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Biomolecules Jan 2022As patients recently diagnosed with T1D and patients with T2D have residual beta cell mass, there is considerable effort in beta cell biology to understand the...
As patients recently diagnosed with T1D and patients with T2D have residual beta cell mass, there is considerable effort in beta cell biology to understand the mechanisms that drive beta cell regeneration as a potential cellular therapy for expanding patients' residual beta cell population. Both mouse and human studies have established that beta cell mass expansion occurs rapidly during pregnancy. To investigate the mechanisms of beta cell mass expansion during pregnancy, we developed a novel in vivo and in vitro models of pseudopregnancy. Our models demonstrate that pseudopregnancy promotes beta cell mass expansion in parous mice, and this expansion is driven by beta cell proliferation rather than hypertrophy. Importantly, estrogen, progesterone, and placental lactogen induce STAT5A signaling in the pseudopregnancy model, demonstrating that this model successfully recapitulates pregnancy-induced beta cell replication. We then created an in vitro model of pseudopregnancy and found that the combination of estrogen and placental lactogen induced beta cell replication in human islets and rat insulinoma cells. Therefore, beta cells both in vitro and in vivo increase proliferation when subjected to the pseudopregnancy cocktail compared to groups treated with estradiol or placental lactogen alone. The pseudopregnancy models described here may help inform novel methods of inducing beta cell replication in patients with diabetes.
Topics: Animals; Cell Division; Female; Humans; Insulin-Secreting Cells; Islets of Langerhans; Mice; Placenta; Placental Lactogen; Pregnancy; Rats
PubMed: 35204716
DOI: 10.3390/biom12020215 -
Biology of Sex Differences Nov 2021Current methods fail to accurately predict women at greatest risk of developing fetal growth restriction (FGR) or related adverse outcomes, including stillbirth. Sexual...
BACKGROUND
Current methods fail to accurately predict women at greatest risk of developing fetal growth restriction (FGR) or related adverse outcomes, including stillbirth. Sexual dimorphism in these adverse pregnancy outcomes is well documented as are sex-specific differences in gene and protein expression in the placenta. Circulating maternal serum microRNAs (miRNAs) offer potential as biomarkers that may also be informative of underlying pathology. We hypothesised that FGR would be associated with an altered miRNA profile and would differ depending on fetal sex.
METHODS
miRNA expression profiles were assessed in maternal serum (> 36 weeks' gestation) from women delivering a severely FGR infant (defined as an individualised birthweight centile (IBC) < 3rd) and matched control participants (AGA; IBC = 20-80th), using miRNA arrays. qPCR was performed using specific miRNA primers in an expanded cohort of patients with IBC < 5th (n = 15 males, n = 16 females/group). Maternal serum human placental lactogen (hPL) was used as a proxy to determine if serum miRNAs were related to placental dysfunction. In silico analyses were performed to predict the potential functions of altered miRNAs.
RESULTS
Initial analyses revealed 11 miRNAs were altered in maternal serum from FGR pregnancies. In silico analyses revealed all 11 altered miRNAs were located in a network of genes that regulate placental function. Subsequent analysis demonstrated four miRNAs showed sexually dimorphic patterns. miR-28-5p was reduced in FGR pregnancies (p < 0.01) only when there was a female offspring and miR-301a-3p was only reduced in FGR pregnancies with a male fetus (p < 0.05). miR-454-3p was decreased in FGR pregnancies (p < 0.05) regardless of fetal sex but was only positively correlated to hPL when the fetus was female. Conversely, miR-29c-3p was correlated to maternal hPL only when the fetus was male. Target genes for sexually dimorphic miRNAs reveal potential functional roles in the placenta including angiogenesis, placental growth, nutrient transport and apoptosis.
CONCLUSIONS
These studies have identified sexually dimorphic patterns for miRNAs in maternal serum in FGR. These miRNAs may have potential as non-invasive biomarkers for FGR and associated placental dysfunction. Further studies to determine if these miRNAs have potential functional roles in the placenta may provide greater understanding of the pathogenesis of placental dysfunction and the differing susceptibility of male and female fetuses to adverse in utero conditions.
Topics: Circulating MicroRNA; Female; Fetal Growth Retardation; Humans; Male; Placenta; Pregnancy; Pregnancy Outcome; Sex Factors
PubMed: 34789323
DOI: 10.1186/s13293-021-00405-z -
International Journal of Molecular... Oct 2022In the ruminant placenta, glucose uptake and transfer are mediated by facilitative glucose transporters SLC2A1 (GLUT1) and SLC2A3 (GLUT3). SLC2A1 is located on the...
In the ruminant placenta, glucose uptake and transfer are mediated by facilitative glucose transporters SLC2A1 (GLUT1) and SLC2A3 (GLUT3). SLC2A1 is located on the basolateral trophoblast membrane, whereas SLC2A3 is located solely on the maternal-facing, apical trophoblast membrane. While SLC2A3 is less abundant than SLC2A1, SLC2A3 has a five-fold greater affinity and transport capacity. Based on its location, SLC2A3 likely plays a significant role in the uptake of glucose into the trophoblast. Fetal hypoglycemia is a hallmark of fetal growth restriction (FGR), and as such, any deficiency in SLC2A3 could impact trophoblast glucose uptake and transfer to the fetus, thus potentially setting the stage for FGR. By utilizing in vivo placenta-specific lentiviral-mediated RNA interference (RNAi) in sheep, we were able to significantly diminish ( ≤ 0.05) placental SLC2A3 concentration, and determine the impact at mid-gestation (75 dGA). In response to SLC2A3 RNAi ( = 6), the fetuses were hypoglycemic ( ≤ 0.05), exhibited reduced fetal growth, including reduced fetal pancreas weight ( ≤ 0.05), which was associated with reduced umbilical artery insulin and glucagon concentrations, when compared to the non-targeting sequence (NTS) RNAi controls ( = 6). By contrast, fetal liver weights were not impacted, nor were umbilical artery concentrations of IGF1, possibly resulting from a 70% increase ( ≤ 0.05) in umbilical vein chorionic somatomammotropin (CSH) concentrations. Thus, during the first half of gestation, a deficiency in SLC2A3 results in fetal hypoglycemia, reduced fetal development, and altered metabolic hormone concentrations. These results suggest that SLC2A3 may be the rate-limiting placental glucose transporter during the first-half of gestation in sheep.
Topics: Humans; Pregnancy; Female; Sheep; Animals; Placental Lactogen; Glucose Transporter Type 3; Glucagon; Glucose Transporter Type 1; Placenta; Fetal Growth Retardation; Fetal Weight; Glucose; Hypoglycemia; Hypoglycemic Agents; Insulins
PubMed: 36293384
DOI: 10.3390/ijms232012530 -
The American Journal of Clinical... Apr 2023The goal of Working Group 1 in the Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN) Project was to outline factors influencing biological processes governing...
Parental factors that impact the ecology of human mammary development, milk secretion, and milk composition-a report from "Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN)" Working Group 1.
The goal of Working Group 1 in the Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN) Project was to outline factors influencing biological processes governing human milk secretion and to evaluate our current knowledge of these processes. Many factors regulate mammary gland development in utero, during puberty, in pregnancy, through secretory activation, and at weaning. These factors include breast anatomy, breast vasculature, diet, and the lactating parent's hormonal milieu including estrogen, progesterone, placental lactogen, cortisol, prolactin, and growth hormone. We examine the effects of time of day and postpartum interval on milk secretion, along with the role and mechanisms of lactating parent-infant interactions on milk secretion and bonding, with particular attention to the actions of oxytocin on the mammary gland and the pleasure systems in the brain. We then consider the potential effects of clinical conditions including infection, pre-eclampsia, preterm birth, cardiovascular health, inflammatory states, mastitis, and particularly, gestational diabetes and obesity. Although we know a great deal about the transporter systems by which zinc and calcium pass from the blood stream into milk, the interactions and cellular localization of transporters that carry substrates such as glucose, amino acids, copper, and the many other trace metals present in human milk across plasma and intracellular membranes require more research. We pose the question of how cultured mammary alveolar cells and animal models can help answer lingering questions about the mechanisms and regulation of human milk secretion. We raise questions about the role of the lactating parent and the infant microbiome and the immune system during breast development, secretion of immune molecules into milk, and protection of the breast from pathogens. Finally, we consider the effect of medications, recreational and illicit drugs, pesticides, and endocrine-disrupting chemicals on milk secretion and composition, emphasizing that this area needs much more research attention.
Topics: Animals; Humans; Female; Infant; Infant, Newborn; Pregnancy; Lactation; Milk; Milk, Human; Placenta; Premature Birth; Parents
PubMed: 37173058
DOI: 10.1016/j.ajcnut.2022.11.026 -
Cureus Feb 2023The immunoexpression of human placental lactogen (hPL) in mammary epithelium is not well studied in the literature. Our overall objective was to delineate the...
The immunoexpression of human placental lactogen (hPL) in mammary epithelium is not well studied in the literature. Our overall objective was to delineate the distribution pattern of hPL across mammary epithelia of varying levels of differentiation. This is the first research to study the level of expression of hPL in human lactational change epithelium. Immunohistochemistry (IHC) for hPL was performed on archival formalin-fixed paraffin-embedded tissue blocks of 97 cases. These consisted of 53 invasive ductal carcinomas, 21 lactational change cases, and 23 cases of normal mammary tissue. The results of this study show underexpression of hPL in malignant epithelium compared to normal and lactational groups individually and combined as a non-malignant group. However, a higher expression of hPL was noted in mammary carcinoma of axillary lymph node (ALN)-positive patients compared to ALN-negative cases. There was no statistically significant difference between hPL expression and tumor grade, estrogen receptors (ER), progesterone receptors (PR), or human epidermal growth factor receptor 2 (HER2) status. The comparison of the immunoexpression of hPL in malignant epithelium versus lactational change epithelium may provide the basis for future studies on the possible role of hPL in the protective mechanism of lactation tissue from carcinogenesis. Our results could be explained by the proposed mechanism in the literature, which is that breast cancer cells have a potential inhibitory effect on the translation of human chorionic somatotropin hormone (CSH) mRNA into hPL protein. Our results support the literature findings of a poorer prognostic outcome for breast malignancies when hPL is expressed but require further studies using a more comprehensive range of clinical parameters.
PubMed: 36945262
DOI: 10.7759/cureus.35125 -
Journal of Obstetrics and Gynaecology... Oct 2021Pregnancy is characterized by a series of metabolic changes that promote insulin resistance. This could be due to increase in the plasma levels of one or more...
INTRODUCTION
Pregnancy is characterized by a series of metabolic changes that promote insulin resistance. This could be due to increase in the plasma levels of one or more pregnancy-related hormones such as oestrogen, progesterone, prolactin, cortisol, and human placental lactogen (HPL). The increased insulin resistance in pregnancy is associated with development of diabetes which has implications for the future gestations also.
AIMS AND OBJECTIVES
To determine status of insulin resistance in pregnant women and correlate the presence of insulin resistance with obstetric outcome.
MATERIAL AND METHOD
A prospective cohort study was conducted in the Department of Obstetrics and Gynaecology, KGMU, Lucknow, over a period of one year. Total 150 pregnant women were enrolled from OPD, out of which 136 women were followed up till delivery. Insulin resistance was calculated by HOMA IR index, twice in whole antenatal period (first in early pregnancy and second in late pregnancy). All women were also tested for GDM by DIPSI test (plasma glucose value after 2 h of 75 gm glucose load irrespective of last meal) as per protocol.
RESULTS
In our study, we found 71 women out of 136 (52.2%) were GDM. Total 30 women out of 136 (22.05%) were GGI (Gestational Glucose Intolerance), and total 38 out of 136 (27.9%) women were found to have insulin resistance using HOMA IR ≥ 2 as cut off. Significant correlation was found in between BMI and insulin resistance ( = 0.001) and between GDM and insulin resistance ( = 0.001). Relative risk of development of complications like Preeclampsia, neonatal hypoglycemia, and respiratory distress syndrome was higher in women having insulin resistance and GDM.
CONCLUSION
Obstetric complications like preeclampsia, neonatal hypoglycemia, and respiratory distress syndrome are more likely to occur in women with insulin resistance, but larger studies are required to delineate whether insulin resistance alone without development of GDM will have the same implication.
PubMed: 34602761
DOI: 10.1007/s13224-021-01426-9 -
Frontiers in Endocrinology 2019Preeclampsia is a hypertensive disorder affecting 3-5% of all pregnancies. The only curative treatment is delivery of the placenta and the pathophysiology is poorly...
Preeclampsia is a hypertensive disorder affecting 3-5% of all pregnancies. The only curative treatment is delivery of the placenta and the pathophysiology is poorly understood. Studies have demonstrated altered levels of antiangiogenic factors in patients with preeclampsia. One such factor is the antiangiogenic and antivasodilatatory peptide hormone vasoinhibin, which is higher in the circulation, urine, and amniotic fluid of women with preeclampsia. Normal pregnancy is characterized by elevated circulating prolactin and placental lactogen levels, both of which can serve as vasoinhibin precursors when they are enzymatically cleaved. A dysregulation of vasoinhibin generation during preeclampsia is indicated by higher vasoinhibin, prolactin, placental lactogen, and vasoinhibin-generating enzymes levels and activity. The present article integrates known vasoinhibin levels, effects, and signaling mechanisms to the clinical characteristics of preeclampsia to substantiate the notion that vasoinhibin dysregulation can be causally linked to the development of preeclampsia. If this view is demonstrated, assessment of vasoinhibin levels and regulation of its activity could help estimate the risk of preeclampsia and improve its treatment.
PubMed: 31998232
DOI: 10.3389/fendo.2019.00893 -
Physiological Reports Jul 2020The psychoactive component in cannabis, delta-9-tetrahydrocannabinol, can restrict fetal growth and development. Delta-9-tetrahydrocannabinol has been shown to...
The psychoactive component in cannabis, delta-9-tetrahydrocannabinol, can restrict fetal growth and development. Delta-9-tetrahydrocannabinol has been shown to negatively impact cellular proliferation and target organelles like the mitochondria resulting in reduced cellular respiration. In the placenta, mitochondrial dysfunction leading to oxidative stress prevents proper placental development and function. A key element of placental development is the proliferation and fusion of cytotrophoblasts to form the syncytium that comprises the materno-fetal interface. The impact of delta-9-tetrahydrocannabinol on this process is not well understood. To elucidate the nature of the mitochondrial dysfunction and its consequences on trophoblast fusion, we treated undifferentiated and differentiated BeWo human trophoblast cells, with 20 µM delta-9-tetrahydrocannabinol for 48 hr. At this concentration, delta-9-tetrahydrocannabinol on BeWo cells reduced the expression of markers involved in syncytialization and mitochondrial dynamics, but had no effect on cell viability. Delta-9-tetrahydrocannabinol significantly attenuated the process of syncytialization and induced oxidative stress responses in BeWo cells. Importantly, delta-9-tetrahydrocannabinol also caused a reduction in the secretion of human chorionic gonadotropin and the production of human placental lactogen and insulin growth factor 2, three hormones known to be important in facilitating fetal growth. Furthermore, we also demonstrate that delta-9-tetrahydrocannabinol attenuated mitochondrial respiration, depleted adenosine triphosphate, and reduced mitochondrial membrane potential. These changes were also associated with an increase in cellular reactive oxygen species, and the expression of stress responsive chaperones, HSP60 and HSP70. These findings have important implications for understanding the role of delta-9-tetrahydrocannabinol-induced mitochondrial injury and the role this might play in compromising human pregnancies.
Topics: Cannabinoid Receptor Agonists; Cell Line, Tumor; Cell Survival; Chaperonin 60; Dronabinol; Female; Giant Cells; Gonadotropins; HSP70 Heat-Shock Proteins; Humans; Insulin-Like Growth Factor II; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Oxidative Stress; Trophoblasts
PubMed: 32628362
DOI: 10.14814/phy2.14476 -
BMC Women's Health Mar 2021Studies have found an association between obesity and an increased risk for peripartum depression, which has also been linked to decreased placental lactogen levels. In...
BACKGROUND
Studies have found an association between obesity and an increased risk for peripartum depression, which has also been linked to decreased placental lactogen levels. In addition, women with obesity treated for gestational diabetes with insulin were found to have increased levels of placental lactogen. Treatment options exist for perinatal and postpartum depression however they pose a risk to the developing offspring. Thus, prevention as well as markers for early identification of peripartum depression are needed. Therefore, our study objective is to identify the association between insulin treatment in pregnancy and the risk of postpartum psychological distress (abbreviated here as PPD) among cohorts of women with and without obesity.
METHODS
Administrative health data (2002/03-2018/19) were used to identify a cohort of women (age 15+ years) who gave birth (N = 250,746) and had no pre-existing mood/anxiety disorders or diabetes (N = 222,863 excluded). Women were then divided into two groups: lean (N = 17,975) and with obesity (N = 9908), which was identified by a recorded maternal weight of > 38 to < 65.6 kg and ≥ 85 to < 186 kg (respectively). The risk of PPD within one year after delivery with and without insulin treatment was assessed by Poisson regression analysis. Models were adjusted for maternal age group (at pregnancy start date) and area-level income (at delivery).
RESULTS
The unadjusted risk of PPD was higher in the obesity group (8.56%; 95% CI 8.00-9.15) than in the lean group (6.93%; 95% CI 6.56-7.33). When no insulin treatment was given during pregnancy, mothers with obesity had a significantly higher risk of PPD than the lean group (aRR 1.27; 95% CI 1.17-1.39; p < 0.0001). However, when women with obesity and insulin treatment were compared to the lean group with no insulin treatment, no significant difference in the risk of PPD was observed between the groups (aRR 1.30; 95% CI 0.83-2.02; p = 0.248).
CONCLUSION
This is the first study to demonstrate a positive association between insulin treatment in pregnancy among women with obesity and reduced PPD rates, suggesting insulin as a possible preventative measure. However, the biological mechanism behind the observed positive effect of insulin on PPD rates remains to be investigated.
Topics: Adolescent; Depression, Postpartum; Female; Humans; Insulins; Obesity, Maternal; Placenta; Population Health; Postpartum Period; Pregnancy; Psychological Distress; Risk Factors
PubMed: 33743677
DOI: 10.1186/s12905-021-01261-0 -
Reproductive Sciences (Thousand Oaks,... Jan 2015Glucocorticoid treatment given in late pregnancy in sheep resulted in altered placental development and function. An imbalance of placental survival and apoptotic... (Comparative Study)
Comparative Study
Glucocorticoid treatment given in late pregnancy in sheep resulted in altered placental development and function. An imbalance of placental survival and apoptotic factors resulting in an increased rate of apoptosis may be involved. We have now investigated the effects of dexamethasone (DEX) in early pregnancy on binucleate cells (BNCs), placental apoptosis, and fetal sex as a determinant of these responses. Pregnant ewes carrying singleton fetuses (n = 105) were randomized to control (n = 56, 2 mL saline/ewe) or DEX treatment (n = 49, intramuscular injections of 0.14 mg/kg ewe weight per 12 hours over 48 hours) at 40 to 41 days of gestation (dG). Placentomes were collected at 50, 100, 125, and 140 dG. At 100 dG, DEX in females reduced BNC numbers, placental antiapoptotic (proliferating cell nuclear antigen), and increased proapoptotic factors (Bax, p53), associated with a temporarily decrease in fetal growth. At 125 dG, BNC numbers and apoptotic markers were restored to normal. In males, ovine placental lactogen-protein levels after DEX were increased at 50 dG, but at 100 and 140 dG significantly decreased compared to controls. In contrast to females, these changes were independent of altered BNC numbers or apoptotic markers. Early DEX was associated with sex-specific, transient alterations in BNC numbers, which may contribute to changes in placental and fetal development. Furthermore, in females, altered placental apoptosis markers may be involved.
Topics: Animals; Apoptosis; Cell Proliferation; Dexamethasone; Female; Fetal Growth Retardation; Fetal Weight; Gestational Age; Glucocorticoids; Male; Placenta; Pregnancy; Proliferating Cell Nuclear Antigen; Sex Factors; Sheep; Time Factors; Tumor Suppressor Protein p53; bcl-2-Associated X Protein
PubMed: 25063551
DOI: 10.1177/1933719114542028