Effect on insulin clearance of different pharmacological treatments in women with polycystic ovary syndrome: a hypothesis-generative study

Purpose: Impaired insulin clearance has been found in women with PCOS and contribute to generate hyperinsulinemia in these subjects. However, the mechanisms underlying this phenomenon remain unknown. The aim of this retrospective study was to explore if the heterogeneous treatments used in these patients to counteract their hormonal and metabolic alterations can also affect insulin clearance. Methods: Forty-seven women with PCOS were included in the study. They belonged to different experimental groups, submitted to treatments with the following drugs: GnRH-agonist (buserelin, n = 10), antiandrogens (spironolactone, n = 9), metformin (n = 18), or placebo (n = 10). Metabolic clearance rate of insulin (MCRI) and insulin sensitivity were measured by the hyperinsulinemic euglycemic clamp, performed before and after treatment. Insulin secretion was estimated by the HOMA β-index. Results: Treatments were associated, as expected, with different clinical effects. In ANOVA analysis, changes in MCRI significantly differed between treatment groups. In particular, metformin increased MCRI as compared with other treatments or placebo. Mediation analysis showed that about 25% of this effect of metformin was mediated by the concurrent BMI change, whereas it was not influenced by changes in peripheral insulin sensitivity or insulin secretion. Conclusion: The impairment of MCRI, which contributes to the hyperinsulinemia typical of PCOS, significantly improved after treatment with metformin. This effect was only partially explained by the reduction of BMI, whereas changes in insulin sensitivity did not show a mediation effect in this phenomenon, suggesting that other metformin-induced mechanisms are involved.