Insulin-related genes expressed in human placenta from normal and diabetic pregnancies.

Abstract

Rapid growth of human fetal tissues requires insulin or insulin-like growth factors. A high rate of human fetal growth occurs between implantation and about 14 weeks of gestation. Fetal pancreatic insulin secretion begins much later. Since maternal insulin does not cross the blood/placental barrier, other sources of insulin or insulin-like growth factors may be provided for fetal development. We report here that placental polyadenylylated RNAs from the first and third trimester of normal pregnancy as well as from term pregnancies of diabetic mothers hybridize to a 32P-labeled cloned cDNA of an insulin-related sequence expressed in fetal pancreas. Moreover, placentas from diabetic women express much more of these sequences. These results suggest that insulinrelated genes are expressed in placental tissue during fetal development and may be a source of growth-promoting hormones for the human fetus. Fetuses developing in diabetic women receive a large influx of glucose. This in turn may stimulate the expression of insulin-related sequences, which may result in higher utilization of glucose, thus bringing about the macrosomia and high incidence of malformation and stillbirths known to result from pregnancies in diabetics.During the first 10 weeks of embryonic and fetal life, which is a critical period of rapid growth for the human conceptus, primary and secondary embryonic induction and organogenesis is taking place (1). Glucose is used as a major source of metabolic energy in the human fetus (2-4) and a glucose imbalance, in addition to affecting the growth of embryonic tissue, may well result in developmental abnormalities such as macrosomia, malformations, and increased rate of stillbirths, as is manifested in pregnancies of diabetic women. Insulin, a regulator of glucose metabolism, is an essential growth factor for fast-growing mammalian tissues, including human embryonic tissues (2-4); however maternal insulin does not cross the blood/placental barrier (5-8). Although it has not been established that insulin or an insulin-like growth factor is necessary for the early development of the human fetus in utero, such a requirement is not unlikely.Explants of multiple tissues from fetal mouse synthesized insulin-like somatomedin (9). The production of the insulinlike growth factors IGF-I and IGF-II is developmentally regulated, and this pattern of expression is maintained in fibroblasts derived from fetal as well as older rats (10). Receptors for insulin-like growth factors (IGF-I, IGF-II, somatomedin A, and multiplication-stimulating activity) and insulin are present in human fetal tissues at different stages of development (11). This evidence suggests that fetal growth may be regulated by insulin and/or insulin-like growth factors.The fetal pancreatic islets of Langerhans are capable of insulin synthesis only after 14 weeks of gestation, several weeks later than the critical growth period mentioned above. Further, the fetal pancreas normally exhibits only limited responses to acute changes in cord blood gl...

Expression of Messenger RNA of Insulin-Like Growth Factors (IGFs) and IGF Binding Proteins (IGFBP1-6) in Placenta of Normal and Diabetic Pregnancy.

“…There was a higher expression of GF-II mRNA in placentas from diabetic mothers than in those from normal mothers (P<0.05), which is consistent with a previous report stating that insulin-related gene expression in the placenta is higher in diabetic patients [6]. IGF-I mRNA expression was also higher in diabetic mothers, but the difference was not significant.…”

“…RNAs of IGF-I, IGF-II and all species of IGFBPs (IGFBP- [1][2][3][4][5][6] were expressed in human placenta.…”

No loss of genomic imprinting of IGF-II and H19 in placentas of diabetic pregnancies with fetal macrosomia

“…Its concentration in cord blood is higher in children of diabetic mothers [25]. Furthermore, expression of IGF1 and IGF-II mRNA is more abundant in placental tissues from diabetic mothers [26]. This may be, at least in part, responsible for the higher placental weight and, thereby, for the higher birth weight in diabetic pregnancy, as fetal growth is closely related to placental growth.…”

Insulin-Like Growth Factors (IGFs) and IGF-Binding Proteins (IGFBP-1, -2 and -3) in Diabetic Pregnancy: Relationship to Macrosomia.

“…It has been established that both IGF-I and -II are produced not only in fetal tissues [30,40] but also by the placenta, suggesting an autocrine/paracrine role of IGFs in placental growth [41]. Furthermore, expression of the mRNA of IGFs is more abundant in placental tissues from diabetic mothers [42]. This may be, at least in part, responsible for the higher placental weight and, thereby, for the higher birth weight in diabetic pregnancy, since fetal growth is closely coupled to placental growth.…”