Insulin signalling and glucose transport in the ovary and ovarian function during the ovarian cycle

Abstract

Data derived principally from peripheral tissues (fat, muscle and liver) show that insulin signals via diverse interconnecting intracellular pathways and that some of the major intersecting points (known as critical nodes) are the IRSs (insulin receptor substrates), PI3K (phosphoinositide kinase)/Akt and MAPK (mitogen-activated protein kinase). Most of these insulin pathways are probably also active in the ovary and their ability to interact with each other and also with follicle-stimulating hormone (FSH) and luteinizing hormone (LH) signalling pathways enables insulin to exert direct modulating influences on ovarian function. The present paper reviews the intracellular actions of insulin and the uptake of glucose by ovarian tissues (granulosa, theca and oocyte) during the oestrous/menstrual cycle of some rodent, primate and ruminant species. Insulin signals through diverse pathways and these are discussed with specific reference to follicular cell types (granulosa, theca and oocyte). The signalling pathways for FSH in granulosa cells and LH in granulosa and theca cells are summarized. The roles of glucose and of insulin-mediated uptake of glucose in folliculogenesis are discussed. It is suggested that glucose in addition to its well-established role of providing energy for cellular function may also have insulin-mediated signalling functions in ovarian cells, involving AMPK (AMP-dependent protein kinase) and/or hexosamine. Potential interactions of insulin signalling with FSH or LH signalling at critical nodes are identified and the available evidence for such interactions in ovarian cells is discussed. Finally the action of the insulin-sensitizing drugs metformin and the thiazolidinedione rosiglitazone on follicular cells is reviewed.

Periovulatory insulin signaling is essential for ovulation, granulosa cell differentiation, and female fertility

“…Thus, synergy between FSH and insulin signaling in antral follicles and the potential role of insulin signaling in response to subsequent LH stimulation could not be examined. Several studies indicate that INSR signaling is subject to cross talk between FSH and LH receptor signaling, through common signaling mediators, that has varying physiological consequences in different stages of follicle growth . For example,…”

“…7,8 Regardless of ligand, activation of INSR and IGF1R initiates a conserved cascade of phosphorylation events mediated by the Ras-MAPK and AKT/PI3K pathways. 1,6 Thus, the in vivo action of insulin signaling may be better examined by ablation of the receptors rather than combinations of ligand and binding protein mutations.…”

“…Several studies indicate that INSR signaling is subject to cross talk between FSH and LH receptor signaling, through common signaling mediators, that has varying physiological consequences in different stages of follicle growth. 6 For example, FSH-dependent activation of the AKT/PI3K pathway in granulosa cells of antral follicles boosts steroidogenesis. 20 However, it subsequently stimulates follicular atresia in non-ovulatory follicles.…”

<b>Papel da insulina sobre a esteroidogênese no corpo lúteo canino</b>

“…Mensuração de estradiol (pg/ml) em meio de cultura sob estímulo insulínico (100 ng/ml (FRANÇA et al, 2015), no folículo e CL de vacas (NISHIMOTO et al, 2006) e no CL canino (PORETSKY et al, 1999;FAN et al, 2009;SETO-YOUNG et al, 2011;KIM et al, 2015;SCARAMUZZI, 2016) KLEIN, 1996). Assim, a luteólise ocorre apesar de um aumento na disponibilidade de hormônios gonadotróficos, hormônios estes considerados luteotróficos, portanto, mecanismos parácrinos e/ou autócrinos devem estar envolvidos no controle da função luteínica e precisam ser elucidados.…”

“…Os efeitos da insulina nos tecidos reprodutivos já foram estudados por diversos grupos que demonstraram que esta molécula está envolvida com a produção de esteroides em diferentes espécies (PORETSKY et al, 1999;FAN et al, 2009;SETO-YOUNG et al, 2011;KIM et al, 2015;SCARAMUZZI, 2016).…”