The role of insulin-like growth factors in the fetus

Abstract

Fetal substrate supply is important in the regulation of fetal growth. The insulin-like growth factors (IGFs), insulin and placental lactogen (PL) may be important mediators in fetal growth regulation. However, nutritional regulation of circulating concentrations of IGFs, their binding proteins (IGFBPs) and PL during fetal life is poorly understood. The objective of this thesis is to characterise the influence of nutrition on the regulation of these hormones in the fetal circulation. Pregnant ewes were starved for 72 h and then refed for 48 h. After 48 h starvation fetuses were infused with glucose, amino acids or insulin while maternal starvation continued. Other fetuses of fed mothers were infused with recombinant oPL or IGF-I for 24 h. Fetal blood glucose, plasma IGF-I, IGF-II and insulin concentrations all fell on maternal starvation. Fetal plasma IGF-I and insulin concentrations returned to near control values on fetal infusion of glucose or insulin but not amino acids suggesting glucose had a more important role than amino acids in plasma IGF-I regulation and that insulin may have mediated the effect of glucose. Fetal plasma IGF-II concentrations returned to control values on fetal infusion of glucose, but not insulin. Thus fetal plasma IGF-I and IGF-II concentrations appear to be regulated differently by fetal glucose and insulin. Fetal plasma IGFBP-1 and Bp-2 levels increased, while fetal plasma IGFBP-3 and type 2 receptor levels decreased, on maternal starvation. Fetal infusion of glucose or insulin returned fetal plasma IGFBP-1 to near control levels. All fetal plasma IGFBPs were near control levels after maternal refeeding. Fetal plasma IGFBPs and type 2 IGF receptor levels were influenced by nutrition but IGFBP-2, Bp-3 and the circulating type 2 IGF receptor appear to be at least partly regulated by factors other than glucose and insulin. In a separate experiment fetal plasma IGF-I concentrations increased on IGF-I infusion to fetuses whose mothers were on a low plane of nutrition but did not increase in fetuses whose mothers were on a high plane of nutrition suggesting that increases in fetal plasma IGFBP concentrations on maternal starvation or undernutrition may increase fetal plasma IGF-carrying capacity. Plasma concentrations of PL in fetuses whose mothers had been on a high plane of nutrition was higher during starvation than in fetuses whose mothers had been on a low plane of nutrition. Fetal plasma PL concentrations increased 3-fold on maternal infusion of glucose at the end of starvation but was unaffected by fetal infusion of glucose at a lower rate. Fetal plasma PL responses to starvation were influenced by prior nutritional status. The rate of glucose infusion appears to determine the occurrence of a fetal plasma PL response. Fetal blood amino acid nitrogen (AN) concentrations fell on fetal infusion of oPL but fetal blood glucose, plasma IGF-I, IGF-II and insulin concentrations were unaffected. PL does not appear to have a role in the endocrine regulation of the IGFs in fetal sheep but may influence fetal amino acid metabolism. In these studies the fetal plasma concentrations of the IGFs, insulin, PL and plasma levels of IGFBP-1 to -4 have been demonstrated to be regulated by fetal substrate supply. These experiments provide further evidence that these hormones may be mediators in the regulation of fetal growth by fetal substrate supply.