Maternal Diabetes Impairs Insulin and IGF-1 Receptor Expression and Signaling in Human Placenta

Abstract

BackgroundMaternal high blood glucose during pregnancy increases the risk for both maternal and fetal adverse outcomes. The mechanisms underlying the regulator effects of hyperglycemia on placental development and growth have not been fully illustrated yet. The placenta expresses high amounts of both insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R). It has been reported that the placenta of diabetic women has structural and functional alterations and the insulin/IGF system is likely to play a role in these changes. The aim of the present study was to measure the content of IR and IGF-1R and their phosphorylation in the placenta of women with type 1 diabetes mellitus (T1D) or with gestational diabetes mellitus (GDM) compared to women with normal glucose tolerance (NGT) during pregnancy.MethodsPlacental tissues were obtained from 80 Caucasian women with a singleton pregnancy. In particular, we collected placenta samples from 20 T1D patients, 20 GDM patients and 40 NGT women during pregnancy. Clinical characteristics and anthropometric measures of all women as well as delivery and newborn characteristics were recorded. Patients were also subdivided on the basis of peripartum glycemia either ≥90 mg/dl or <90 mg/dl, regardless of the diagnosis.ResultsIn T1D patients, a higher rate of adverse outcomes was observed. Compared to the GDM women, the T1D group showed significantly higher average capillary blood glucose levels at the third trimester of pregnancy and at peripartum, and higher third-trimester HbA1c values. In both T1D and GDM women, HbA1c values during pregnancy correlated with glucose values in the peripartum period (R-squared 0.14, p=0.02). A positive correlation was observed between phosphorylation of placental IR and the glucose levels during the third trimester of GDM and T1D pregnancy (R-squared 0.21, p=0.003). In the placenta of T1D patients, IGF-1R phosphorylation and IR isoform A (IR-A) expression were significantly increased (p=0.006 and p=0.040, respectively), compared to the NGT women. Moreover, IGF-1R phosphorylation was significantly increased (p<0.0001) in the placenta of patients with peripartum glucose >90 mg/dl, while IR-A expression was increased in those with peripartum blood glucose higher than 120 mg/dl (p=0.046).ConclusionsTo the best of our knowledge, our study represents the first one in which an increased maternal blood glucose level during pregnancy is associated with an increased IGF-1R phosphorylation and IR-A expression in the placenta. Both these mechanisms can promote an excessive fetal growth.

Immunoendocrine Dysregulation during Gestational Diabetes Mellitus: The Central Role of the Placenta

“…The deficit in the total protein levels of these mediators results in insufficient placental glucose uptake, and consequently in a hyperglycemic state [56,57]. Although, other authors did not observe differences in the total protein levels of placental IR and IRS-1 [54,58]. Considering these inconsistencies, we believe more studies are needed to clarify insulin signaling in GDM placentae and to understand how placental imbalance in these signaling pathways results in higher levels of inflammatory cytokines, adipokines and oxidative reactive species, insulin resistance, and vascular disorders, all of which prevail in the local placenta and peripheral tissues of GDM mothers.…”

“…Consequently, diminished levels of IGFBPs and IGFBP-rPs result in higher cord blood levels of free-IGF-I in GDM patients [ 75 ]. Further, the research group of Dr. Sciacca identified an increased phosphorylation pattern of IGF-1R in placentae from metabolic uncontrolled mothers with GDM and T2DM [ 58 ]. These changes support a persistently activated IGF-I signaling in GDM placentae by increased activity of free-IGF-I (see Figure 1 ).…”

Maternal, placental, and fetal Insulin-Like Growth Factor-I (IGF-1) and IGF Binding proteins (IGFBPs) in Diabetic pregnancies: Effects on fetal growth and birth size.

“…Both these mechanisms can promote excessive fetal growth. (40) Shang M et al studied placental tissues collected from 20 T1DM patients, 20 GDM patients, and 40 NGT women during pregnancy. They found that birth weights were positively correlated to maternal IGF1.…”

Knowledge, attitude, and practice of the 2009 Institute of Medicine (IOM) recommendations on the nutritional management of diabetes in pregnancy: an online national survey

“…Carbohydrates are the main source of energy even in pregnancy, their contribution, mainly provided by polysaccharides, must be equal to 45–60% of the energy total daily. In presence of diabetes, the dietary plan should also aim to reduce glycemic fluctuations, especially post-prandial excursions, to avoid ketosis and hypoglycemia in women on drug therapy, and allowing an optimal fetal growth [ 54 ].The IOM nutritional guidelines[ 18 ] and the Italian Recommended Dietary Allowance[ 55 ] advise to guarantee a carbohydrate content of not less than 175 g per day during pregnancy, to allow an adequate substrate for the brain, as this quantity reflects both maternal and fetal cerebral utilization of glucose. Therefore, considering Italian eating habits, national guidelines suggest a carbohydrate content of 40–50% of total energy, preferring foods with low-glycemic index [ 34 ].…”