.45 ± 0.05 ng/mL, p<0.05), and adiponectin (19.2 ± 1.3 mg/mL vs 14.4 ± 1.0 mg/mL, p<0.05) and increased glucosuria (89 ± 8 mg/dL vs 4065± 400 mg/dL, p < 0.0001). In PCOS rats, EMPA did not affect BW (309.0 ± 11.0 g vs 293.7 ± 6.1 g, p=0.6288), cumulative FI (251.8 ± 8.5 g vs 261.1 ± 6.5 g, p=0.8123), or lean mass. In PCOS rats, EMPA did not affect fasting glycemia, fasting insulin (17.6 ± 1.3 mU/mL, p= vs 18.0 ± 1.7 mU/mL, p=0.9922), or insulin sensitivity through the quantitative insulin‐sensitivity check index (0.302 ± 0.003 vs 0.299 ± 0.003, p=0.8615). While causing increased glucosuria in PBO rats, EMPA did not affect fat mass, BW, cumulative food intake, lean mass, fasting glycemia, or insulin sensitivity. In summary, SGLT‐2 inhibition had beneficial effects on fat mass and leptin in PCOS‐like rats. This occurred in the absence of changes in food intake, fasting glycemia, and insulin sensitivity. This suggests that SGLT‐2 inhibition is exerting a positive impact on the cardiometabolic profile in female hyperandrogenemia via more than excessive loss of glucose in the urine alone. Therefore, EMPA could be a novel therapeutic approach to treat obesity in PCOS women to ameliorate the adverse cardiometabolic profile associated with this pathology. Support or Funding Information AHA 0830239N and 12SDG8980032, EFFERG, and NIH R21 DK‐113500 and P20 GM‐121334