Serum Soluble Glycoprotein 130 Concentration Is Inversely Related to Insulin Sensitivity in Women With Polycystic Ovary Syndrome

OBJECTIVE

Insulin resistance might play a role in the pathogenesis of polycystic ovarian syndrome (PCOS). The family of glycoprotein 130 (gp130) cytokines could influence insulin action. One of these cytokines is interleukin (IL)-6, which exerts a short-term insulin-sensitizing effect, whereas in a long-term period, it might induce insulin resistance. Some other gp130 activators are supposed to have beneficial metabolic effects. Gp130 is present in the circulation in the soluble form (sgp130), which inhibits intracellular gp130 signaling. The aim of the present study was to estimate the relation between sgp130 and insulin sensitivity in women with PCOS.

RESEARCH DESIGN AND METHODS

We studied 78 women with PCOS (35 lean and 43 obese) and 34 healthy women (18 lean and 16 obese). The euglycemic-hyperinsulinemic clamp and the measurements of serum sgp130, IL-6, soluble IL-6 receptor (sIL-6R), and sex hormones were performed.

RESULTS

Both obesity and PCOS were characterized by an increased sgp130 (P < 0.0001 and P = 0.0002, respectively). sIL-6R concentration was lower (P = 0.0036) in women with PCOS independently of obesity. Serum sgp130 was negatively correlated with insulin sensitivity when control and PCOS women were analyzed together (r = −0.36, P < 0.0001) and in the PCOS subjects separately (r = −0.34, P = 0.002). In multiple regression analysis, this correlation was significant after adjustment for BMI, waist, percent of body fat, postload glucose and insulin, triglycerides, and high-sensitive C-reactive protein.

CONCLUSIONS

Serum sgp130 is inversely and independently associated with insulin sensitivity in women with PCOS. An increased serum sgp130 in obesity and PCOS suggests an inhibition of intracellular gp130 signaling in insulin-resistant conditions.Polycystic ovarian syndrome (PCOS) is a common endocrine disorder with a diverse and heterogeneous nature that is present in 5–10% of reproductive-age women. PCOS is characterized by hyperandrogenism and chronic anovulation (1,2). Insulin resistance is a common feature of PCOS and might be the cause of significant metabolic and cardiovascular complications observed in this condition (3).The family of glycoprotein 130 (gp130) cytokines might influence insulin action (4). This family includes interleukin (IL)-6, IL-11, leukemia inhibitory factor, ciliary neurotrophic factor, oncostatin, and cardiotrophin-1 (5). Gp130 cytokines play a pivotal role in the regulation of the immune, hematopoietic, nervous, cardiovascular, and endocrine systems (5). These cytokines exert their actions through a heterodimeric or homodimeric receptor consisting of two membrane-bound glycoproteins: a cytokine binding subunit and a glycoprotein termed IL-6 transducer, or IL6ST, also known as gp130, which is responsible for signal transduction (6).IL-6 was thought to be an insulin-desensitizing factor (7). However, it might have some beneficial metabolic actions, and it was hypothesized that it exerts a short-term insulin-sensitizing effect, whereas in the long-term period, IL-6 might induce insulin resistance (8). IL-6 increased glycogen synthesis and enhanced lipid oxidation via an AMP-activated protein kinase (AMPK)-dependent mechanism in skeletal muscle (9). Another gp130 cytokine, ciliary neurotrophic factor, prevented weight gain and stimulated AMPK in skeletal muscle (10). Therefore, it is supposed that gp130 activators might be useful in the treatment of obesity and insulin resistance (4). Gp130 is expressed in most cells of the body (6) and is present in the circulation in soluble form (sgp130), which inhibits intracellular gp130 signaling (11). The role of sgp130 in the pathogenesis of human insulin resistance has not been studied so far.Soluble form of the IL-6R (sIL-6R) occurs in various body fluids and might induce gp130 dimerization and signaling when complexed with IL-6. The presence of sIL-6R leads to sensitization of IL-6–responsive cells toward the ligand (12). The IL-6/sIL-6R complex stimulates several types of cells that only express gp130 and are unresponsive to IL-6 alone. This process is called trans-signaling (13). Sgp130 exerts also inhibitory effects toward the IL-6/sIL-6R complex (14).We hypothesized that serum spg130 might be altered in insulin-resistant conditions in humans and might be related to insulin sensitivity. To test this hypothesis, we studied serum sgp130, IL-6, and sIL-6R in relation to insulin sensitivity in lean and obese women with PCOS and BMI-matched healthy control subjects.