ESPE2024 Poster Category 2 Late Breaking (107 abstracts)
IRS-1 as a key point in the regulation of insulin-sensitivity in granulosa cells from PCOS women.
Veronica Buia 1,2 , Cecilia Catellani 1 , Stefania Croci 1 , Alessandro Zerbini 1 , Beatrice Righi 3 , Daria Morini 4 , Angela Falbo 4 , Alessia Nicoli 4 , Alessandro De Fanti 3 , Maria Teresa Villani 4 , Chiara Sartori 3 & Maria Elisabeth Street 5,6
1Unit of Clinical Immunology, Allergy and Advanced Biotechnology, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy. 2Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy. 3Unit of Pediatrics, Department of Mother and Child, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy. 4Fertility Centre, Department of Obstetrics and Gynaecology, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy. 5Department of Medicine and Surgery, University of Parma, Parma, Italy. 6Unit of Paediatrics, University Hospital of Parma, Parma, Italy
Background: Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder among women and is characterised by chronic low-grade inflammation, ovulatory dysfunction, hyperandrogenism, and often by insulin-resistance. However, little is really known on insulin/IGF signalling in PCOS ovaries. This study aim ed to investigate the amount of Insulin (IR) and IGF-I receptor type I (IGF-IR1) and their intracellular mediators in granulosa cells from PCOS women with respect to controls.
Methods: 28 women with PCOS [age: 34.8±4.2 yr; BMI: 25.4±5.5 kg/m2] diagnosed following the Rotterdam criteria, and 44 healthy controls [age: 37.7±4.3 yr; BMI: 23.4±4.3 kg/m2] were enrolled. Granulosa cells were isolated from follicular fluids and were lysed. Total protein content was quantified using a spectrophotometer. Total and phosphorylated insulin receptor (INSR) [pY1162/pY1163], total IGF1-receptor (IGF1R), total and phosphorylated AKT [pS473], total and phosphorylated ERK1 [pT202/pY204]- ERK2 [pT185/pY187], and phosphorylated IRS-1 [pS312] were measured by using specific ELISA kits. Moreover, due to the low amount of protein content obtained from each sample, a multiplex bead-based assay was performed in other 14 PCOS women and 14 controls in order to evaluate total and phosphorylated GSK3β [pS9], IRS1 [pS636], AKT [pS473], mTOR [pS2448], P70S6K [pT412], IR [pY1162/pT1163], PTEN [pS380], GSK3α [pS21], TSC2 [pS939], RPS6 [pS235/pS236], IGF1R [pY1135/pY1136], belonging to the Akt/mTOR pathway which is pivotal for insulin and IGF1R signaling. Student’s T-test and Fisher’s exact test were used to analyze the data.
Results: Phosphorylated IRS-1 was measurable in 9/21 PCOS patients and was undetectable in controls (P = 0.0002). Total and phosphorylated INSR, total IGF1R, total and phosphorylated AKT and total and phosphorylated ERK1-2 were similar in PCOS and controls. The multiplex analysis showed, however, that phosphorylated IGF1R (P = 0.02), IRS1 (P = 0.04), mTOR (P = 0.05), p70S6K (P <0.0001), INSR (P = 0.01), GSK3α (P = 0.02), and TSC2 (P = 0.01) were higher in PCOS with respect to controls. No differences were found in phosphorylated GSK3β, AKT, PTEN, RPS6 between PCOS and controls.
Conclusion: The phosphorylated fraction of IRS-1 observed in PCOS with both methodologies, methods suggests that IRS1 has a key role in the regulation of insulin-sensitivity in PCOS. Indeed, the increased phosphorylation at the Ser312 and Ser636 sites of IRS-1 is compatible with reduced insulin sensitivity.
Acknowledgments: This work was funded by the Italian Ministry of Health (grant number GR-2018-12367635 “Bando di Ricerca Finalizzata-Giovani Ricercatori 2018”).
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