Serum High Mobility Group Box 1 (HMGB1) levels are independently associated with glucose clamp-derived measures of insulin resistance in PCOS

Polycystic Ovary Syndrome (PCOS) is one of the most common endocrine disorders among women of reproductive age, and is characterised by chronic inflammation and in most cases by insulin resistance besides ovulatory dysfunction and hyperandrogenism. HMGB1 is a small protein with cytokine activity that can activate nuclear factor kappa light chain enhancer of activated B cells (Nf-kB), and signals through the Receptor for advanced glycation end products (RAGEs) and through the Toll like receptor family. HMGB1 is involved also with IR/hyperinsulinemia related diseases as diabetes type 2 and obesity, and its circulating concentrations have been reported to be higher in PCOS women with IR by us and in one previous study. The aim of the present study was to investigate the relationships between serum HMGB1 levels and clinical, endocrine and metabolic parameters of PCOS 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); 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. HMGB1 levels did not differ in PCOS women with respect to 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. HMGB1 blood levels showed an independent association with insulin resistance in women with PCOS. However, no associations with other typical features of the syndrome were found. Further research is needed to elucidate a possible role of this protein in the pathogenesis of PCOS.