Impairment of insulin receptor signal transduction in placentas of intra-uterine growth-restricted newborns and its relationship with fetal growth

Abstract

Objective: Intra-uterine growth restriction (IUGR) is related to a higher incidence of type 2 diabetes mellitus. We previously reported reduced adiponectin and increased interleukin 6 (IL6) concentrations in IUGR placentas, which are features of insulin resistance. We aimed to investigate placental insulin receptor (IR) function and activation in human placenta and subsequently the relationships of insulin signalling peptides with placental protein content in IL6, insulin, resistin and adiponectin, and with parameters of fetal growth. Design and methods: Whole villous tissue was collected from 18 IUGR and 24 appropriate for gestational age (AGA) placentas of comparable gestational age. Insulin signalling peptides, suppressors of cytokine signalling-2 (SOCS2), insulin, adiponectin, resistin, and IL6 concentrations were determined by using western immunoblotting or specific research kits. Results: The amount of total IR was similar in both groups but activated IR significantly higher in IUGR. Total IR substrate-1 (IRS1) was increased in IUGR, whereas total IRS2 and activated IRS1 were similar. AKT content was reduced and activated AKT was undetectable in IUGR placentas. c-Jun N-terminal kinase content was reduced in IUGR. Total and activated ERK1/2 was similar in IUGR and AGA groups, and total SOCS2 was increased in IUGR. IL6 lysate concentrations correlated with AKT content and activated IR. Correlations were found also with adiponectin and resistin. SOCS2 correlated negatively with all growth parameters at birth. Conclusions: IR was more activated in placentas of IUGR compared with AGA; however, signal transduction downstream of the receptor was impaired. The increase in activated IR could be in favour of a compensatory mechanism to increase insulin sensitivity. Close relationships of insulin action in placenta with fetal growth were shown.

Maternal and fetal genomes interplay through phosphoinositol 3-kinase(PI3K)-p110α signaling to modify placental resource allocation

“…5). These findings are important in the context of human pregnancy as dysregulated expression of both up-and down-stream components of the PI3K pathway has been reported in human placenta associated with abnormal fetal growth (44)(45)(46)(47)(48)(49)(50). Furthermore, our study highlights the usefulness of the PI3K α/+ mouse as a tool for investigating the role and mechanisms of maternal-fetal genomic interactions in determining feto-placental phenotype and the programming of subsequent offspring health.…”

The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming

“…It is well established that maternal insulin is dysregulated in pregnancies complicated by diabetes, obesity, undernutrition, and preeclampsia, and insulin resistance also occurs in the placentas from diabetic, preeclamptic, and growth-restricted pregnancies (Colomiere et al, 2009;Rademacher et al, 2007;Scioscia et al, 2006;Street et al, 2011). Maternal infection during pregnancy increases cytokines within the placenta and is predicted to disrupt insulin signaling due to the inhibitory effects of cytokines on insulin action (Aguirre et al, 2002;Sykiotis and Papavassiliou, 2001;Tanti and Jager, 2009).…”

The Role of Placental Nutrient Sensing in Maternal-Fetal Resource Allocation1

“…In the human placenta, GSK-3 is activated in pregnancies complicated by fetal growth restriction [96], but the underlying mechanisms remain unclear [96,104,105]. In addition, placental GSK-3 is activated in maternal nutrient restriction in the baboon, which is associated with downregulation of placental nutrient transporters, decreased circulating fetal levels of amino acids, and fetal growth restriction [27].…”

“…Both maternal undernutrition and overnutrition alter circulating levels of hormones and factors including insulin, IGF-I, adiponectin, and leptin. Mechanistic target of rapamycin complex 1 is activated by insulin and IGF-I, and placental insulin/IGF-I signaling is inhibited in IUGR [96,104,105]. In addition, leptin signaling activates and cortisol inhibits mTORC1 [2].…”