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Query: UMLS:C0011849 (diabetes)
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Intrauterine growth restriction is associated with a range of alterations in placental transport functions: the activity of a number of transporters is reduced (Systems A, L and Tau, transporters for cationic amino acids, the sodium-proton exchanger and the sodium pump), placental glucose transporter activity and expression are unchanged whereas the activity of the calcium pump is increased. In contrast, accelerated fetal growth in association to diabetes is characterized by increased activity of placental Systems A and L and glucose transporters. Evidence suggests that these placental transport alterations are the result of specific regulation and that they, at least in part, contribute to the development of pathological fetal growth rather than representing a consequence to altered fetal growth. One interpretation of this data is that the placenta functions as a nutrient sensor, altering placental transport functions according to the ability of the maternal supply line to provide nutrients. Placental transporters are subjected to regulation by hormones. Insulin up-regulates several key placental transporters and maternal insulin may represent a "good nutrition" signal to increase placental nutrient transfer and the growth of the fetus. Preliminary evidence suggests that placental mammalian target of rapamycin, a protein kinase regulating protein translation and transcription in response to nutrient stimuli, may be involved in placental nutrient sensing.
Placenta 2006 Apr
PMID:IFPA 2005 Award in Placentology Lecture. Human placental transport in altered fetal growth: does the placenta function as a nutrient sensor? -- a review. 1644 15

During pregnancy, the developing fetus is dependent on its mother for all nutritional requirements. It is not surprising, therefore, that variations in maternal nutrition can be reflected in alterations in fetal health and well-being. Interestingly, the changes can persist into adulthood and may result in increased risk of diseases such as diabetes, obesity and cardiovascular disease. The first observations of these phenomena resulted in the development of hypotheses collectively brought under the heading of "fetal" or, more recently, "developmental" programming. In this review, we will examine some of the animal models used to understand the mechanisms involved and attempt to determine whether there are common, "gatekeeper", pathways or genes, altered by the different nutritional stresses. We will concentrate primarily on nutrition related to post-natal development of hypertension and will restrict the review to studies in rodents, since that is where most of the mechanistic studies are being undertaken. Our conclusions are that, while there may well be some common gatekeeper pathways, there is also some diversity of mechanism which may contribute to the generation of the same or similar phenotypes.
Placenta 2006 Apr
PMID:Fetal programming: causes and consequences as revealed by studies of dietary manipulation in rats -- a review. 1653 23

Fetal overgrowth in pregnancies complicated by diabetes is the result of an increased substrate availability which stimulates fetal insulin secretion and fetal growth. However, despite strict glycemic control in modern clinical management of the pregnant woman with diabetes, fetal overgrowth remains an important clinical problem. Recent studies in vivo provide evidence for increased delivery of amino acids to the fetus in gestational diabetes (GDM) even when metabolic control is strict. This could be due to that truly normal maternal substrate levels cannot be achieved in diabetic pregnancies and/or caused by altered placental nutrient transport and metabolism. Studies in vitro demonstrate an up-regulation of placental transport systems for certain amino acids in GDM associated with fetal overgrowth. GDM is also characterized by changes in placental gene expression, including up-regulation of inflammatory mediators and Leptin. In type-I diabetes with fetal overgrowth the in vitro activity of placental transporters for both glucose and certain amino acids as well as placental lipoprotein lipase is increased. Furthermore, both clinical observations in type-I diabetic pregnancies and preliminary animal experimental studies suggest that even brief periods of metabolic perturbation early in pregnancy may affect placental growth and transport function for the remainder of pregnancy, thereby contributing to fetal overgrowth. Ultrasound measurements of fetal fat deposits and abdominal circumference as well as 3D ultrasound assessment of placental volume represent non-invasive techniques for in utero diagnosis of fetal and placental overgrowth. It is proposed that these methods represent valuable additions to the clinical management of the diabetic pregnancy. In conclusion, altered placental function may be a mechanism contributing to fetal overgrowth in diabetic pregnancies with apparent optimal metabolic control. It is proposed that detailed information on placental metabolism and transport functions obtained in vitro and in vivo represent a placental phenotype that provides important information and may facilitate diagnosis and improve clinical management of fetal overgrowth.
Placenta 2006 Apr
PMID:Placental transport and metabolism in fetal overgrowth -- a workshop report. 1654 22

Impaired glucose metabolism with diabetes may alter the expressions of proteoglycans (PGs), which may impair the biological functions of placenta. In this study, we investigated the expression of PGs and their conjugated glycosaminoglycan (GAG) composition in the placentas of mothers with gestational diabetes mellitus (GDM) and trophoblasts cultured in a high-glucose condition. The PGs by guanidine/HCl extraction and DEAE Sepharose fractionation followed by GAG degradation enzyme digestion analyses showed that the expression of chondroitin sulfate and/or dermatan sulfate (CS/DS) PGs was increased whereas the heparan sulfate (HS) PG was decreased in GDM placentas compared to controls. Western blot analyses demonstrated that the increased CS/DS PGs in GDM placentas were predominantly the small leucine-rich proteoglycans (SLRPs), decorin and biglycan. Increased mRNA expression level was consistently shown by quantitative real-time PCR. Immunohistochemistry indicated intensive staining of decorin and biglycan in the diabetic placenta with different localizations. Additionally, the basement membrane HSPG, perlecan was found to contain both CS/DS and HS in GDM placentas and plain HS in controls. Similar findings of PG alterations induced by hyperglycemia were observed in cultured trophoblast in a high-glucose condition. This study demonstrated that hyperglycemia induced not only the gene expressions of PGs but also alterations in the carried GAG type and composition.
Placenta
PMID:High glucose alters proteoglycan expression and the glycosaminoglycan composition in placentas of women with gestational diabetes mellitus and in cultured trophoblasts. 1663 Jun 54

The discovery of the peroxisome proliferator-activated receptors (PPARs) in 1990s provided new insights in understanding the mechanisms involved in the control of energy homeostasis and in cell differentiation, proliferation, apoptosis and the inflammatory process. The PPARs became thus an exciting therapeutic target for diabetes, metabolic syndrome, atherosclerosis, and cancer. Unexpectedly, genetic studies performed in mice established that PPARgamma are essential for placental development. After a brief description of structural and functional features of PPARs, we will summarize in this review the most recent results concerning expression and the role of PPARs in placenta and of PPARgamma in human trophoblastic cells in particular.
Placenta
PMID:PPARs and the placenta. 1683 93

Previously maternal and fetal alterations resembling human pre-eclampsia were induced in pregnant rats by injections of the angiogenesis inhibitor Suramin. These alterations were aggravated by maternal diabetes and partly rectified by vitamin E supplementation. In the present study we evaluated the morphology of placentae and kidneys in this model. Non-diabetic and streptozotocin-induced diabetic pregnant rats of two rat strains (U and H) were treated with Suramin or saline, and given standard or vitamin E-enriched food. On gestational day 20 one placenta and the left kidney of the mother were collected for morphological and stereological analysis. In the placental trophospongium Suramin treatment caused cysts, which were further enhanced by maternal diabetes. Vitamin E treatment had no effect on the vacuolization. In the placental labyrinth of the non-diabetic rats Suramin treatment restricted maternal placental blood volume and increased the interface between maternal and fetal circulation. These changes were reversed by vitamin E treatment. Diabetes increased slightly the interface between the circulations in both rat strains. Suramin treatment decreased the interface, and vitamin E further decreased the interface in the diabetic U rats, whereas neither treatment affected the maternal-fetal interface in the diabetic H rats. The kidneys of Suramin-treated and diabetic rats were heavier compared to controls. Suramin treatment and maternal diabetes damaged renal glomeruli to a similar extent. Vitamin E treatment diminished the Suramin- and diabetes-induced glomerular damage in U rats, but not in H rats. The average cell count per glomerulus was decreased by Suramin in the U rats. Vitamin E treatment did not affect cell number per glomerulus in any group. We conclude that Suramin-injected pregnant rats constitute a valid animal model for placental dysfunction and pre-eclampsia, also from the histological perspective. The present work supports the notion that one important effect of untreated maternal diabetes may be impaired placentation, leading to oxidative stress, morphological damage, and compromised placental function.
Placenta
PMID:Suramin-restricted blood volume in the placenta of normal and diabetic rats is normalized by vitamin E treatment. 1692 Jan 89

In this study, morphometric measures of placental terminal villi and villous vessels were compared in overt, as well as gestational diabetes mellitus, and mild hyperglycemia diagnosed by oral 100 g glucose tolerance test (100 g-OGTT) and glucose profile (GP). At delivery (gestational age> or =34 weeks) a total of 207 placentas were assigned to a control group (n=56) or to one of three groups complicated by mild hyperglycemia (n=51), gestational diabetes (n=59) and overt diabetes (n=41). Placenta samples were randomly selected for blind morphometric assessment with an image analyser. Morphometric measures obtained included area and number of terminal villi and their respective villous vessels. Statistical analyses were performed using the chi-square test, ANOVA and stepwise regression (p< or =0.05). Glycemic means were 86.2 mg/dL in controls, 98.9 mg/dL in mild hyperglycemia, 114.1 mg/dL in gestational diabetes and 122.1 mg/dL in overt diabetes. Our results show that abnormal maternal glycemic levels may change the placental morphometric characteristics related to materno-fetal exchanges.
Diabetes Res Clin Pract 2007 Oct
PMID:Morphometric study of placental villi and vessels in women with mild hyperglycemia or gestational or overt diabetes. 1736 67

Distinctive patterns of vascular cell adhesion molecule expression in early mouse decidua establish niches that recruit different subtypes of immune cells. In normal gestation day (gd)8 decidua, vascular cell adhesion molecule (VCAM)-1 and mucosal addressin cell adhesion molecule (MAdCAM)-1 occur in different regions enriched by uterine Natural Killer (uNK) cells and monocytes, respectively. UNK cells prepare endometrial spiral arteries for pregnancy-induced structural modifications, a process deficient in decidua of type 1 diabetic mice and women. In non-obese diabetic (NOD) mice, onset of insulitis coincides with islet expression of VCAM-1, MAdCAM-1 and peripheral lymph node addressin (PNAd), a molecule implicated in extravasation of human uNK precursor cells. We used immunohistochemistry to address the combined effects of diabetes and pregnancy on gd6 and 8 pancreatic and decidual expression of VCAM-1, MAdCAM-1 and PNAd and assessed the effect of diabetes on early uNK cell numbers. Normoglycemic (n) and diabetic (d) NOD and C57Bl/6 (B6) mice were studied. Pregnancy increased addressin expression in the pancreata of all mice with n- and d-NOD pancreata having stronger endothelial expression of VCAM-1, MAdCAM-1 and PNAd than B6. VCAM-1 expression was localized to uterine endothelium, including that of spiral arteries and was lower in d- than in n-NOD or B6 mice. MAdCAM-1 was localized to uterine endothelium and was lower in n- and d-NOD than in B6. PNAd expression was only observed in uterine epithelium and was stronger in d- than in n-NOD or B6. In all groups, only VCAM-1 had stronger expression in decidua than in pancreas. A mild elevation in uNK cells was present in n-and d-NOD mice at gd6 but not at gd8 when a higher proliferation index was found compared with B6. Thus, in type 1 diabetic gestations in mice, signals for the recruitment of circulating cells are reduced in uterus and elevated in pancreas.
Placenta 2008 Feb
PMID:Vascular addressins in the uterus and pancreas of type 1 diabetic mice in early pregnancy. 1803 9

Research on intrauterine growth restriction (IUGR) and subsequent development of obesity, type 2 diabetes and the metabolic syndrome is rapidly expanding, and potential implications for primary prevention are considerable. We have critically appraised one of the experimental animal models frequently used as mimic of human fetal growth restriction, which involves bilateral ligation of the uterine artery in rats (Lig). Our experimental study showed that Lig performed on day 17 of pregnancy neither leads to IUGR nor to neonatal catch-up growth, an important pathogenetic co-factor in humans. Meta-analysis of the literature revealed domination by studies in which Lig pups with IUGR were actively selected. Accordingly, publication bias is evident (p=0.007). Altered placental perfusion--the main cause of IUGR in humans in Western countries--neither led to IUGR nor to neonatal catch-up growth in Lig offspring, i.e., to none of the etiological factors of the human 'small baby syndrome'. Appropriate and reproducible rodent models of IUGR through decreased placental flow remain to be established to uncover the pathophysiological basis of the 'small baby syndrome'. This may lead to new strategies of primary prevention of diabetes, obesity, and the metabolic syndrome.
Placenta 2008 Mar
PMID:Intrauterine growth restriction in a rodent model and developmental programming of the metabolic syndrome: a critical appraisal of the experimental evidence. 1820 35

The placenta, in addition to its myriad of functions during development, is recognized as a target for the toxic actions of chemicals. Presentations in this workshop summarized the state of the science with respect to drug metabolizing enzyme expression and activity as well as drug transporter protein expression. Chemical induction of reactive oxygen species (ROS) formation was presented as a unifying mechanism potentially important in the development of teratogenesis, postnatal cancers, and diabetes.
Placenta 2008 Mar
PMID:Reactive oxygen species, diabetes and toxicity in the placenta - a workshop report. 1828 Oct 91


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