Diabetic Placenta Research Articles

A Study on Morphohistometric Changes of Placenta in Gestational Diabetes- A Comparative Analysis

Introduction:The placenta is a complex fetal organ that fulfills pleotrophic roles during fetal growth. Placenta is the most accurate record of the infant’s prenatal experience. Gestational diabetes is much common than preexisting diabetes .i.e. it complicates 2% to 5% of pregnancies. It seems reasonable to expect that biochemical changes occurring in the pregnant women with diabetes should be reflected in the placental structure. Aim & objectives: In the present study an attempt is made to know the morphological changes of placenta in gestational diabetes mellitus.Subjects and Methods:In this study totally 60 placentae were studied, of which 30 were nondiabetic placentae and 30 from Gestational Diabetic mothers were studied macroscopically. Morphologically the shape, site of attachment of umbilical cord, central thickness of placenta was noted. Birth weight of the neonate and the placental ratio were also recorded. By using routine staining techniques and direct microscopy tissues of Gestational Diabetic placenta were studied qualitatively and compared them with normal placenta.Results:Our study demonstrates that there is a significant increase in weight and central thickness of placenta. Neonatal weight and placental ratio were also increased; there was no change in shape and site of attachment of umbilical cord in case of diabetic placenta when compared to normal. Conclusion:On the basis of results of present study it is concluded that diabetic placentae showed increase in weight and central thickness. Neonatal weight and placental ratio were also increased. These findings indicate that control of hyperglycemia only partially prevents the development of placental abnormalities.

A study of microscopic changes in the placenta in gestational diabetes mellitus

Introduction: Gestational diabetes mellitus is a complication connected with pregnancy defined as any degree of glucose intolerance that appears during pregnancy with normal values before and usually after the pregnancy. We investigated histological changes of the gestational diabetic placenta and non-diabetic placenta. Research work accomplished in the department of Anatomy, government medical college and superfacility hospital Azamgarh. Placenta collected from the labour room/operation theatre of the department of Obstetrics and Gynecology, government medical college and superficiality hospital, Azamgarh. Material and Methods: Sixty-two freshly delivered placentas were collected – 31 placentas from diabetic mother and 31 placentas from non-diabetic mother (control group). All parturient were aged between 20 to 44 years. This placenta measured on a weighing machine graduated in grams. An approximately 5mm piece of the diabetic placenta was taken and processed for histological examination. Results: Microscopic examination explained dilated blood vessels, subtrophoblastic basement membrane thickness and chorangiosis present in all gestational diabetic placenta. Vessels thrombosis present in 83.87 per cent of the gestational diabetic placenta. Nucleated RBCs. were present in 93.54 per cent of the gestational diabetic placenta. Discussion and Conclusion: Gestational diabetes mellitus induces significant changes in the placenta, both gross and histologic. Effective glycemic regulation is better options for reducing anomalies that cause gestational diabetes. We find dilated blood vessels and necrosis in 100 percent of gestational diabetic placenta and 9.60 percent of nondiabetic placenta. The thickness of the subtrophoblastic basement membrane was present in 100% of the gestational diabetic placenta and 16.12% of the non-diabetic placenta. Vessel thrombosis occurs in 83.87% of gestational diabetic placenta, and 12.90% of non-diabetic placenta. In 93.54 percent of gestational diabetic placenta and 32.25 percent of non-diabetic placenta, nucleated RBC occurs.

Gross and Histological Alteration in the Placenta in Gestational Diabetes - A Comparative Study

Gross and Histological Alteration in the Placenta in Gestational Diabetes - A Comparative Study

Increased placental expressions of nuclear factor erythroid 2–related factor 2 and antioxidant enzymes in gestational diabetes: Protective mechanisms against the placental oxidative stress?

Objective: Gestational diabetes mellitus is associated with increased oxidative stress. Oxidative stress may contribute to the risk for pregnancy pathologies associated with gestational diabetes mellitus. In this study we investigated the expression of placental nuclear factor erythroid 2–related factor 2 (Nrf2) and antioxidant enzymes of gestational diabetes mellitus and healthy pregnant women and correlated them with the maternal and cord plasma as well as placental tissue oxidative stress parameters.Study design: A cross sectional study was carried out in a South Indian Tamil population. Forty healthy pregnant women and forty gestational diabetes mellitus patients in the gestational age of 32 ± 4weeks were recruited. Maternal plasma, cord plasma and placental oxidative stress parameters were measured. Placental expression of Nrf2, phospho Nrf2, catalase and superoxide dismutase 1(SOD1) were analyzed by western blotting and immunohistochemistry.Results: Placental expression of Nrf2, catalase and SOD1 were found to be significantly higher in gestational diabetes mellitus. The maternal plasma, cord plasma and placental tissue oxidative stress parameters, total antioxidant status (TAS) levels were significantly lower; whereas MDA (malondialdehyde) and MDA/TAS levels were significantly higher in gestational diabetes mellitus. Placental Nrf2 expression correlated positively with the placental catalase expression and negatively with placental TAS levels in both groups.Conclusion: Maternal, fetal and placental oxidative stress was observed in gestational diabetes mellitus. The gestational diabetic placenta had an increased Nrf2 protein expression. The activated placental Nrf2/ antioxidant response element (ARE) pathway might have led to an increased expression of antioxidant enzymes SOD1 and catalase. This may be viewed as a protective mechanism in placenta from the further onslaught of oxidative stress.

The Human Placenta in Diabetes and Obesity: Friend or Foe? The 2017 Norbert Freinkel Award Lecture.

The placenta plays a key role in sustaining fetal growth and development. Due to its position between mother and fetus, it is exposed to changes in the intrauterine environment in both circulations. The relative influence of changes in those circulations depends on the period of gestation. Early in pregnancy, maternal influences prevail and may affect the complex biological processes characteristic for this pregnancy period, such as placentation, early cell differentiation, and spiral artery remodeling. It is still unclear whether the placenta early in pregnancy is a friend or foe for the fetus. Later in pregnancy, when the fetal circulation is gradually establishing, fetal signals gain importance in regulating placental structure and function. Many of the placental alterations seen at term of pregnancy are the result of fetoplacental interactions often driven by fetal signals associated with maternal diabetes or obesity. These alterations, such as hypervascularization or enhanced cholesterol removal from placental endothelial cells, can be regarded as adaptations to maintain homeostasis at the fetoplacental interface and, thus, to protect the fetus. However, extreme conditions such as poorly controlled diabetes or pronounced obesity may exceed placental homeostatic capacity, with potentially adverse consequences for the fetus. Thus, in late pregnancy, the placenta acts mostly as a friend as long as the environmental perturbations do not exceed placental capacity for mounting adaptive responses.

Histopathological study with immunohistochemical expression of vascular endothelial growth factor in placentas of hyperglycemic and diabetic women.

AIMS AND OBJECTIVES:Spectrum of hyperglycemia in pregnancy includes gestational diabetes mellitus (GDM), mild hyperglycemia, and overt diabetes. Many authors have worked on morphological changes of the placenta in diabetes, but few studies have correlated histopathological changes with vascular endothelial growth factor (VEGF) immunoexpression. The aim of this study was to detect different histopathological changes in various groups of diabetic placentas and to correlate with VEGF immunoexpression.MATERIALS AND METHODS:Pregnant women were screened for diabetes. They were subsequently divided into normoglycemic (12 cases), GDM (33 cases), mild hyperglycemic (13 cases), and overt diabetes (18 cases). Placentas collected were subjected to histopathological examination. VEGF expressions were studied by immunohistochemistry.RESULTS:Overt diabetic placenta displayed villous immaturity (44.4%), villous edema (38.9%), chorangiosis (61.1%), fibrinoid substance deposition (38.9%), and Hofbauer cell hyperplasia in 44.4% cases. GDM placentas displayed villous immaturity (45.5%), villous edema (45.5%), chorangiosis (42.4%), and fibrinoid substance deposition in 75.6% cases. Mild hyperglycemic placentas displayed villous immaturity (38.5%), chorangiosis (61.5%), and fibrinoid substance deposition in 61.5% cases. VEGF immunoexpression in GDM placentas was absent in all placental components except syncytiotrophoblast. VEGF expression in overt diabetic placentas was increased in syncytiotrophoblast and capillary endothelium compared to normoglycemic placentas. Mild hyperglycemic placentas expressed similar VEGF expression in all components when compared to normoglycemic controls. However, it displayed weak expression in vessel endothelium.CONCLUSION:Histopathological changes in diabetic placentas might be a consequence of altered or abnormal VEGF expression in diabetic placentas. Pathogenesis and VEGF expression in GDM placentas are significantly different from overt diabetic placentas.

Mesenchymal stromal cells isolated from gestationally diabetic human placenta exhibit insulin resistance, decreased clonogenicity and angiogenesis

Pregnancy is known to be a diabetogenic state. With sedentary lifestyle and wrong dietary choices, gestational diabetes mellitus is on the rise. This raises a concern as placenta is becoming an acceptable choice, as a source of Mesenchymal Stromal Cells (MSCs). In our current study we questioned whether there exists a difference between MSCs isolated from normal and diabetic (Gd-P-MSCs) placenta, as the health of the cells used in therapy is of prime importance. We isolated and verified the Gd-P-MSCs based on their surface markers and differentiation potential. We looked at viability and proliferation and did not see a difference between the two. We analysed the glucose uptake potential of these cells by assessing the remnant glucose in the media, glucose within the cells by 2-NBDG and by glycogen storage. Despite only a slight downregulation of mRNA expression levels of glucose transporters, Gd-P-MSCs exhibited decreased glucose uptake even upon insulin stimulation and decreased glycogen storage, indicative of an insulin resistant state. We then assessed the colony forming ability of the cells and found a decreased clonogenicity in Gd-P-MSCs. We also examined the angiogenic potential of the cells by tube formation. Gd-P-MSCs showed decreased angiogenic potential when compared to normal cells. Thus we show for the first time, the effect of gestational diabetes on cells isolated from the chorionic villi of term placenta. Gd-P-MSCs are indeed insulin resistant, exhibit decreased clonogenicity and angiogenic potential. The present investigation is of relevance to the choice of sample for MSC isolation for therapeutic purposes.

Stereological study of human placental barrier in pregnant women suffering from gestational diabetes

A prospective case control study conducted at Basrah maternity and child hospital and Basrah medical college. The study includes twenty samples of placental tissue from gestational diabetic pregnant women and ten samples of placental tissue from normal pregnant women ( control group). Tissue sections of all samples were stained by Haematoxylin and eosinand examined under light microscope with screen for stereological investigation to the placental barrier stereological quantitation of placental barrier; comparison between different placental barrier parameters of the placenta in normal and gestational diabetes. Although there is an increase in all means of placental barrier parameters in placenta of gestational diabetes pregnant women than placenta of normal pregnant women but there is no statistical difference at (P<0.05).There are only exception that (TDD,FBP and MBP are statistically differ at(P<o.05) tables (1,2). In addition: Qualitative (morphological observations and structural) changes are obtained as following:-Differences in thickness of the syncytiotrophoblast and basement membrane thickness in villi more marked in gestational diabetes. Thrombosis of fetal arteries and infracted villi more than normal some regions have extensive infraction than other regions. Villous vessels with multilayered and fibrinoid necrosis of villi more in gestational diabetes.Capillary proliferation and cellularity were increased in gestational diabetes. Fibrosis of villi in gestational diabetes.

Placental Expression of Glucose Transporter Proteins in Pregnancies Complicated by Gestational and Pregestational Diabetes Mellitus.

Gestational diabetes mellitus and pregestational diabetes mellitus constitute carbohydrate metabolism disorders, which, if not diagnosed and adequately treated, lead to serious and often life-threatening pregnancy complications. According to a recently formulated hypothesis, some diabetes-related complications, such as fetal macrosomia, may be the result of disturbances in the transplacental transport of nutrients-in particular, excessive maternal-fetal glucose transfer. Throughout pregnancy, glucose flux across the placenta is mediated by the group of facilitative glucose transporters (GLUT), the expression of which in different placental compartments is the precondition for effective glucose uptake from maternal blood and its subsequent transfer to the fetal circulation. In diabetes-complicated pregnancies, the location, expression and activity of glucose transporters are modified to an extent that results in alterations in the maternal-fetal glucose exchange, potentially leading to an excessive supply of energy substrates to the fetus. This paper reviews the literature on the expression and activity of glucose transporter proteins-GLUT-1, GLUT-3, GLUT-4, GLUT-8, GLUT-9 and GLUT-12-in the human placenta, with a special focus on diabetes-complicated pregnancy. The characteristics of transporters in conditions of maternal normoglycemia and modifications occurring in the diabetic placenta are summarized, and the factors responsible for the regulation of the expression of selected isoforms are described. Finally, the impact of alterations in the placental expression of the aforementioned members of the GLUT family on intrauterine fetal development in pregnancies complicated by diabetes mellitus is discussed.

Gestational diabetes affects fetal autophagy

Autophagy is a catabolic process involved in the preservation of energy homeostasis and its dysregulation has been implicated in the development of metabolic disorders, including diabetes mellitus. Gestational diabetes mellitus represents a risk for fetal morbidity and mortality. The present study focuses on the autophagy process in human diabetic placenta and fetal pancreas, compared with controls. Analysis of the autophagy markers LC3, Beclin-1 and p62 suggests an impairment of the autophagy process in diabetic placentas. Results indicate an association between gestational diabetes and autophagy, emphasizing the importance of unravelling the mechanisms regulating this relationship.

Relative amount of telomeric sequences in terminal villi does not differ between normal term placentas and placentas from patients with well-controlled type 1 diabetes mellitus

We applied qPCR to compare relative telomere length in terminal villi microdissected from term control placentas and placentas of patients suffering from type 1 diabetes. Significant differences were not found in the relative T/S ratios between placental groups or between the diabetic placentas affected and those not affected with chorangiosis. We hypothesize that there is no relationship between decreased placental proliferative ability in maternal diabetes type 1 and telomere shortening.

605: Metabolomic alterations in pregestational diabetic placentas at term

605: Metabolomic alterations in pregestational diabetic placentas at term

Expression and localization of FoxO4 in normal term and gestational diabetic placentas

Expression and localization of FoxO4 in normal term and gestational diabetic placentas

Morphological and histomorphometrical study of gestational diabetes placenta in relation to oxidative stress

Morphological and histomorphometrical study of gestational diabetes placenta in relation to oxidative stress

Telomere homeostasis in placentas from pregnancies with uncontrolled diabetes

ObjectiveDiabetes during pregnancy causes an intrauterine environment that influences lifetime sickness of the mother and the fetus. There is a correlation between diabetes and telomere shortening; however, very little is known about telomere homeostasis in the placenta. We aimed to study the telomerase complex in placentas and in cord blood leukocytes from patients with poorly controlled diabetes. MethodsBiopsies from 16 third-trimester placentas and cord blood samples from pregnancies complicated with uncontrolled diabetes and from 16 gestational age-matched controls from uncomplicated pregnancies were examined. The expression of hTERT (human telomerase reverse transcriptase) was evaluated by immunohistochemistry and by RT-RCR. TERC gene copy number and telomere capture were evaluated by FISH. ResultsTelomerase expression was significantly lower in the diabetic placentas, both the protein (17.8 ± 2.8% cellular staining vs. 37 ± 5.32%, P = 0.012) and the mRNA levels (0.42 ± 0.03 folds, P = 0.022). Lower expression of TERC gene copy number were shown in the diabetic placentas compared to the healthy controls (1.7 ± 0.8% vs. 3.7 ± 1.6%, P = 0.035). We also detected higher percentage of cells with telomere capture among the diabetic trophoblasts compared to the healthy controls (19.8 ± 5.12% vs. 9.6 ± 3.65%, P = 0.038). Those differences were not observed in cord blood leukocytes from the same samples. ConclusionsUncontrolled diabetes during pregnancy disrupts telomere-telomerase homeostasis in the trophoblasts. These changes may increase the risk for metabolic diseases in adulthood among offspring of pregnancies complicated by gestational diabetes mellitus as part of intrauterine programming. These variations were not observed in cord blood leukocytes, which imply different telomere homeostasis mechanisms in fetal cord blood.

Oxidative stress in the gestational diabetes mellitus mother and placenta

Oxidative stress in the gestational diabetes mellitus mother and placenta

Expression of Mammalian Target of Rapamycin and Downstream Targets in Normal and Gestational Diabetic Human Term Placenta.

Mammalian target of rapamycin (mTOR) signaling serves as a central regulator of cell growth, proliferation, and survival by interacting with various proteins. To date, few studies implicated mTOR in placenta. Human placenta in gestational diabetes mellitus (GDM) shows several alterations including villous immaturity, impaired placental function, and overgrowth. Hence, we aimed to investigate the expression of mTOR, phospho-mTOR (p-mTOR), and the 2 phosphorylated downstream targets of mTOR, ribosomal protein S6 kinase 1 (p-p70S6K), and eukaryotic initiation factor 4E-binding protein 1 (p-4EBP1) in normal term and gestational diabetic human placentas. Immunohistochemistry and Western blot were performed with antibodies against mTOR, p-mTOR, p-p70S6K, and p-4EBP1 (Thr37/46) in normal and diabetic placentas (n = 6 each) and quantified by ImageJ. All mTOR pathway components that we studied were immunolocalized in both normal and diabetic placenta groups. Syncytiotrophoblast and the vascular wall in villi displayed cytoplasmic mTOR and p-mTOR (S2448) immunoreactivities in all placenta samples. However, increased expression of p70S6K in syncytiotrophoblast and p-4EBP1 (Thr37/46) in villous stromal cells was observed in gestational diabetic placentas. Western blot analysis also confirmed the statistically significant increase in p-p70S6K (T389) expression in diabetic placentas. The altered expression of downstream components of mTOR signaling in gestational diabetic placentas suggests an involvement of mTOR activity in the placental pathology of GDM. However, whether increased nutrient transport via this pathway will stimulate fetal and placental overgrowth is still unknown. Although this is a descriptive study, further studies with a functional analysis to highlight the molecular mechanisms underlying this placental pathology are proposed.

Altered expression of human endogenous retroviruses syncytin-1, syncytin-2 and their receptors in human normal and gestational diabetic placenta.

Syncytins belong to the Human Endogenous Retrovirus family. The syncytin-1 receptor, SLC1A5, and syncytin-2 receptor, MFSD2, interact with their respective syncytin proteins to induce syncytiotrophoblast formation. However, there is no information about syncytins in gestational diabetic placenta. Therefore, we studied the expression and localization of syncytins and their receptors during normal placental development and in gestational diabetic placenta. Immunohistochemistry and Western-blot methods were performed with antibodies against syncytin-1, syncytin-2, SLC1A5 and MFSD2 in human first trimester placental tissues, normal term and gestational diabetic placentas. Syncytin-1, syncytin-2 and MFSD2 mRNA transcripts were determined by qRT-PCR in normal and diabetic term placentas. Cytoplasmic syncytin-1, syncytin-2, SLC1A5 and MFSD2 immunoreactions were observed in the trophoblastic layers in all placental samples. Some of the stromal cells showed strong cytoplasmic punctate staining. There were significantly weak syncytin-2 and MFSD2 immunoreaction intensities in diabetic placentas by ImageJ analysis, in parallel with decreased syncytin-2 and MFSD2 proteins in diabetic placentas by Western-blot. Protein expression of SLC1A5 increased dramatically in early pregnancy compared to term placenta. Syncytin-1, syncytin-2 and MFSD2 mRNA transcripts showed similar relative expression pattern by qRT-PCR. Syncytins were localized not only in cytotrophoblast cells and the basement membrane of the syncytiotrophoblast but also in the apical microvillous membrane and cytoplasm of syncytiotrophoblast, and some of the stromal cells and endothelium. Decreased syncytin-2 and MFSD2 proteins in gestational diabetic placentas might cause abnormal syncytiotrophoblast formation and possibly be involved in the pathology. Therefore, our study highlights an important potential relationship between syncytins and gestational diabetic placenta.

Impact of maternal diabetes type 1 on proliferative potential, differentiation and apoptotic activity in villous capillaries of term placenta

IntroductionMaternal diabetes mellitus changes morphology and impairs function of placental capillaries. Here, quantitative parameters characterizing cell proliferation using detection of Ki67, differentiation reflected by nestin expression and apoptosis in placental capillary bed with active caspase 3 as a marker were compared in normal term placentas and placentas from pregnancies complicated by Type 1 maternal diabetes mellitus. MethodsSpecimens of sixteen diabetic placentas and eight control placentas were collected by systematic uniform random sampling. Immunohistochemical detections of Ki67, nestin, and active caspase 3 were performed in histological sections of five haphazardly chosen blocks per placenta. Twenty fields of view per section, i.e. one hundred fields of view per placenta, were used for analysis of proliferation as well as of apoptosis, and in approximately 70 capillary cross-sections per placenta the nestin-positive segments of their circumference were measured. ResultsThe percentage of Ki67-positive cells counted in the capillary wall was significantly lower in diabetic group. The counts of Ki67-labelled nuclei per villous area unit were significantly lower in cytotrophoblast and capillary wall of terminal villi in diabetic placenta. The proportion of nestin-labeled segments of capillary circumference was significantly higher in placentas of diabetic group. No differences in the numbers of apoptotic cells were found between studied groups. DiscussionThe results show that the term placenta in Type 1 diabetes has lower potential to enlarge the surface area of structures involved in maternofetal transport, and that the villous capillary bed displays delayed differentiation. Those factors may participate in decreased ability of diabetic placenta to comply with fetal requirements in the final stage of pregnancy.

Healthy and Gestational Diabetic Human Placental Fructose 1,6 Bisphosphate Aldolase; Comparative Investigation of Kinetic Properties and Inhibition Effects of DHAP, ATP, and Mg<sup>+2</sup> ion

Fructose-1,6-bisphosphate aldolase plays an effective role in glucose metabolism and gluconeogenic pathway, and reversibly catalyzes the split of fructose 1,6-bisphosphate into the triose phosphates D-glyceraldehyde phosphate and dihydroxyacetone phosphate. Aldolase has 160 kDa molecular weight and three tissue specific isozymes. Gestational diabetes mellitus is defined as glucose intolerance that begins or is first detected during pregnancy. The placenta is a temporary established organ that operates exclusively for the time of pregnancy. It acts as a natural barrier between the maternal and fetal blood circulations and performs a wide range of endocrine and transport functions. In diabetes, the placenta undergoes a variety of structural and functional changes. Healthy and gestational diabetic human placental fructose-1, 6-bisphosphate aldolases were purified and investigated the substrate kinetic properties, in the previous studies. In this comparative study, we wanted to carry out characteristics of inhibition kinetics of aldolase in healthy and diabetic human placenta. The specific activity was defined as the number of activity units per mg of protein. Inhibition kinetics of fructose-bisphosphate aldolase was studied using dihydroxyacetone-phosphate, adenosine triphosphate, and magnesium ion as inhibitors. For healthy placental Aldolase it was detected that, adenosine triphosphate is partial competitive; dihydroxyacetone-phosphate is noncompetitive and magnesium metal is pure-competitive inhibitor. It was found that, dihydroxyacetone-phosphate is competitive; adenosine triphosphate is partial competitive and magnesium is partial competitive inhibitor of gestational diabetic human placental Aldolase.