Metformin improves defects on ovarian insulin signaling caused by fetal programming

SILVANA FERREIRA; GISELLE ADRIANA ABRUZZESE; OMAR PIGNATARO; MARGARITA VEGA BLANCO; MARIA FLORENCIA HEBER; TRINIDAD RAICES; MOTTA, ALICIA BEATRIZ

JOURNAL OF ENDOCRINOLOGY

BIOSCIENTIFICA LTD

Lugar: Bristol; Año: 2019 vol. 3 p. 431 - 443

0022-0795

Insulin resistance is the decreased ability of insulin to mediatemetabolic actions. In the ovary, insulin controls ovulation and oocyte quality.Alterations in ovarian insulin signaling pathway could compromise ovarianphysiology. Here, we aimed to investigate the effects of fetal programming onovarian insulin signaling and evaluate the effect of metformin treatment.Pregnant rats were hyperandrogenized with testosterone and female offspring ofthese dams were used; at adulthood, prenatally hyperandrogenized (PH) offspringpresented two phenotypes: irregular ovulatory (PHiov) and anovulatory (PHanov).Half of each group was orally treated with metformin. Metformin treatmentimproved the estrous cyclicity in both PH groups. Both PH groups showed lowmRNA levels of IR, IRS1 andGlut4. IRS2 wasdecreased only in PHanov. Metformin upregulated the mRNA levels of some of themediators studied. Protein expression of IR, IRS1/2 and GLUT4 was decreased inboth PH groups. In PHiov, metformin restored the expression of all themediators, whereas, in PHanov, metformin restored only that of IR and IRS1/2. IRS1phosphorylation was measured in tyrosine residues, which activates the pathway,and in serine residues, which impairs insulin action. PHiov presented high IRS1phosphorylation on tyrosine and serine residues, whereas PHanov showed highserine phosphorylation and low tyrosine phosphorylation. Metformin treatmentlowered serine phosphorylation only in PHanov rats. Our results suggest thatPHanov rats have a defective insulin action, partially restored with metformin.PHiov rats had less severe alterations, and metformin treatment was moreeffective in this phenotype.