EFFECT OF IN UTERO ANDROGEN EXCESS ON OVARIAN INSULIN SIGNALING. ROLE OF METFORMIN TREATMENT.

FERREIRA, SILVANA ROCÍO; ALICIA BEATRIZ MOTTA; ABRUZZESE, GISELLE ADRIANA; HEBER, MARÍA FLORENCIA; VEGA, MARGARITA

Concon

Congreso; XXIX reunión anual de la SCHRD; 2018

SCHRD

Insulin resistance is the decreased ability of insulin to mediate metabolic actions. Insulin controls ovulation and oocyte quality. Alterations on ovarian insulin signaling pathway, that inhibits glucose uptake, could compromise ovarian physiology. We aimed to investigate the effects of in utero androgen excess on ovarian insulin signaling pathway and evaluate the effect of metformin treatment. Pregnant rats were hyperandrogenized with 1mg of testosterone during days 16-19 of gestation; at adulthood prenatally hyperandrogenized (PH) female offspring, presented 2 phenotypes: oligo-ovulatory (PHiov) and anovulatory (PHanov), a third group without treatment was the control group. Half of each group was treated orally from day 70-90 of life with 50 mg/kg of metformin. After metformin treatment estral cyclycity was recovered in PHiov and partially in PHanov. Both PH groups presented systemic insulin resistance, that was reverted by metformin treatment. Protein expression of IR, IRS-1/2 and Glut4 were decreased in both PH groups. In the PHiov group metformin restored expression of all the mediators, whereas in the PHanov group only IR and IRS-1/2. IRS-1 phosphorylation was measured in tyrosine residues which activate the pathway and in serine residues which impairs insulin action. PHiov group presented high IRS-1 phosphorylation on tyrosine and serine residues. In contrast, PHanov showed augmented serine phosphorylation and low tyrosine phosphorylation. Metformin treatment lowered serine phosphorylation only in PHanov group. Our results suggest that PHanov group has a defective insulin action that's partially restored with metformin. The PHiov group has less severe alterations and metformin treatment results more effective in this phenotype.