mild placental insufficiency and gestational diabetes
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Mild placental insufficiency and gestational diabetes

After delivery, glycemia reverts to a normal state, making Lepr db mice a good model for GDM investigation. This model induced diabetes and obesity with hyperinsulinemia and hyperlipidemia, and females return to normal weight and glucose tolerance after gestation[ 57 ]. Goto Kakizaki GK is a rodent model of non obese type 2 diabetes that was produced by selective breeding of individuals with mild glucose intolerance from a non diabetic Wistar rat colony.

A stable and heritable DM is obtained by selection of a diabetic line isolated by repeated breeding of normal animals[ 58 ]. These rats are not obese and not hyperinsulinemic. Offspring of GK females is exposed in utero to mild diabetes throughout gestation. Thus, maternal mild hyperglycemia might contribute to endocrine pancreas defects in the first offspring generation. The feto-placental expression of insulin, IGF1, IGF2 and their receptors is regulated in a tissue-specific manner and can be affected by nutritional and endocrine conditions[ 59 ].

Hiden et al[ 60 ] have demonstrated that there is a spatio-temporal change in placental insulin receptor IR expression, suggesting a shift in the regulation of placental insulin effects from mother to fetus. In the first trimester, IR is predominantly expressed on the syncytiotrophoblast facing the maternal circulation, whereas at term, the placental endothelial cells facing the fetal circulation are the main expression site.

They are key modulators of the ligand-receptor interaction. Fetal cord blood data suggest that these binding proteins may be dysregulated by diabetes during pregnancy[ 62 ]. The endocrine interaction between mother, fetus and placenta is exemplified by the effect of maternal and fetal insulin on the placenta. Maternal insulin affects placental development via receptors expressed on the microvillous membrane of the syncytiotrophoblast[ 21 ].

Fetal insulin affects gene expression in endothelial cells from placental arteries and veins, which will affect placental development. The spatio-temporal change of IR expression in the placenta allows a shift in the control of insulin regulation from the mother to the fetus. In the first trimester, maternal insulin influences the placenta by interaction with trophoblast IRs.

This may in turn affect the mother by secretion of other factors as cytokines and hormones. Later, the fetus takes over control of insulin-dependent placental processes by fetal insulin interacting with placental endothelial cells. In addition, in the first trimester, IGF1 and IGF2 produced by trophoblasts stimulate various processes that are involved in trophoblast invasion into the maternal uterus such as invasiveness, migration, MMP2 production, proliferation and MT1-MMP expression.

Hence, in GDM, transplacental amino acid transport and fetal growth may be promoted by the diabetes-associated increase in maternal concentrations of growth factors. Changes can also be seen in the fetal circulation. However, the consequences of these changes for the fetus remain unclear. The extensive cross-talk between insulin and leptin signaling cascades may represent a major factor to the diabetes-induced placental changes.

In humans, leptin levels correlate with adiposity. This hormone has different functions such as stimulation of angiogenesis, regulation of hematopoiesis and inflammatory response[ 65 ]. The leptin receptor is expressed in the syncytiotrophoblast. Hauguel-de Mouzon et al[ 65 ] have shown that leptin induces hCG production, enhances mitogenesis, stimulates amino acid uptake and increases the synthesis of extracellular matrix proteins and metalloproteinases.

So leptin plays a role in the regulation of placental growth. However, hyperleptinemia contributes to other placental modifications in the case of diabetes as basement membrane thickening owing to its ability to alter collagen synthesis[ 66 ]. Hiden et al[ 67 ] have proposed a hypothetical model for diabetes-induced alterations in human placenta.

Maternal hyperglycemia induces thickening of the placental basement membrane, hence reducing oxygen transport. Increased levels of placental leptin may even further contribute to the excessive extracellular matrix synthesis. These modifications in the feto-placental compartment are characteristic of GDM, overt diabetes or both[ 67 ]. The nature and extent of these changes depend on the type of diabetes and on the gestational period.

For a complex disease syndrome, no animal model can be expected to serve all needs of research. Although each animal model has limitations and strengths, used together in a complementary fashion, they are essential for research on the metabolic syndrome and for rapid progress in understanding the etiology and pathogenesis towards a cure. Animal models have shown convincingly that diabetes may be transmitted by intrauterine exposure to maternal hyperglycemia.

Intrauterine exposure to mild hyperglycemia is associated with normal weight or macrosomic newborns and IGT at adult age, related to a deficient insulin secretion. In contrast, a newborn offspring of severely hyperglycemic mothers is microsomic and displays, at adult age, a decreased insulin action. In addition, long-term and persistent effects of gestational diabetes on glucose homeostasis in the offspring may be transmitted through generations.

These data support the concept of programming of physiological metabolism in offspring by manipulating maternal nutrition. It is known that hyperglycemia is not the only causal factor. Maternal and fetal concentrations of several growth factors, hormones and cytokines are altered in diabetes and may affect the placenta and the fetal development. It is thus necessary to identify the specific biological effects and the mechanisms underlying them.

International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Catalano PM. Obesity and pregnancy--the propagation of a viscous cycle? J Clin Endocrinol Metab. Simmons R. Developmental origins of adult metabolic disease.

Endocrinol Metab Clin North Am. Grattan DR. Fetal programming from maternal obesity: eating too much for two? Birth weight and non-insulin dependent diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype? Desoye G, Hauguel-de Mouzon S. The human placenta in gestational diabetes mellitus. The insulin and cytokine network.

Analysis of the collagens of diabetic placental villi. Cell Mol Biol. Isolation and characterization of human fetal macrophages from placenta. Clin Exp Immunol. Activation of phospholipase A2 is associated with generation of placental lipid signals and fetal obesity.

Prenatal ultrasonographic assessment of the ductus arteriosus: a review. Obstet Gynecol. Foetal and placental weights in relation to maternal characteristics in gestational diabetes. Effects of gestational diabetes on fetal oxygen and glucose levels in vivo. Alterations in the activity of placental amino acid transporters in pregnancies complicated by diabetes.

Altered activity of the system A amino acid transporter in microvillous membrane vesicles from placentas of macrosomic babies born to diabetic women. J Clin Invest. Serum-dependent effects of IGF-I and insulin on proliferation and invasion of human first trimester trophoblast cell models. Histochem Cell Biol. Madsen H, Ditzel J. Blood-oxygen transport in first trimester of diabetic pregnancy.

Acta Obstet Gynecol Scand. Transcription factors having impact on vascular endothelial growth factor VEGF gene expression in angiogenesis. Med Sci Monit. Regulation of fibroblast growth factor-2 expression in pulmonary arterial smooth muscle cells involves increased reactive oxygen species generation.

Am J Physiol Cell Physiol. Hyperglycaemia in vitro alters the proliferation and mitochondrial activity of the choriocarcinoma cell lines BeWo, JAR and JEG-3 as models for human first-trimester trophoblast. MT1-MMP expression in first-trimester placental tissue is upregulated in type 1 diabetes as a result of elevated insulin and tumor necrosis factor-alpha levels.

Baird JD, Aerts L. Research priorities in diabetic pregnancy today: the role of animal models. Biol Neonate. Impaired insulin secretion after intravenous glucose in neonatal rhesus monkeys that had been chronically hyperinsulinemic in utero. Proc Soc Exp Biol Med.

Randomized trial of human versus animal species insulin in diabetic pregnant women: improved glycemic control, not fewer antibodies to insulin, influences birthweight. Am J Obstet Gynecol. McNeill JH. Experimental Models of Diabetes. N Engl J Med. Burguet A.

Long-term outcome in children of mothers with gestational diabetes. Diabetes Metab. Sybulski S, Maughan GB. Use of streptozotocin as diabetic agent in pregnant rats. Endocrine pancreas in the offspring of rats with experimentally induced diabetes. J Endocrinol.

Impaired insulin response and action in offspring of severely diabetes rats. In: Shafir E, editor. Frontiers in Diabetes Research. London: Slmith Godon; The neonatal STZ model of diabetes. In: McNeill JH, editor. Experimental models of diabetes. Modulation of lipid metabolism by n-3 polyunsaturated fatty acids in gestational diabetic rats and their macrosomic offspring. Clin Sci Lond ;— Animal models for clinical and gestational diabetes: maternal and fetal outcomes.

Diabetol Metab Syndr. Experimental NIDDM: development of a new model in adult rats administered streptozotocin and nicotinamide. Blondel O, Portha B. Early appearance of in vivo insulin resistance in adult streptozotocin-injected rats. Diabete Metab. Is low-dose streptozotocin in rats an adequate model for gestational diabetes mellitus?

J Soc Gynecol Investig. Different diabetogenic response to moderate doses of streptozotocin in pregnant rats, and its long-term consequences in the offspring. Exp Diabesity Res. Sexual dimorphism in insulin sensitivity and susceptibility to develop diabetes in rats. The protective effect of testosterone on streptozotocin-induced apoptosis in beta cells is sex specific.

Association of disproportionate growth of fetal rats in late gestation with raised systolic blood pressure in later life. J Reprod Fertil. The thrifty phenotype hypothesis. Br Med Bull. Yajnik C. Interactions of perturbations in intrauterine growth and growth during childhood on the risk of adult-onset disease.

Proc Nutr Soc. Gestational high-fat programming impairs insulin release and reduces Pdx-1 and glucokinase immunoreactivity in neonatal Wistar rats. Poston L. Developmental programming and diabetes - The human experience and insight from animal models. Dietary restriction in pregnant rats causes gender-related hypertension and vascular dysfunction in offspring.

J Physiol. Effect of high-fat diet on body composition and hormone responses to glucose tolerance tests. Down-regulation of placental transport of amino acids precedes the development of intrauterine growth restriction in rats fed a low protein diet.

The effects of maternal protein restriction on the growth of the rat fetus and its amino acid supply. Br J Nutr. Different mechanisms operating during different critical time-windows reduce rat fetal beta cell mass due to a maternal low-protein or low-energy diet. Brief hyperglycaemia in the early pregnant rat increases fetal weight at term by stimulating placental growth and affecting placental nutrient transport.

Maternal prenatal undernutrition alters the response of POMC neurons to energy status variation in adult male rat offspring. Am J Physiol Endocrinol Metab. Acta Endocrinol Copenh ;— Maternal hyperglycemia is not the only cause of macrosomia: lessons learned from the nonobese diabetic mouse.

Gestational diabetic symptoms disappear following delivery. Approximately 3 to 8 percent of all pregnant women in the United States are diagnosed with gestational diabetes. What causes gestational diabetes mellitus? Although the cause of GDM is not known, there are some theories as to why the condition occurs.

The placenta supplies a growing fetus with nutrients and water, and also produces a variety of hormones to maintain the pregnancy. Some of these hormones estrogen, cortisol, and human placental lactogen can have a blocking effect on insulin. This is called contra-insulin effect, which usually begins about 20 to 24 weeks into the pregnancy. As the placenta grows, more of these hormones are produced, and the risk of insulin resistance becomes greater. Normally, the pancreas is able to make additional insulin to overcome insulin resistance, but when the production of insulin is not enough to overcome the effect of the placental hormones, gestational diabetes results.

What are the risks factors associated with gestational diabetes mellitus? Although any woman can develop GDM during pregnancy, some of the factors that may increase the risk include the following: Overweight or obesity Family history of diabetes Having given birth previously to an infant weighing greater than 9 pounds Age women who are older than 25 are at a greater risk for developing gestational diabetes than younger women Race women who are African-American, American Indian, Asian American, Hispanic or Latino, or Pacific Islander have a higher risk Prediabetes, also known as impaired glucose tolerance Although increased glucose in the urine is often included in the list of risk factors, it is not believed to be a reliable indicator for GDM.

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The current view is that the abnormal maternal metabolic environment may generate stimuli within the adipose tissue and the placental cells resulting in the increased production of inflammatory cytokines whose expression is minimal under normal pregnancy. Likewise, the fetal environment is also changed in diabetes, and elevated levels of insulin, leptin, and other cytokines have been well documented. This review will concentrate on insulin and cytokines as contributors to this network and potential regulators of placental function in GDM.

Intensive research has tried to establish alterations in maternal-fetal transport of the most important insulin secretagogues, i. Although the placental glucose transporter GLUT1 is subject to changes by the ambient level of glycemia, i. This will only have an effect if maternal glucose concentrations are high above postprandial glucose levels 10 , 11 , because of the high capacity of the transplacental glucose transport system Changes in placental amino acid transporters, if at all, are not associated with maternal diabetes, but rather with elevated fetal weight However, because of the complex nature of amino acid transporter systems in the human placenta, any generalization has to be avoided, and perfusion studies across the intact organ are still pending.

Yet, according to current knowledge, fetal hyperinsulinemia in diabetes is the result of the steeper transplacental glucose gradient associated with maternal hyperglycemia and is not accounted for by placental transporter changes. The placenta expresses high amounts of insulin receptors relative to other tissues in the body.

Their location undergoes developmental changes. At the beginning of gestation, they are located at the microvillous membrane of the syncytiotrophoblast, whereas at term, they are predominantly found at the endothelium 14 , This strongly suggests a shift in control of insulin-dependent processes from the mother at the beginning of pregnancy to the fetus at the end.

The spatio-temporal change in insulin receptor location is paralleled by a change in function, since insulin-induced gene expression is highest in first trimester trophoblast At term, insulin has a stronger effect on the endothelium than on the trophoblast. This is important for diabetic pregnancies in general and for GDM in particular, because it can be assumed that the fetal hyperinsulinemia will affect the placental endothelium.

As a current concept Fig. This may lead to altered synthesis and secretion of hormones and cytokines that in turn will act back on the mother, thus forming a feedback loop. As gestation advances, the fetus, i. Whether one of the results will be the placental release of molecules or nutrients to the fetus as another feedback loop is currently under investigation.

Changes in the number, affinity, and signaling properties of placental insulin receptors may confound this concept, but available information is scant. In diet-treated GDM, the amount of trophoblast insulin receptors is lower than in nondiabetic pregnancies, whereas in insulin-treated GDM, the placenta contains more insulin receptors Whether endothelial insulin receptors are also altered is unknown. Recent evidence demonstrated that insulin receptors at the different locations preferentially activate different intracellular signaling pathways.

This may indicate a mitogenic effect of insulin on the trophoblast, predominantly at the beginning of pregnancy, whereas fetal insulin will stimulate metabolic processes within the endothelium. In fact, in vitro studies confirmed the mitogenic potency of insulin in trophoblast models This may explain the biphasic growth of the placenta and fetus at around mid-gestation in type 1 and experimental diabetes 20 , Fetal insulin in normal pregnancies and even more so in diabetic pregnancies with hyperinsulinemia may have direct and indirect effects on the placenta Fig.

In addition to altering the expression of genes 16 , it will stimulate endothelial glycogen synthesis Although diet-treated GDM is associated with even lower than normal glycogen levels, elevation of placental glycogen levels in all other forms of diabetes has been well established rev. In this respect, the placenta is a paradoxical tissue, since in the classic insulin target tissues, glycogen levels are reduced in diabetes because of the insulin resistance.

Insulin does not change glycogen levels in the trophoblast. Glycogen increments in diabetes are found around the villous vessels and capillaries, suggesting that the glycogen stores are built up by glucose derived from the fetal circulation. In fact, not only the ubiquitous glucose transporter GLUT1, but also the high affinity transporter GLUT3, is expressed in the placental endothelium, where it colocalizes with glycogenin, the protein precursor for glycogen synthesis Increased glycogenin gene expression in placenta with GDM supports our hypothesis 6.

In addition, the insulin-sensitive GLUT4 is located on the endothelium Fetal glucose can be transported back into the placenta 25 , and this back transport is increased in diabetic rats The placenta is the only fetal tissue that can store excess fetal glucose.

The buffer function of the placental endothelium will be stimulated by insulin, not only in vitro, as in human, but also in vivo in the rodent This has led to a hypothesis proposing that some types of fetal macrosomia are the result of placental failure to store excess fetal glucose In addition to the direct effects of fetal insulin on the placenta that have been established so far, i.

Insulin stimulates fetal aerobic glucose metabolism and will hence increase oxygen demand of the fetus. If adequate supply is not available because of reduced oxygen delivery to the intervillous space as a result of the higher oxygen affinity of glycated hemoglobin 29 , thickening of the placental basement membrane 30 , 31 , and reduced utero-placental or fetoplacental blood flow 32 , 33 , fetal hypoxemia will ensue Hypoxia is a potent stimulator of hypoxia-sensitive transcription factors such as the hypoxia inducible factor HIF and will therefore lead to the stimulated expression and synthesis of a variety of molecules, some of which are key players, especially in angiogenesis 35 , Diabetic pregnancies are associated with elevated fetal levels of fibroblast growth factor-2 37 , 38 , which will stimulate placental angiogenesis and lead to the hypercapillarization seen in placentas of type 1 diabetic pregnancies.

Reports in GDM are conflicting 39 — Some, but not all, studies found increased longitudinal vascular growth and enhanced branching angiogenesis, which may reflect different time points of GDM onset in gestation either within or after the critical developmental stages of vasculogenesis and angiogenesis One of the characteristic features of a placenta in GDM is its increased weight, which is accompanied by enlarged surface areas of exchange on the maternal syncytiotrophoblast and fetal endothelium side 3.

Teleologically, it may appear paradoxical that in a situation of maternal nutritional oversupply, the placenta increases its surface, thus potentially contributing to enhanced maternal fetal transport, but this reflects the prime importance of adequate oxygen supply to the fetus and the effect of excess growth factors such as insulin, which collectively dictate some of the placental changes even at the cost of adverse side effects.

Adipose tissue represents an additional source of cytokines, making possible a functional cooperation between the immune system and metabolism 43 , The placenta acts as a natural selective barrier between maternal and fetal blood circulations. Placenta is sensitive to the hyperglycemic milieu and responses with adaptive changes of the structure and function.

Alteration of the placental development and subsequent vascular dysfunction are presented in 6 out of 7 women with all ranges of diabetic severity. Most placentas from GDM pregnancies present typical histological findings such as villous immaturity, villous fibrinoid necrosis, chorangiosis, and increased angiogenesis.

The type of dysfunction depends on how early in pregnancy glycaemia disorders occurred. Generally, if impaired glucose metabolism is diagnosed in the early pregnancy, mainly structural dysfunctions are observed. GDM that is detected in late gestation affects placental function to a greater extent.

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Enterprising Research: Detecting placental insufficiency in pregnant women

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