Malgré l’amélioration des prises en charge diabétologiques et obstétricales, la grossesse chez la patiente ayant un diabète pré-gestationnel ou gestationnel reste à ce jour à haut risque pour la mère et pour l’enfant. Chez l’enfant, les anomalies de croissance, macrosomie, mais parfois Retard de Croissance Intra-Utérin (RCIU) restent à ce jour très fréquentes avec des conséquences à court et à long terme. La croissance fœtale est un processus complexe mettant en jeu la susceptibilité génétique fœtale mais surtout le milieu intra-utérin à savoir l’environnement métabolique maternel et placentaire. Les mécanismes physiopathologiques en lien avec ces anomalies de croissance dans ce contexte de diabète restent encore incompris et mal expliqués par l’hyperglycémie maternelle seule. A l’interface entre la mère et le fœtus, le placenta exerce plusieurs fonctions influençant le métabolisme maternel et fœto-placentaire donc le développement de l’unité fœto-placentaire. Le placenta, acteur crucial de la programmation fœtale, va s’adapter à son environnement afin de permettre la survie fœtale.L’objectif de ce travail de thèse était d’étudier le compartiment placentaire en analysant l’expression des gènes impliqués dans la croissance fœto-placentaire afin de déterminer des facteurs prédictifs des anomalies de croissance au cours du diabète maternel. Pour répondre à cet objectif, nous avons d'abord utilisé un modèle de rate gestante rendue diabétique par la streptozotocine seule ou associée avec la nicotinamide et validé certains de nos résultats dans des placentas issus de patientes diabétiques de type 1. L’analyse du transcriptome placentaire a mis en évidence l’implication prépondérante de certains gènes appartenant à la famille prolactine (PRL), au système rénine-angiotensine et aux métalloprotéases. La caractéristique phénotypique de ces ratons était de présenter un RCIU à la naissance avec sur le plan histologique une hypovascularisation placentaire associée.Nous nous sommes surtout intéressés aux gènes placentaires appartenant à la famille PRL, non décrits auparavant dans la littérature dans le diabète, comme prl8a2, connu aussi sous le nom de Dprp (Decidual Prolactin Related-Protein). La PRL dans sa forme native de 23-kDa a des propriétés pro-angiogéniques alors que clivée en vasoinhibines par la Bone morphogenetic protein1 (BMP1), la cathepsine D, a des propriétés anti-angiogéniques. Chez nos 2 modèles de rates, nous confirmons une surexpression par qPCR de Dprp, et de Bmp1 et une augmentation du rapport du clivage de la PRL et donc des vasoinhibines par rapport aux contrôles.Nous avons pu valider ces résultats dans des placentas de patientes diabétiques de type 1 dont la caractéristique chez les nouveaux nés était un petit poids de naissance. Enfin, nous nous sommes intéressés à la cinétique de ces anomalies concernant la famille PRL dans nos modèles animaux. Nous avons pu montrer chez la rate gestante diabétique que le RCIU était présent dès le 14ème jour de gestation et que la quantité en vasoinhibines et l’expression des gènes Bmp1 et Dprp n'étaient modifiées qu'à partir du 17ème jour de gestation.Ces travaux sont en faveur d’une implication de la PRL placentaire et de ses vasoinhibines dans le diabète maternel laissant leur supposer un rôle dans l’hypovascularisation placentaire, mise en évidence à la fois chez l'homme et l'animal. En perspective, nous envisageons de poursuivre ces travaux avec une approche plus fonctionnelle. Il convient de préciser l’implication de la BMP1 en confirmant sa responsabilité dans le clivage de la PRL, en analysant plus finement la relation entre vasoinhibines et hyperglycémie en tenant compte du degré et de la durée d’exposition de l'hyperglycémie. Enfin, il serait intéressant de regarder l’implication de la PRL placentaire non plus au cours du RCIU mais plutôt au cours de la macrosomie fœtale, qui reste l’anomalie de croissance la plus fréquente au cours du diabète maternel. / Despite the improvement of obstetrical and diabetological care, the pregnancy of the patient presenting a gestational or pregestational diabetes remains ourdays at a high risk for the mother and for its child. For the child, fetal growth disorders such as macrosomia but also intra-uterine growth restriction (IUGR) are still very frequent with short and long-term consequences. Fetal growth is a complex process involving the fetal genetic susceptibility but also the intra-uterine environment especially in its maternal and placental metabolic aspects. The link between the physiopathological mechanisms of these disorders and fetal growth in this context of maternal diabetes remains unclear and partially explained by maternal hyperglycemia only. At an interface between the mother and the fetus, the placenta employes multiples functions that influence maternal, fetal and placental metabolisms and consequently the fetoplacental unit development. The placenta, as crucial actor of fetal programming, must adapt to its environnment for the survival of the fetus.The objectives of this thesis were to study the placental compartment with an analysis of expression of genes involved in feto-placental growth to determine the predictive factors of these growth disorders during maternal diabetes. To bring a response to these objectives, we used initially a model of gestant rat diabetes induced by streptozotocin alone or in combination with nicotinamide and we validated some of our results in the placenta from type 1 diabetic mothers.The placental transcriptomic analysis pointed out the involvment of some genes of the prolactin (PRL) family, of the renine-angiotensin-aldosterone system and of metalloproteinase family. The principal phenotypical characteristic of the pups at birth was an IUGR with an histological aspect of a placental hypovascularization associated.We focused especially to the placental genes of the PRL familly, non described before in the litterature in diabetes, such as prl8a2 also known as Dprp (decidual prolactin related-protein). PRL in its native form of 23 kDa is proangiogenic but when processed by Bone morphogenetic protein 1 (BMP-1) or cathepsin D (CTSD) to vasoinhibins has antiangiogenic properties. In our 2 rat models, we demonstrated by qPCR an upregulation of Bmp-1 and Dprp with an increase amount of vasoinhibins when compared to controls.We could validate some of our results in the placenta from diabetic type 1 women with a characteristic of small birth weight of the newborns.Finally, we interested in the course of these disorders concerning PRL family in our animal models during their pregnancy. We could demonstrate that IUGR was present by 14th day of gestation. Bmp-1 or Dprp gene expression and the vasoinhibin amount were not different between groups at the 14th day of gestation but modified by 17th day of gestation.These studies highlighted a placental involvment of PRL and its vasoinhibins during maternal diabetes suggesting a role in placental hypovascularisation in animal and women.The perspectives will be in continuing these studies with a more functional approach. We have to bring more details about the involvment of BMP-1 in this PRL process with an in-depth analysis of the link between hyperglycemia and vasoinhibins among the degree and the time of exposition to hyperglycemia. Finally, it would be interesting to study the involvment of placental PRL not only in the cases of IUGR but also in that of macrosomia, that remains the most frequent fetal growth disorder during maternal diabetes.

Contexte. La corpulence de la mère au moment de la conception et son évolution pondérale pendant la grossesse ont été mises en relation dans de nombreuses études avec le poids de naissance de l’enfant et sa croissance postnatale, ainsi qu’avec le risque ultérieur d’obésité et d’anomalies métaboliques de la mère et de l’enfant. Néanmoins, peu d’études se sont intéressées à la trajectoire pondérale de la mère avant grossesse et à son lien avec le déroulement de la grossesse et avec la croissance et l’adiposité des enfants.Objectif : Etudier les relations entre différents paramètres de l’histoire pondérale de la mère avant et pendant la grossesse et leurs liens avec le risque de diabète gestationnel et la corpulence des enfants.Populations. Nous avons utilisé les données de deux cohortes mère-enfant françaises : ELFE et EDEN. L’étude Elfe (Etude longitudinale française depuis l’enfance) a inclus 18329 nouveau-nés dans un échantillon aléatoire de 344 maternités en 2011 en France métropolitaine. La cohorte EDEN (l’Étude des Déterminants pré- et postnatals du développement et de la santé de l’Enfant) a recruté 2002 femmes enceintes dans les maternités de Nancy et Poitiers entre 2003 et 2006. Dans les deux cohortes nous avons utilisé des données du dossier obstétrical et des questionnaires remplis par les parents. Dans la cohorte EDEN nous disposions également des données des examens cliniques des femmes pendant la grossesse et en post-partum, du nouveau-né et de l’enfant à 5-6 ans, incluant l’estimation de la composition corporelle par impédancemétrie des enfants à 5-6 ans.Résultats. Dans la cohorte Elfe, un régime avant grossesse, une perte ou un gain de poids important avant grossesse étaient associés à un gain de poids pendant la grossesse plus important, indépendamment de l’IMC pré-conceptionnel et du statut socio-économique. L’association positive entre la perte pondérale avant grossesse et la prise de poids gestationnelle était plus marquée chez les femmes obèses en début de grossesse ou ayant suivi un régime avant la grossesse. Les femmes ayant pris beaucoup de poids dans l’année avant grossesse présentaient un risque plus élevé de diabète gestationnel, indépendamment de la corpulence atteinte à la conception.Dans la cohorte EDEN, l’IMC maternel pré-conceptionnel était positivement associé à l’IMC, au pourcentage de masse grasse et à une distribution plus défavorable de l’adiposité (tronculaire, viscérale) des enfants à 5-6 ans. Ces associations étaient observées indépendamment de la prise de poids pendant la grossesse et du statut socio-économique des femmes. Une analyse fine de la forme des relations a permis de souligner l’existence de liens essentiellement aux deux extrémités de la corpulence maternelle. Après ajustement sur l’IMC pré-conceptionnel, le gain pondéral gestationnel était positivement associé au Z-score d’IMC des enfants à 5-6 ans, surtout chez les femmes maigres avant grossesse. Un ajustement supplémentaire sur le poids de naissance des enfants a diminué la force des associations entre le Z-score d’IMC des enfants et l’IMC maternel ou la prise de poids pendant la grossesse, mais les deux associations restaient significatives.Conclusion. Une perte de poids avant grossesse, surtout si elle est intentionnelle, semble engendrer une augmentation compensatoire du gain de poids pendant la grossesse. La prise de poids importante avant grossesse, au-delà de la corpulence maternelle en début de grossesse, pourrait être considérée comme un facteur de risque indépendant de diabète gestationnel. A l’âge de 5-6 ans, l’effet rémanent de l’environnement nutritionnel intra-utérin sur l’adiposité des enfants n’est détecté que chez les femmes maigres ou très obèses avant grossesse. D’autres études chez l’enfant sont nécessaires pour pouvoir conclure sur des recommandations de perte de poids avant grossesse chez les femmes en surpoids et obèses. / Context. Maternal BMI at conception and weight gain during pregnancy were related in numerous studies with offspring’s birth weight and postnatal growth, as well as with mothers’ and children’s obesity and metabolic risk later on. Nevertheless, few studies addressed the weight trajectory of the mother before pregnancy and its association with children’s growth and adiposity.Objective: To study the associations between different parameters of maternal weight history before and during pregnancy and their relations with the risk of gestational diabetes and with children’s BMI and adiposity.Populations. We used data from two French mother-child cohorts: ELFE and EDEN. The ELFE study (Etude longitudinale française depuis l’enfance) included 18329 newborns in a random sample of 344 maternity wards in 2011 in mainland France. The EDEN cohort (study of pre- and early postnatal determinants of child development and health) recruited 2002 pregnant women in the maternity wards of Nancy and Poitiers between 2003 and 2006. We used data from obstetric files and from questionnaires filled-in by parents in both cohorts. In addition, the EDEN cohort had data from clinical examinations (of mothers during pregnancy and after delivery and of children at birth and at 5-6 years of age), including the estimation of children’s body composition by bio-impedancemetry at 5-6 years.Results. In the ELFE study, either maternal dieting to lose weight or an important weight gain or loss in the year before pregnancy were associated with a higher weight gain during pregnancy, independently of maternal pre-pregnancy BMI and socioeconomic status. The positive association between weight loss before pregnancy and weight gain during pregnancy was stronger in women who were obese or who had reported weight-reducing diets before pregnancy. Women who had gained an important amount of weight in the year before pregnancy had a higher risk of gestational diabetes, independently of the BMI reached at the beginning of pregnancy.Our analyses on the EDEN cohort showed that maternal pre-pregnancy BMI was positively related with children’s BMI, fat mass percent and central adiposity at 5-6 years of age. These associations were observed independently of women’s weight gain during pregnancy and socioeconomic status. A more thorough analysis of the shape of these relations showed associations essentially at the extremities of the maternal BMI range. Gestational weight gain was positively associated with children’s BMI Z-score at 5-6 years, after adjustment for maternal pre-pregnancy BMI, especially in women who were thin before pregnancy. Additional adjustment for children’s birth weight decreased the force of associations between children’s BMI Z-score and both maternal pre-pregnancy BMI and gestational weight gain, but both associations remained statistically significant.Conclusion. Important weight loss before pregnancy, especially if intentional, seems to enhance a compensatory increase in gestational weight gain. Important weight gain before pregnancy, beyond its role in maternal BMI reached before pregnancy, might be considered as an independent risk factor of gestational diabetes. At 5-6 years, the persistent effect of the intra-uterine environment on children’s BMI and adiposity is only detected in women who were thin or severely obese before pregnancy. Additional studies on children are necessary in order to conclude on weight loss recommendations before pregnancy in overweight and obese women.

Preeclampsia (PE), intrauterine growth restriction (IUGR) and gestational diabetes (GDM) increase the risk of maternal and fetal morbidity and mortality. The roles of Advanced Glycation End-products (AGEs) are already well documented concerning inflammation, hypoxia and oxidative stress. AGEs bind to its receptor, Receptor for Advanced Glycation End-products (RAGE), and activate an inflammatory pathway. This pathway alters the efficacy of invasive trophoblast cells and in the placenta and can result in placental dysfunction. We hypothesized that the placental dysfunction found in PE, IUGR, and GDM resulted from an over activation of the RAGE-mediated inflammatory pathway. Using human placental samples, we found that RAGE protein expression via western blotting was increased in PE and decreased in IUGR while GDM remained similar to that of control placentas. We then wanted to determine the efficacy of RAGE activation to alter the invasive nature of invasive cytotrophoblasts cells. We found that the addition of AGEs to SW71 cells decreases invasion through the activation of JNK and ERK cellular signaling pathways. Altogether these findings suggest that RAGE activation in trophoblast cells seems result in insufficient placental pathogenesis causing PE, however the IUGR and GDM samples we obtained did not seem to have resulted from RAGE activation. We also found that RAGE activation can alter the ability of invasive trophoblasts to invade, thus limiting the ability of the placental cells to remodel the maternal spiral arteries. We believe that further research into specific triggers of IUGR (smoking-induced) and un-treated diabetes could result in RAGE stimulated placental insufficiency.

Objective To evaluate the relationship between dietary habits, physical activity and cognitive views and the risk of gestational diabetes mellitus (GDM) in Chinese women. Design A cross-sectional study to explore the potential risk factors of GMD through the International Physical Activity Questionnaire, an FFQ and a self-designed structured questionnaire, respectively. Setting Guangzhou, Guangdong Province, China. Subjects Chinese pregnant women (n 571) who underwent a 75-g oral glucose tolerance test at their 24th to 28th gestational week. Results Thirteen per cent of the investigated women were identified as having GDM, and an increased intake of local featured foods and lower physical activity were observed in the GDM-positive group v. The GDM-negative group. Women who regarded early-pregnancy morning sickness as relevant to fetal abnormalities and those with unlimited dietary intake after the ending of morning sickness both had an increased risk for GDM (P = 0·018 and P = 0·038, respectively). After multiple logistic regression analysis, cognitive views for unlimited food intake subsequent to morning sickness, increased consumption of energy-dense snack foods and high-glycaemic-index fruits were strongly associated with the risk of GDM (OR = 1·911, P = 0·032; OR = 1·050, P = 0·001; and OR = 1·002, P = 0·017, respectively). Conclusions Local featured foods and incorrect cognitive views on pregnancy-related health were closely related to the risk of GDM in Chinese women. Intensive health education about pregnancy physiology and reasonable dietary and physical exercise behaviours should be strengthened for the control of GDM.

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第21458号 / 人健博第65号 / 新制||人健||5(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 任 和子, 教授 古田 真里枝, 教授 万代 昌紀 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

No description available.

Pregnancy brings numerous physiological and psychosocial changes and conditions, which can include gestational diabetes mellitus (GDM), and mental health conditions, including anxiety, and mood disorders such as depression. Food insecurity, or not having access to a diet that meets needs and preferences, may make management of pregnancy complications more challenging. I examined whether or not food insecurity was associated with a greater prevalence of mental health conditions, or GDM during pregnancy. I used the biocultural and syndemics approaches to the investigate the relationships among these conditions and to understand their interactions with the larger environment. The main questions are: (1) Does pregnancy increase the risk of developing or worsening food insecurity? (2) Are there positive associations between food insecurity during pregnancy and GDM as well as mental health conditions? (3) How does food insecurity impact the management of above-mentioned issues? (4) What are the experiences of individuals who have had GDM during pregnancy? To answer these questions, I undertook a mixed methods approach that involved quantitative analysis of the Canadian Community Health Survey, as well as a survey administered to pregnant people in the city of Hamilton. I also quantitatively analyzed pre-existing focus group transcripts and conducted one-on-one interviews with pregnant and postpartum people in Hamilton. This study found that there is a syndemic interaction between food insecurity, GDM, and mental health conditions in Canada. Analysis of focus group and interview transcripts provided further insight into the complex environments that shape risk for developing one, or more of these conditions during pregnancy. These results indicate how the pregnancy experience is impacted by a multitude of factors, which can lead to increasing complication risk. / Thesis / Master of Arts (MA)

OBJECTIVE: Our purpose was to determine the effects of insulin and glucose on glucose transport and expression of GLUT1 glucose transporter messenger ribonucleic acid in first-trimester human trophoblast-like cells. STUDY DESIGN: First-trimester human trophoblast-like cells were maintained as a continuous cell line. For 2[3H]deoxy-d-glucose uptake and messenger ribonucleic acid studies the cells were incubated in the presence or absence of insulin (10-7 to 10-11 mol/L) or d-glucose (0 to 50 mmol/L) for 0 to 24 hours. Glucose transport was measured by incubating cells with 0.1 mmol/L,2[3H]deoxy-d-glucose for 5 minutes. Specific uptake was determined by incubating companion cultures with 10 μmol/L cytochalasin B. The cells were then solubilized with sodium hydroxide and the radioactivity counted. Data were expressed as nanomoles of 2[3H]deoxy-d-glucose transported per milligram of protein per 5 minutes and analyzed by one-way analysis of variance with post hoc testing by the method of Tukey. GLUT1 messenger ribonucleic acid was measured by Northern blotting of total ribonucleic acid samples hybridized to a phosphorus 32-labeled complementary deoxyribonucleic encoding the rat GLUT1 glucose transporter. As a control for loading efficiency, blots were stripped and rehybridized to a 40-mer phosphorus 32-labeled β-actin oligonucleotide probe. RESULTS: Insulin treatment resulted in a dose-dependent increase in the transport of 2[3H]deoxy-d-glucose at 24 hours (p < 0.001 at 10-7 mol/L). This change was first detected at 12 hours of incubation. These data closely paralled the insulin-induced increase in GLUT1 messenger ribonucleic acid seen in Northern blots. In contrast to insulin, increasing concentrations of d-glucose did not change the transport of 2[3H]deoxy-d-glucose. However, when cells were incubated in low concentrations of d-glucose (0 or 1 mmol/L), an enhancement in the uptake of 2[3H]deoxy-d-glucose (p < 0.001) was observed. Kinetic studies indicated that d-glucose augmentation of 2[3H]deoxy-d-glucose uptake was significant at 9 hours (p < 0.05). The effects of d-glucose on GLUT1 messenger ribonucleic acid expression paralleled the uptake of 2[3H]deoxy-d-glucose, although the modulation of GLUT1 messenger ribonucleic acid levels by glucose was much less pronounced than in insulin-treated cells. CONCLUSION: Although it has been assumed that the placenta has a limited role in influencing glucose transport to the fetus, our in vitro data demonstrate that both insulin and glucose can modulate glucose transport at the cellular level of the placental trophoblast. Thus maternal insulin and glycemic status may influence the expression of GLUT1, the major trophoblast glucose transporter protein, therefore directly affecting first-trimester placental glucose transport. These in vitro data may help explain the association between maternal glucose abnormalities and impaired fetal development during the first trimester when placental GLUT1 messenger ribonucleic acid expression is at its peak.

Gestational diabetes (GDM) occurs in up to 9% of pregnancies. Perinatal depression affects up to 20% of women during pregnancy, and can extend into the postpartum period. A number of studies have linked depression and diabetes, however, whether this applies to GDM or which might come first is less understood. The purpose of this study was to examine the potential relationship between depression identified in the first trimester of pregnancy and the subsequent development of GDM. Women without pre-existing Type I/II diabetes (n = 1021) were evaluated for depression during the first trimester of pregnancy, and medical records were reviewed to identify a positive history of diabetes. Women identified as depressed during the first trimester were more likely to have GDM compared to those not depressed. After controlling for demographic factors and weight-related variables level of depression in the first trimester still predicted later GDM development. Depression identified in early pregnancy may predict increased risk of subsequent GDM development. Due to the numerous maternal, fetal and neonatal complications associated with GDM, early recognition is essential to promote the best possible outcomes for mother and infant. Recognizing depression as a possible risk factor for GDM development could lead to earlier screening and preventative measures.

Introduction: Gestational diabetes (GDM) affects one in three pregnancies and women with GDM have a 10-fold higher risk of developing type-2 diabetes during their lifetime. Similarly, hypertensive disorders (HPD) of pregnancy affect up to one in seven pregnancies and have a 4-fold increase in the risk of hypertension and a 2-fold risk of cardiovascular diseases (CVD) over the lifetime. Primary care (PC) transitions are critical for the management of GDM and HDP to reduce the long-term risk of developing type-2 diabetes, hypertension, and CVD. Despite clinical guidelines recommending PC follow-up for continuous and sustainable care practice, only 50% of postpartum mothers transition to PC within 12 months. Few studies examine this issue and none in South Carolina. Therefore, our study uses Medicaid Claims data to examine the extent to which postpartum mothers with GDM and HDP transition to PC within 12 months of childbirth. Methods: We examined cross-sectional data of Medicaid women with a live birth in the years 2017 and 2018 in South Carolina. Women above the age of 20, receiving postpartum services within 12 months of delivery were included in the study. Primary care visits was the outcome variable of interest. Any women with at least one primary care visit (Family/General Practice Physician visit) claim in the 12 months following birth were considered as a primary care transition. GDM, HDP, and both (GDM &HDP) were the primary independent variables of interest. Results: In 14,273 postpartum mothers, the prevalence of GDM, HDP, and both (GDM & HDP) were found to be 10.02%, 15.05%, and 3.60% respectively. Among the women with GDM, 47.02% had visited PC compared to 35.02% of women without GDM (p<0.001). Similarly, 48.12% of women with HDP visited PC compared to 34.23% of women without HDP (p<0.001). In addition, 52.66% of women with both (GDM & HDP) visited PC compared to 35.72% of women without both (GDM & HDP) (p<0.001). After adjusting for maternal age, ethnicity, residence, and pay category, women with GDM were 1.43 times more likely to visit PC as compared to the women with no GDM (95% CI: 1.27–1.61). Similarly, the odds of visiting PC by women with HDP was 1.67 times higher as compared to women without HDP (95% CI: 1.51 – 1.84). Conclusion: In this study, postpartum mothers with GDM and HDP had higher odds of PC visits compared with those without GDM and without HDP respectively. This is positive. However, the overall percentage of women visiting PC with chronic disease was lower than 50%. To change health outcomes among women with chronic diseases like GDM and HDP, lifelong screening and disease management are needed. It is necessary to link postpartum mothers with PC to improve illness management and raise screening adherence. However, more barriers preventing under-resourced women from receiving PC should be analyzed and addressed.