Circulating HMGB1 Levels Are Associated With Glucose Clamp-Derived Measures of Insulin Resistance in Women With PCOS

Abstract

Abstract Context: High mobility group box 1 (HMGB1) is a nuclear constitutive and highly conserved mammalian protein which shows several important physiologic functions, playing a crucial role in local and systemic inflammation. It also seems to be implicated in the development of metabolic syndrome, whereas some in vitro and animal models and recent preliminary human studies suggested its potential role in polycystic ovary syndrome (PCOS) pathophysiology. In particular, some data suggested a potential role of HMGB1 in follicular maturation block. Moreover, increased blood and follicular fluid HMGB1 concentrations have been reported in PCOS women, showing a direct correlation with surrogate indexes of insulin-resistance (IR) (i.e. HOMA-IR). Objective: The purpose of the present study was to investigate the relationships between serum HMGB1 levels and clinical, endocrine and metabolic parameters of PCOS patients. Design and patients: Sixty women with PCOS, 30 with IR and 30 with normal insulin sensitivity (IS), and 30 healthy controls were included in the study. In these subjects, body fat was quantified by bioelectrical impedance; plasma HMGB1 levels were measured using a specific ELISA method (Tecan, Mannedorf, Switzerland); and serum androgens were measured by liquid chromatography/mass spectrometry and equilibrium dialysis. In PCOS women, IR was measured using the gold standard hyperinsulinemic-euglycemic clamp technique, combined with indirect calorimetry. Results: HMGB1 levels did not differ between PCOS women and healthy controls (4.11 ± 3.22 vs 3.77 ± 2.50 ng/mL, respectively; p=0.61). Moreover, HMGB1 levels did not differ between PCOS phenotype subgroups. However, PCOS IR women showed higher levels of this protein as compared with PCOS IS (5.00 ± 3.53 vs 3.16 ± 2.59 ng/mL, respectively; p=0.017). In women with PCOS, HMGB1 levels were associated with several metabolic parameters, including IR measured by glucose utilization during the clamp (rho -0.37, p=0.005). This correlation was preserved after adjusting for potential confounding parameters, such as age, fat mass and serum free testosterone. HMGB1 levels did not change during glucose-clamp induced acute hyperinsulinemia, either in the whole cohort of patients or in IR and IS subgroups analyzed separately. Both in the whole population under study and in PCOS women, HMGB1 levels did not correlate with anthropometric parameters, hormonal features and ovarian morphology. Conclusions: In women with PCOS, HMGB1 blood levels show an independent association with insulin resistance. However, no associations with other typical features of the syndrome were found. Further research is needed in order to establish whether this protein may play a role in the pathogenesis of PCOS.