MON-028 Chronic Resveratrol Exposure Improves Glucose Homeostasis and Cardiac Function in a Rat Model of Polycystic Ovarian Syndrome

Abstract

Polycystic ovary syndrome (PCOS) is the commonest endocrinopathy in women of reproductive age, with a prevalence of 5-8%. Long-term complications seen in PCOS include cardiovascular disease and type 2 Diabetes Mellitus. Current therapies do not completely address the cardiometabolic perturbations seen in women with PCOS. Resveratrol (RSV), a natural polyphenol, is shown to have beneficial cardio-metabolic effects in various pathological conditions including that on insulin sensitivity, cardiovascular function. In-vitro studies suggest it’s beneficial effects on ovarian function as well. Therefore, we hypothesized that chronic exposure to RSV would improve both cardiovascular and metabolic phenotypes in PCOS. To test this hypothesis we used an established rat model of PCOS that develops metabolic derangement and irregular cycles. A 7.5 mg (90-day release) dihydrotestosterone (DHT) pellet providing a daily dose of 83 mcg was implanted in 5-week-old female rats. Studies were also conducted on littermate matched controls (C) with no DHT implant. A subgroup of the control and DHT treated rats (n=6 per group) received a 0.84 g/kg dose of resveratrol (RSV) in their chow starting at age 5 weeks. At 8 weeks, animals were weighed weekly (n=6 per group). Oral glucose tolerance test (OGTT n=6 per group) and cardiac echocardiogram (C n=12, C+RSV n=6, DHT n=10, DHT+RSV n=6) were conducted at 16-weeks of age. Body weight increased significantly in DHT treated rats compared to C between 8 and 16 weeks (40 vs 22 grams, p <0.001). RSV treatment did not mitigate the effects of DHT on body weight (34 vs 40 grams, p>0.5). There was significantly higher glucose excursion at 30 minutes post glucose load in both DHT (148± 7.4 mg/dl) and DHT+RSV (139± 7.4 mg/dl) compared to C group (121± 13 mg/dl, p<0.001, p=0.03 respectively). However, by 60 and 90 minutes only DHT group had a significantly higher glucose excursion compared to both DHT+RSV and C groups (131± 4.1,124± 5.7,110 ± 5.9 mg/dl, p=0.015,p=0.21 respectively); 90min (118±5.8,110±4.7,96±4.2 mg/dl, p<0.01,p=0.09 respectively). By 120 minutes, no significant difference in glucose levels existed between groups. Cardiac echocardiogram showed significantly lower mitral valve E/A ratio (and increased MV isovolumic relaxation time (IVRT) in DHT group compared to C. RSV treatment reversed these changes. In conclusion, RSV improved glucose homeostasis and diastolic dysfunction in the DHT induced rodent model of PCOS and may serve as a novel treatment option targeting the cardiometabolic derangement seen in PCOS. Further studies elucidating the mechanisms underlying the beneficial effects of RSV on cardio-metabolic phenotype in this PCOS rodent model is warranted.