Circulating plasma pigment epithelium-derived factor (PEDF) levels are associated with insulin resistance in women with estrogen deficiency

Abstract

Pigment epithelium-derived factor (PEDF) is implicated in murine insulin resistance and metabolic dysfunctions. Women have lower serum PEDF levels and 17β-estradiol inhibits the transcription of PEDF in human ovarian epithelial cells. To investigate whether estradiol regulates PEDF in vivo, we studied the changes in PEDF levels in 21 pre-menopausal women (age = 49.6 ± 3.5 years) following bilateral oophorectomy for benign gynaecological conditions. Body mass index (BMI), waist circumference (WC), percentage body fat, and plasma PEDF (ng/ml) and estradiol (pmol/l) levels were measured before and after oophorectomy. The changes (Δ) in PEDF, estradiol, homeostatic model assessment of insulin resistance (HOMA-IR) and quantitative insulin-sensitivity check index (QUICKI) were analyzed with repeated measure ANOVA. The mean duration between pre- and post-operative assessment was 4.0±0.7 months. BMI was marginally reduced in the post-operative period (25.2 ± 4.0 kg/m2 pre-op vs. 24.8 ± 4.3 kg/m2 post-op; p = 0.048). There were no significant changes in WC or percentage body fat The marked post-operative reduction in plasma estradiol levels (225 [109-418] pmol/l pre-op vs. 32 [19-50] pmol/l post-op; p < 0.001) was associated with increases in plasma PEDF levels (7.7 ± 1.6 ng/ml pre-op vs. 8.8 ± 1.5 ng/ml post-op; p = 0.001). An inverse relationship was found between Δestradiol and ΔPEDF (r = -0.497; p = 0.022). Insulin resistance increased post-operatively, as indicated by HOMA-IR (1.06 [0.73-1.93] pre-op vs. 1.63 [1.06-2.26] post-op; p = 0.002) and QUICKI (0.38 ± 0.04 pre-op vs. 0.36 ± 0.03 post-op; p = 0.006). ΔHOMA-IR and ΔQUICKI became insignificant (p = 0.101 and 0.141 respectively) after adjusting for ΔPEDF. In conclusion, the reduction in plasma estradiol levels following oophorectomy was significantly associated with increases in plasma PEDF levels and insulin resistance. Our data suggest that estradiol is a physiological regulator of PEDF expression in humans and that an increase in circulating PEDF contributes to the increase in insulin resistance in these women with estrogen deficiency following bilateral oophorectomy.