Role of the fetal pancreas size in prediction of early neonatal hypoglycemia in maternal diabetes mellitus

Введение. Поджелудочная железа (ПЖ) плода играет роль в регуляции гликемии как у плода, так и у матери. Гипергликемия матери, независимо от типа сахарного диабета (CД) сопровождается гипергликемией у плода. Напряжение функции ПЖ плода обусловливает компенсаторное увеличение eё размеров, формирование фетальной гиперинсулинемии и развитие в первые часы жизни неонатальной гипогликемии. Клинические симптомы гипогликемии присутствуют в 25-33% случаев, частота лабораторной гипогликемии - в 21-60%. Цель - оценка прогностического значения увеличения размеров ПЖ плода накануне родов в качестве предиктора неонатальной гипогликемии при CД у матери. Методика. Проведена ультразвуковая морфометрия ПЖ у 241 беременной c CД (основная группа) и у 427 здоровых беременных (контрольная группа). В основной группе у 141 (58,5%) беременной родились дети c признаками диабетической фетопатии (ДФ). Оценивались размеры ПЖ плода. У новорождённых оценивалась гликемия в динамике в 1-e и 3-и сут жизни. Проведён ретроспективный корреляционный анализ размеров поджелудочной железы плода и характер гликемии новорожденных в 1-e и 3-и cут жизни. Результаты. Выявлена отрицательная корреляция толщины ПЖ и гипогликемии новорождённого в 1-e сут жизни c линейным коэффициентом корреляции (R) минус 0,66. В 1-e сут жизни у 87,5 % этих детей возникает гипогликемия, более выраженная у недоношенных, у 50% из них, сохраняющаяся к 3-м сут жизни. Заключение. Толщина ПЖ плода более информативный и воспроизводимый показатель, чем её длина, статистически значимый как в группе ДФ, так и без неё. Неудовлетворительный контроль за течением CД у матерей увеличивает риск гипогликемии новорождённого до 100%. Более выраженная гипогликемия выявляется у недоношенных детей, у половины которых гипогликемия сохраняется к 3-м сут жизни. Background. The fetal pancreas is involved in regulation of glucose levels in both fetal and maternal plasma. Maternal hyperglycemia, regardless of the type of diabetes mellitus (DM), is accompanied by fetal hyperglycemia. This stress of the fetal pancreatic function causes a compensatory increase in the pancreas size, the development of fetal hyperinsulinemia and of neonatal hypoglycemia in the first hours of life. The frequency of laboratory hypoglycemia varies 21-60%, while its clinical symptoms are present in 25-33% of cases. Aim. To assess the prognostic value of the increase in fetal pancreas size on the eve of delivery as a predictor of neonatal hypoglycemia in maternal DM. Methods. Ultrasound of the fetal pancreas was performed in 241 pregnant women with DM (main group) and in 427 healthy pregnant women (control group). In the main group, 141 (58.5%) pregnant women had children with signs of diabetic fetopathy (DF). The size of the fetal pancreas was estimated. In newborns, glycemia was measured on the 1st and 3rd days of life. A retrospective correlation analysis of the fetal pancreas size and the neonatal glycemia was performed on the 1st and the 3rd days of life. Results. A negative linear correlation was found between the pancreas thickness and neonatal hypoglycemia on the 1st day of life (linear correlation coefficient, R, -0.66). On the 1st day of life in 87.5-100% of these newborns, hypoglycemia is observed, which is more pronounced in premature infants and which remains through the 3rd day of life in 50% of them. Conclusion. The thickness of the fetal pancreas is a more informative and reproducible indicator than its length, which was statistically significant in groups both with and without DF. Poor glycemic control in mothers increases the risk of neonatal hypoglycemia up to 100%. More pronounced hypoglycemia is observed in premature infants and persists through the 3rd day of life in half of them.

Sonographic measurement of the fetal pancreas in women with gestational diabetes

IntroductionThe aim of our study was to assess fetal pancreas size of the in a population of well controlled mothers with gestational diabetes.Material and methodsA cross sectional, prospective observational study. Pregnant women at 19-38 weeks of gestation who received glycemic control treatment for pre- or gestational diabetes were recruited. The fetal pancreas circumference (PC) was measured and compared to normal reference range. The Z score of the difference between measured and normal predicted mean PC, the regression analysis throughout pregnancy and the correlation between estimated fetal weight centile and PC were calculated.ResultsNinety-one gestational diabetic (GDM) and thirty-four pre gestational diabetic (PGDM) mothers were included in the study. For both groups, fetal PC correlated significantly with AC, EFW and GA. For GDM, the mean Z score between the predicted and the normal predicted PC for each week of gestation peaked at around 24 weeks of gestation (1.1) and decreased gradually afterwards to a zero value at 37 weeks. For PGDM, the mean Z score per week of gestation decreased constantly with advancing of pregnancy. It was positive until the 25th week of gestation and then presented negative values towards term.ConclusionsWe present preliminary data linking glycemic control treatment and fetal pancreas size. This correlation supports Pedersen's hypothesis and may serve as an indirect method for assessment of the effect of maternal hyperglycemia on the glucose-insulin environment within the fetal compartment.

A 3D system to model human pancreas development and its reference single-cell transcriptome atlas identify signaling pathways required for progenitor expansion

Human organogenesis remains relatively unexplored for ethical and practical reasons. Here we report the establishment of a single cell transcriptome atlas of the human fetal pancreas between 7 and 10 post-conceptional weeks of development. To interrogate cell-cell interactions we developed InterCom, an R-Package for identifying receptors-ligand pairs and their downstream effects. We further report the establishment of a human pancreas culture system starting from fetal tissue or human pluripotent stem cells, enabling the long-term maintenance of pancreas progenitors in a minimal, defined medium in three-dimensions. Benchmarking the cells produced in 2D and those expanded in 3D to fetal tissue reveals that progenitors expanded in 3D are transcriptionally closer to the fetal pancreas. We further demonstrate the potential of this system as a screening platform and identify the importance of the EGF and FGF pathways controlling human pancreas progenitor expansion.

A 3D system to model human pancreas development and its reference single-cell transcriptome atlas identify signaling pathways required for progenitor expansion

Human organogenesis remains relatively unexplored for ethical and practical reasons. Here we report the establishment of a single cell transcriptome atlas of the human fetal pancreas between 7 and 10 post-conceptional weeks of development. To interrogate cell-cell interactions we developed InterCom, an R-Package for identifying receptors-ligand pairs and their downstream effects. We further report the establishment of a human pancreas culture system starting from fetal tissue or human pluripotent stem cells, enabling the long-term maintenance of pancreas progenitors in a minimal, defined medium in three-dimensions. Benchmarking the cells produced in 2D and those expanded in 3D to fetal tissue reveals that progenitors expanded in 3D are transcriptionally closer to the fetal pancreas. We further demonstrate the potential of this system as a screening platform and identify the importance of the EGF and FGF pathways controlling human pancreas progenitor expansion.

A 3D system to model human pancreas development and its reference single-cell transcriptome atlas identify signaling pathways required for progenitor expansion

Human organogenesis remains relatively unexplored for ethical and practical reasons. Here, we report the establishment of a single-cell transcriptome atlas of the human fetal pancreas between 7 and 10 post-conceptional weeks of development. To interrogate cell–cell interactions, we describe InterCom, an R-Package we developed for identifying receptor–ligand pairs and their downstream effects. We further report the establishment of a human pancreas culture system starting from fetal tissue or human pluripotent stem cells, enabling the long-term maintenance of pancreas progenitors in a minimal, defined medium in three-dimensions. Benchmarking the cells produced in 2-dimensions and those expanded in 3-dimensions to fetal tissue identifies that progenitors expanded in 3-dimensions are transcriptionally closer to the fetal pancreas. We further demonstrate the potential of this system as a screening platform and identify the importance of the EGF and FGF pathways controlling human pancreas progenitor expansion.

Application of antibodies to the vesicular transporter of acetylcholine and acetylcholinesterase in the studies of prenatal development of parasympathetic innervation of the human pancreas

Introduction. Parasympathetic fibers innervating the pancreas are involved in the regulation of both exo-crine and endocrine function, in the regulation of endocrine cell proliferation, and are also implicated in the pathogenesis of type 1 diabetes. Nonetheless, data concerning the distribution of parasympathetic fibers within the human pancreas in prenatal development are absent in the literature. Our aim was to evaluate the possibility of using the markers of cholinergic neurons and nerve fibers, namely vesicular acetylcholine transporter (VAChT) and acetylcholinesterase (AChE) in studies of prenatal develop-ment of parasympathetic innervation of the human pancreas. Materials and methods. The study was performed on 10 autopsies of the fetal pancreas (gestational age 10-34 weeks) using immunoperoxidase labeling with antibodies to VAChT and AChE. Results. Immunopositive reaction to AChE was detected in bundles of nerve fibers of various diameters, networks of thin nerve fibers as well as in individual neurons of the intramural ganglia. The structures of the nervous system were immunonegative to VAChT. In the exocrine pancreas, that is, in the interlobular connective tissue, near the ducts and inside the forming lobules, thin cholinergic fibers prevailed on the studied developmental periods. In pancreatic islets, cholinergic fibers were detected less frequently and were located at the periphery.Immunopositive reaction with antibodies to AChE and mouse monoclonal antibodies to VAChT was also detected in some endocrine cells in the pancreatic islets. Conclusion. We have shown that antibodies to AChE detect cholinergic neurons and nerve fibers in the developing human pancreas. We have also demonstrated that in the fetal pancreas thin cholinergic fibers prevail in the exocrine part and rarely are detected in the pancreatic islets, which is typical in adults. The results showing the VAChT and AChE immunoreactivity in the endocrine cells of fetal pancreatic islets are in agreement with data obtained in the adult human pancreas and suggest that the endocrine cells can be a source of acetylcholine. Keywords: pancreas, human development, parasympathetic innervation, VAChT, AChE

Dysregulation in the Unfolded Protein Response in the FGR Rat Pancreas

Accumulating evidence suggests that fetal growth restriction (FGR) leads to the development of diabetes mellitus in adults. The aim of this study was to investigate the effect of protein malnutrition in utero on the pancreatic unfolded protein response (UPR) pathway in FGR offspring. An FGR model was developed by feeding a low-protein diet to pregnant rats throughout gestation. Eighty-four UPR pathway components in the pancreas were investigated by quantitative PCR arrays and confirmed by qPCR and western blotting. Activating transcription factor (Atf4 and Atf6), herpud1, protein kinase R-like endoplasmic reticulum kinase (Perk), X-box binding protein 1 (Xbp1), and the phosphorylation of eIF2α were upregulated, while cyclic AMP-responsive element-binding protein 3-like protein was markedly downregulated in FGR fetuses compared with controls. Investigation in adult offspring revealed temporal changes, for most UPR factors restored to normal, except that dysregulation of Atf6 and Creb3l3 maintained until adulthood. Moreover, autophagy was suppressed in FGR fetal pancreas and may be associated with decreased activation of AMP-activated protein kinase (Ampk). Apoptosis regulators Bax and cleaved-caspase 3 and 9 were upregulated in FGR fetal pancreas. Given that islet size and number were decreased in FGR fetus, we speculated that the aberrant intrauterine milieu impaired UPR signaling in fetal pancreas development. Whether these alterations early in life contribute to the predisposition of FGR fetuses to adult metabolic disorders invites further exploration.