Metformin and sitagliptin combination therapy ameliorates polycystic ovary syndrome with insulin resistance through upregulation of lncRNA H19

Insulin resistance (IR) is prevalent in women with polycystic ovary syndrome (PCOS). Improvement in insulin sensitivity remains one of the most effective treatment strategies for women with PCOS. This study aims to investigate the efficacy and potential mechanism of the combination therapy with metformin (DMBG) and sitagliptin (TECOS) in PCOS. To address this, insulin was used to treat rat ovarian granulosa cells to establish the cellular PCOS model. Insulin and human chorionic gonadotropin (HCG) were subcutaneously injected into SD rats to establish a rat model of hyperandrogenism with pathogenesis similar to PCOS. Our results showed that co-treatment with TECOS and DMBG attenuated the induced apoptosis and insulin resistance (IR) in PCOS model cells, and improved reproductive hormone disorders, ovarian polycystic changes, and IR of PCOS rats. Mechanistically, upregulation of H19 by H19-expressing lentiviruses enhanced efficacy of combination therapy. Furthermore, co-treatment with TECOS and DMBG induced H19 expression via suppressing the PI3K/AKT-DNMT1 pathway. Collectively, these findings demonstrate that combination treatment with TECOS and DMBG ameliorates PCOS with IR, at least partially, through upregulation of lncRNA H19.