IGF2 stimulates fetal growth in a sex- and organ-dependent manner.

BackgroundInsulin-like growth factor 2 (IGF2) is a key determinant of fetal growth, and the altered expression of IGF2 is implicated in fetal growth disorders and maternal metabolic derangements including gestational diabetes. Here we studied how increased levels of IGF2 in late pregnancy affect fetal growth.MethodsWe employed a rat model of repeated intrafetal IGF2 administration in late pregnancy, i.e., during GD19-GD21, and measured the consequences on fetal organ weight and expression of insulin/IGF-axis components.ResultsIGF2 treatment tended to increase fetal weight, but only weight increase of the fetal stomach reached significance (+33±9%; P<0.01). Sex-dependent data analysis revealed a sexual dimorphism of IGF2 action. In male fetuses, IGF2 administration significantly increased fetal weight (+13±3%; P<0.05) and weight of fetal stomach (+42±10%; P<0.01), intestine (+26±5%; P<0.05), liver (+13±4%; P<0.05), and pancreas (+25±8%; P<0.05). Weights of heart, lungs, and kidneys were unchanged. In female fetuses, IGF2 increased only stomach weight (+26±9%; P<0.05). Furthermore, gene expression of insulin/IGF axis in the heart, lungs, liver, and stomach was more sensitive toward IGF2 treatment in male than in female fetuses.ConclusionData suggest that elevated circulating IGF2 in late pregnancy predominantly stimulates organ growth of the digestive system, and male fetuses are more susceptible toward the IGF2 effects than female fetuses.

[Physiology of the GH-IGF axis]. / Fisiologia do eixo GH-sistema IGF.

Growth, the main characteristic of childhood and adolescence, has a similar pattern in the majority of the individuals. Genetic background and GH-IGF axis are the factors that directly influence this process. Pituitary GH acts on growth mainly through the regulation of IGF system. The IGFs (IGF-1 and IGF-2) are growth factors produced in the majority of the organs and body tissues. They have autocrine, paracrine and endocrine actions on metabolism and cell proliferation, growth and differentiation. The IGFs bind with high specificity and affinity to a family of 6 binding proteins, called IGFBPs (1 to 6) that modulate their bioactivity. Most of the known IGF actions are mediated via IGF type 1 receptor (IGF1R). In this article we are going to review the composition and regulation of the GH-IGF axis and the role of each component in the regulation of the growth process.

Fisiologia do eixo GH-sistema IGF / Physiology of the GH-IGF axis

O crescimento, principal característica da infância e da adolescência, apresenta padrão semelhante na maioria dos indivíduos. A herança genética e os componentes do eixo GH-IGF são os fatores que diretamente influenciam esse processo. O GH, produzido na hipófise, exerce sua ação sobre o crescimento mediante regulação do sistema IGF. Os IGFs (IGF-1 e IGF-2) são fatores de crescimento produzidos na maioria dos órgãos e tecidos do organismo, possuindo ações autócrinas, parácrinas e endócrinas sobre o metabolismo intermediário, proliferação, crescimento e diferenciação celular. Associam-se com elevado grau de especificidade e de afinidade à família de seis proteínas carreadoras, denominadas IGFBPs (IGFBP-1 a -6), as quais modulam suas bioati-vidades. A maioria das ações conhecidas dos IGFs é exercida mediante sua ligação com o receptor tipo 1 (IGF-1R). Neste artigo será revisada a composição e a regulação do eixo GH-sistema IGF, assim como a participação de cada um dos seus diferentes componentes no processo de regulação do crescimento humano.

Growth, the main characteristic of childhood and adolescence, has a similar pattern in the majority of the individuals. Genetic background and GH-IGF axis are the factors that directly influence this process. Pituitary GH acts on growth mainly through the regulation of IGF system. The IGFs (IGF-1 and IGF-2) are growth factors produced in the majority of the organs and body tissues. They have autocrine, paracrine and endocrine actions on metabolism and cell proliferation, growth and differentiation. The IGFs bind with high specificity and affinity to a family of 6 binding proteins, called IGFBPs (1 to 6) that modulate their bioactivity. Most of the known IGF actions are mediated via IGF type 1 receptor (IGF1R). In this article we are going to review the composition and regulation of the GH-IGF axis and the role of each component in the regulation of the growth process.

IGF-II regulates metastatic properties of choriocarcinoma cells through the activation of the insulin receptor.

Choriocarcinoma is a highly malignant tumor that can arise from trophoblasts of any type of gestational event but most often from complete hydatidiform mole. IGF-II plays a fundamental role in placental development and may play a role in gestational trophoblastic diseases. Several studies have shown that IGF-II is expressed at high levels in hydatidiform moles and choriocarcinoma tissues; however, conflicting data exist on how IGF-II regulates the behaviour of choriocarcinoma cells. The purpose of this study was to determine the contribution of the receptors for IGF-I and insulin to the actions of IGF-II on the regulation of choriocarcinoma cells metastasis. An Immuno Radio Metric Assay was used to analyse the circulating and tissue levels of IGF-I and IGF-II in 24 cases of hydatidiform mole, two cases of choriocarcinoma and eight cases of spontaneous abortion at the same gestational age. The JEG-3 choriocarcinoma cell line was used to investigate the role of IGF-II in the regulation of cell invasion. We found that mole and choriocarcinoma tissue express high levels of IGF-II compared to first trimester placenta. Both IGF-I and IGF-II regulate choriocarcinoma cell invasion in a dose dependent manner but through a different mechanism. IGF-II effects involve the activation of the InsR while IGF-I uses the IGF-IR. The positive effects of IGF-II on invasion are the result of enhanced cell adhesion and chemotaxis (specifically towards collagen IV). The actions of IGF-II but not those of IGF-I were sensitive to inhibition by the insulin receptor inhibitor HNMPA(AM)3. Our results demonstrate that the insulin receptor regulates choriocarcinoma cell invasion.

Involvement of insulin-like growth factors-I and -II and their receptors in medroxyprogesterone acetate-induced growth of mouse mammary adenocarcinomas.

The role of the insulin-like growth factors (IGFs) system was investigated in hormone-dependent (HD) and -independent (HI) in vivo lines of the medroxyprogesterone acetate (MPA)-induced mammary tumor model in Balb/c mice. IGF-II protein and message showed a three- to four-fold increase in HD lines growing in MPA-treated mice, as compared with HD tumors growing in untreated mice. Progression to a hormone-independent phenotype in all these lines was accompanied by a high constitutive expression of IGF-II. Similar IGF-I mRNA levels were detected in HD and HI lines. Both IGF-I and -II messages arose from the malignant epithelial cells, as shown by in situ hybridization studies. A significant decrease in Man-6P/type II IGF-R content was detected in HD tumors growing in MPA-treated mice as compared with HD lines growing in untreated mice. On the other hand, in HI tumors, notwithstanding high IGF-II synthesis, the levels of Man-6P/type II IGF-R remain high. Competitive inhibition and affinity labeling studies showed an almost exclusive binding of IGF-II to Man-6P/type II IGF-R on tumor membranes. The involvement of IGFs in the growth of epithelial primary cultures of the C4-HD line was evaluated. Exogenous IGF-I potentiated MPA stimulatory effect at concentrations of 50-100 ng/ml. Treatment of C4-HD cells with antisense oligodeoxynucleotides (ASODNs) to type I IGF-R and to IGF-II RNA resulted in a dose-dependent inhibition of MPA-mediated cell proliferation. The inhibition caused by IGF-II ASODNs could not be overcome by the addition of IGF-II up to 150 ng/ml. ASODNs to type I IGF-R at 40 microg/ml reduced by 75% the number of type I IGF-R; ASODNs to IGF-II at 1 microM decreased by 83% the levels of IGF-II protein. Our results provide support for the involvement of IGF-I and -II in MPA-induced mammary tumor growth by autocrine pathways.

Niveles séricos materno y neonatales de insulina y factores de crecimiento insulino-similes I y II (IGF y II) en la altura y a nivel del mar / Serum maternal and neonates levels of insuline and grow factors insuline-simil I and II (IGF and II) at high altitude and sea level

El presente estudio se ha diseñado para determinar los niveles de IGF-I en insulina en gestantes durante la labor del parto y en recién nacidos. Para tal efecto se han estudiado diez mujeres de ambas altitudes apareadas por edad, paridad, peso y talla. Ellas fueron estudiadas durante la labor del parto. La IGF-I e IGF-II fueron medidas por radioinmunometría (IRMA) e insulina por radioinmunoensayo (RIA) en suero materno y en sangre de cordón de los productos. En relación a las mujeres del nivel del mar, las concentraciones séricas de IGF-I e Insulina de las mujeres de altura fueron menores, 78.3 + 45.3 vs 455.2 _ 499.1 ng/ml(p es igual a 0.029) y 11.3 + 7.3 vs 22.9 + 15.1 uU/ml(p es igual a 0.045), respectivamente. No se encontró diferencia en IGF-II. La relación peso placentario/peso neonatal fue mayor en la altura, 0,18 + 0.03 vs 0,15 + 0,025 (p es igual a 0.026). No hubo diferencia por efecto de la altura en los niveles séricos neonatales de IGF-I, IGF-II ni insulina. La IGF-I correlacionó con el peso al nacer en ambas altitudes, NM: r es igual a 0.87 (p es igual a 0.005), altura: r es igual a 0.97 (p es igual a 0.0001), e insulina cortrelacionó con el peso al nacer en NM, r es igual a 0.82 (p es igual a 0.024), no siendo significativa esta correlación en la altura, r es igual a 0.60 (p es igual a 0.065); valor marginal, probablemente por el tamaño de la muestra. Se concluye que el menor peso del recién nacido en la altura puede deberse a los menores niveles de IGF-I e insulina.