Preconceptional Lipid-Based Nutrient Supplementation in 2 Low-Resource Countries Results in Distinctly Different IGF-1/mTOR Placental Responses

ABSTRACT Background Preconceptional maternal small-quantity lipid-based nutrient supplementation (SQLNS) improved intrauterine linear growth in low-resource countries as demonstrated by the Women First Preconception Maternal Nutrition Trial (WF). Fetal growth is dependent on nutrient availability and regulated by insulin-like growth factor 1 (IGF-1) through changes in placental transfer capacity, mediated by the mechanistic target of rapamycin (mTOR) pathway. Objectives Our objective was to evaluate the role of placental mTOR and IGF-1 signaling on fetal growth in women from 2 low-resource countries with high rates of stunting after they received preconceptional SQLNS. Methods We studied 48 women from preconception through delivery who were from Guatemala and Pakistan and received SQLNS or not, as part of the WF study. Placental samples were obtained at delivery (control, n = 24; SQLNS, n = 24). Placental protein or mRNA expression of eukaryotic translation initiation factor binding protein-1 (4E-BP1), ribosomal protein S6 (rpS6), AMP-activated protein kinase α (AMPKA), IGF-1, insulin-like growth factor receptor (IGF-1R), and pregnancy associated plasma protein (PAPP)-A, and DNA methylation of the IGF1 promoter were determined. Maternal serum IGF-1, insulin-like growth factor binding protein (IGFBP)-3, IGFBP-4, IGFBP-5, PAPP-A, PAPP-A2, and zinc were measured. Results Mean ± SEM maternal prepregnancy BMI differed between participants in Guatemala (26.5 ± 1.3) and Pakistan (19.8 ± 0.7) (P < 0.001). In Pakistani participants, SQLNS increased the placental rpS6(T37/46):rpS6 ratio (1.5-fold) and decreased the AMPKA(T172):AMPKA ratio. Placental IGF1 mRNA expression was positively correlated with birth length and birth weight z-scores. Placental PAPP-A (30-fold) and maternal serum zinc (1.2-fold) increased with SQLNS. In Guatemalan participants SQLNS did not influence placental mTOR signaling. Placental IGF-1R protein expression was positively associated with birth length and birth weight z-scores. SQLNS increased placental PAPP-A (40-fold) and maternal serum IGFBP-4 (1.6-fold). Conclusions In Pakistani pregnant women with poor nutritional status, preconceptional SQLNS activated placental mTOR and IGF-1 signaling and was associated with improved fetal growth. In contrast, in Guatemalan women SQLNS did not activate placental nutrient-sensing pathways. In populations experiencing childhood stunting, preconceptional SQLNS improves placental function and fetal growth only in the context of poor maternal nutrition. This trial was registered at clinicaltrials.gov as NCT01883193.

Download Full-text

Effects of Maternal Diabetes on Fetal Expression of Insulin-Like Growth Factor and Insulin-Like Growth Factor Binding Protein MRNAs in the Rat

Journal of Endocrinology ◽

10.1677/joe.0.147r005 ◽

1995 ◽

Vol 147 (2) ◽

pp. R5-R8 ◽

Cited By ~ 6

Author(s):

Randal D. Streck ◽

Veeraramani S. Rajaratnam ◽

Renata B. Fishman ◽

Peggy J. Webb

Keyword(s):

Growth Factor ◽

Mrna Expression ◽

Fetal Growth ◽

Fetal Liver ◽

Expression Patterns ◽

Maternal Diabetes ◽

Limb Bud ◽

Insulin Like Growth Factor ◽

Igf Binding Proteins ◽

Increased Risk

ABSTRACT Matemal diabetes is associated in humans and rats with an increased risk for fetal growth abnormalities and malformations. Therefore, the effect of maternal diabetes on expression of genes that regulate fetal growth and differentiation is of considerable interest. Developmental growth is regulated in part by the expression and availability of insulin-like growth factors (IGFs). Postnatal expression of a subset of the IGFs and IGF binding proteins (IGFBPs) has been demonstrated to be regulated in response to diabetes and other metabolic conditions. We used in situ hybridization to analyze the effect of maternal diabetes, induced by streptozotocin (STZ) prior to mating, upon prenatal rat IGF and IGFBP mRNA expression. At gestational day (GD) 14, the most striking effect of maternal diabetes on fetal IGF/IGFBP gene expression was a marked increase in the abundance of IGFBP-1 mRNA within the liver primordia of fetuses isolated from diabetic dams compared to age-matched controls. This upregulation cannot be entirely due to the approximately one-half-day delay in fetal development (based on limb bud staging) associated with maternal diabetes, as there was no gross difference in the level of IGFBP-1 mRNA between GD13 and GD14 control fetal livers. In contrast, the fetal mRNA expression patterns of IGF-I, IGF-II and IGFBP-2, -3, -4, -5 and -6 were not grossly altered by maternal diabetes. These data are consistent with the hypothesis that IGFBP-1 produced within the fetal liver and secreted into fetal circulation may play a role in regulating rat fetal growth.

Download Full-text

Effect of a high maternal dietary intake during mid-gestation on components of the utero-placental insulin-like growth factor (IGF) system in adolescent sheep with retarded placental development

Reproduction ◽

10.1530/reprod/118.2.407 ◽

2000 ◽

pp. 407-416 ◽

Cited By ~ 11

Author(s):

TS Gadd ◽

RP Aitken ◽

JM Wallace ◽

DC Wathes

Keyword(s):

Growth Factor ◽

Mrna Expression ◽

Maternal Nutrition ◽

Limit Of Detection ◽

Receptor Expression ◽

Insulin Like Growth Factor ◽

Placental Development ◽

Igf System ◽

Igf I ◽

Igfbp 3

The aim of the present study was to investigate the effects of administering a high plane diet during early to mid-gestation on the uterine and placental insulin-like growth factor (IGF) system and on systemic IGF-I concentrations in pregnant adolescent ewes with restricted placental growth. Embryos recovered from superovulated ewes inseminated by a single sire were transferred in singleton to the uterus of adolescent recipients. After transfer ewes were offered a high (H) or moderate (M) amount of a complete diet calculated to promote rapid or normal maternal growth rates, respectively. Five ewes from each group were switched from either M to H or H to M diets at day 52 of gestation. Maternal and fetal blood samples and placental tissues were collected from all animals at day 104. Ewes on the high plane diet from mid-gestation (HH, MH groups) had restricted placental mass (P < 0.01) and tended to have smaller fetuses. This was associated with increased maternal plasma IGF-I concentrations (P < 0.001). The pattern of expression of components of the IGF system in the uterus and placenta was studied by in situ hybridization. IGF-I mRNA concentrations were below the limit of detection. IGF-II mRNA expression was high in the fetal mesoderm and present in maternal stroma, but was not influenced by nutritional treatment. In contrast, IGF binding protein 1 (IGFBP-1) mRNA expression was higher (P < 0.05) and IGFBP-3 mRNA expression was lower (P < 0.05) in the endometrial glands of ewes in HH and MH groups. In the fetal trophoblast, IGFBP-3 mRNA expression was higher in the MH group. Type 1 IGF receptor expression was increased (P < 0. 01) in the luminal epithelium of the HM group and IGFBP-2 mRNA expression was highest in the placentome capsule of ewes in the HH group. Together, these results indicate that reprogramming of the uterine and placental IGF axis by maternal nutrition could contribute to placental growth retardation in growing adolescent sheep.

Download Full-text

MATERNAL DIABETES INDUCES UPREGULATION OF HEPATIC INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN-1 MRNA EXPRESSION, GROWTH RETARDATION AND DEVELOPMENTAL DELAY AT THE SAME STAGE OF RAT FETAL DEVELOPMENT

Journal of Endocrinology ◽

10.1677/joe.0.152r001 ◽

1997 ◽

Vol 152 (1) ◽

pp. R1-R6 ◽

Cited By ~ 10

Author(s):

Veeraramani S. Rajaratnam ◽

Peggy J. Webb ◽

Renata B. Fishman ◽

Randal D. Streck

Keyword(s):

Growth Factor ◽

Mrna Expression ◽

Developmental Delay ◽

Fetal Growth ◽

Growth Retardation ◽

Fetal Development ◽

Growth And Development ◽

Maternal Diabetes ◽

Insulin Like Growth Factor ◽

Factor Binding

ABSTRACT Since maternal diabetes is associated with fetal growth abnormalities in humans and rats, effects of maternal diabetes on fetal expression of genes regulating growth are of interest. Increased expression of Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1) is associated with several examples of growth retardation and is upregulated in response to diabetes. As we have shown previously, IGFBP-1 expression is upregulated in gestational day (GD) 14 rat fetuses in response to maternal diabetes. Here we analyze the effect of streptozotocin-induced maternal diabetes on IGFBP-1 mRNA expression during GD12-16 of rat fetal development, using in situ hybridization. IGFBP-1 mRNA was more abundant in GD12-14 fetal livers from diabetic dams than in livers of age-matched controls. This upregulation is not due to the approximately 1-day fetal developmental delay associated with maternal diabetes, as there is no gross difference in the level of IGFBP-1 mRNA in GD13 vs GD12 or GD14 vs GD13 control fetal livers. At GD15-16, however, we detected little difference in IGFBP-1 expression between experimental and control fetuses. This transient period of maternal diabetes-stimulated IGFBP-1 mRNA expression (GD12-14) is coincident with the sensitive period for maternal diabetes-induced defects in fetal growth and development, suggesting that IGFBP-1 is involved in the regulation of fetal growth and development in response to the maternal condition.

Download Full-text

Maternal serum insulin-like growth factor binding protein-2 and -3 and fetal growth

Human Reproduction ◽

10.1093/humrep/14.7.1879 ◽

1999 ◽

Vol 14 (7) ◽

pp. 1879-1884 ◽

Cited By ~ 6

Author(s):

R.P. Holmes ◽

J.M.P. Holly ◽

P.W. Soothill

Keyword(s):

Growth Factor ◽

Fetal Growth ◽

Binding Protein ◽

Serum Insulin ◽

Maternal Serum ◽

Insulin Like Growth Factor ◽

Factor Binding

Download Full-text

Effects of refeeding of undernourished and insulin treatment of diabetic neonatal rats on IGF and IGFBP

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.271.2.e223 ◽

1996 ◽

Vol 271 (2) ◽

pp. E223-E231 ◽

Cited By ~ 6

Author(s):

L. Goya ◽

F. Rivero ◽

M. A. Martin ◽

R. Arahuetes ◽

E. R. Hernandez ◽

...

Keyword(s):

Growth Hormone ◽

Body Weight ◽

Growth Factor ◽

Mrna Expression ◽

Insulin Treatment ◽

Diabetic Rats ◽

Insulin Like Growth Factor ◽

Neonatal Rats ◽

Igf I ◽

Serum Gh

The effect of refeeding and insulin treatment of undernourished and diabetic neonatal rats, respectively, on the regulation of insulin-like growth factor (IGF) and insulin-like growth factor binding protein (IGFBP) was investigated. The changes in body weight, insulinemia, glycemia, serum IGF-I, and growth hormone (GH) as well as the increase of the 30-kDa IGFBP in undernourished and diabetic neonatal rats previously shown elsewhere were reversed by refeeding and insulin treatment, respectively. Also, changes in liver mRNA expression of IGF-I and-II and IGFBP-1 and -2 were restored in refed undernourished and IGF-I and IGFBP-1 levels recovered in insulin-treated diabetic rats. However, serum GH was still below normal after rehabilitation in both situations. Thus the present results support the idea of a GH-independent IGF/ IGFBP regulation mediated by a balance of insulin and nutrients as has already been suggested in previous neonatal studies.

Download Full-text