Placental proteome abnormalities in women with gestational diabetes and large-for-gestational-age newborns

Assi, Emma; D’Addio, Francesca; Mandò, Chiara; Maestroni, Anna; Loretelli, Cristian; Nasr, Moufida Ben; Usuelli, Vera; Abdelsalam, Ahmed; Seelam, Andy Joe; Pastore, Ida; Magagnotti, Cinzia; Abdi, Reza; Essawy, Basset El; Folli, Franco; Corradi, Domenico; Zuccotti, Gianvincenzo; Cetin, Irene; Fiorina, Paolo

doi:10.1136/bmjdrc-2020-001586

Cited by 19 publications

(12 citation statements)

References 34 publications

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“…With the establishment of the tissue model and single-cell RNA profiles 56,57 , more precise roles for PAPP-A activity will be discovered. ProMBP is abnormal in large-for-gestationalage (LGA) and shows mislocation in fetal membranes 58,59 . STC2 is regarded to be highly related to human height, as some STC2 variants containing the height-increasing alleles display compromised proteolytic inhibition of PAPP-A, leading to increased cleavage of IGFBP4 60,61 .…”

Section: Discussionmentioning

confidence: 99%

Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2

et al. 2022

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Originally discovered in the circulation of pregnant women as a protein secreted by placental trophoblasts, the metalloprotease pregnancy-associated plasma protein A (PAPP-A) is also widely expressed by many other tissues. It cleaves insulin-like growth factor-binding proteins (IGFBPs) to increase the bioavailability of IGFs and plays essential roles in multiple growth-promoting processes. While the vast majority of the circulatory PAPP-A in pregnancy is proteolytically inactive due to covalent inhibition by proform of eosinophil major basic protein (proMBP), the activity of PAPP-A can also be covalently inhibited by another less characterized modulator, stanniocalcin-2 (STC2). However, the structural basis of PAPP-A proteolysis and the mechanistic differences between these two modulators are poorly understood. Here we present two cryo-EM structures of endogenous purified PAPP-A in complex with either proMBP or STC2. Both modulators form 2:2 heterotetramer with PAPP-A and establish extensive interactions with multiple domains of PAPP-A that are distal to the catalytic cleft. This exosite-binding property results in a steric hindrance to prevent the binding and cleavage of IGFBPs, while the IGFBP linker region-derived peptides harboring the cleavage sites are no longer sensitive to the modulator treatment. Functional investigation into proMBP-mediated PAPP-A regulation in selective intrauterine growth restriction (sIUGR) pregnancy elucidates that PAPP-A and proMBP collaboratively regulate extravillous trophoblast invasion and the consequent fetal growth. Collectively, our work reveals a novel covalent exosite-competitive inhibition mechanism of PAPP-A and its regulatory effect on placental function.

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Section: Discussionmentioning

confidence: 99%

Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2

et al. 2022

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“…It is known that the placenta is the main organ for the mother to transport nutrients to the fetus. At present, it has been found that placental dysfunction may be the direct cause of abnormal growth and development of the offspring of pregnant women with GDM through proteomics 37. This view deserves our attention and also provides new ideas for our next research.…”

Section: Discussionmentioning

confidence: 86%

Effect of the interaction between advanced maternal age and pre-pregnancy BMI on pre-eclampsia and GDM in Central China

Sun

Luo

Wang

et al. 2023

BMJ Open Diab Res Care

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IntroductionTo investigate the independent and combined effects of advanced maternal age and pre-pregnancy body mass index (BMI) on the risk of pre-eclampsia and gestational diabetes mellitus (GDM).Research design and methodsLogistic regression models were used to estimate the OR and 95% CIs of pre-eclampsia and GDM with advanced maternal age and pre-pregnancy BMI, respectively, and the interaction between advanced maternal age and pre-pregnancy BMI. We also used causal mediation analysis to assess the mediating role of pre-pregnancy BMI on maternal age–pre-eclampsia/GDM associations.ResultsIn this study, 788 cases (2.31%) were diagnosed with pre-eclampsia and 5430 cases (15.92%) were diagnosed with GDM. We found that advanced maternal age was associated with a higher risk for pre-eclampsia and GDM, with adjusted ORs (aORs) of 1.74 (95% CI 1.49–2.05) and 1.76 (95% CI 1.65–1.89) after adjusting for potential confounders, respectively. In addition, maternal pre-pregnancy overweight/obesity was associated with the risk of pre-eclampsia and GDM, with the corresponding aORs of 3.64 (95% CI 3.12–4.24) and 1.71 (95% CI 1.60–1.85), respectively. We also observed the interaction between maternal age and pre-pregnancy BMI for the risk of pre-eclampsia/GDM (all p for interaction <0.001). In the mediating effect analysis, we found that maternal pre-pregnancy BMI mediated the associations between maternal age and the development of pre-eclampsia and GDM.ConclusionsAdvanced maternal age and pre-pregnancy BMI were respectively associated with the risk of pre-eclampsia/GDM, and there was an interaction between the two risk factors. In addition, we found that pre-pregnancy BMI served as a mediator of the association between advanced maternal age and the risk of pre-eclampsia/GDM, providing an essential target for the prevention of maternal overweight/obesity.

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“…Mothers with GDM displayed a significantly increased global placental DNA methylation (3.22 ± 0.63 vs. 3.00 ± 0.46% (±SD), p = 0.013) [ 57 ]. Additional light was shed on the pathogenesis of GDM by studies on disorders of the placental proteome, where the placental proteome was altered in pregnant women affected by GDM with large-for-gestational-age (LGA), with at least 37 proteins being differentially expressed to a higher degree ( p < 0.05) as compared with those with GDM but without LGA [ 59 ]. In addition, Khosrowbeygi et al showed that women with GDM had higher values of TNF-α (225.08 ± 27.35 vs. 115.68 ± 12.64 pg/mL, p < 0.001) and lower values of adiponectin (4.50 ± 0.38 vs. 6.37 ± 0.59 µg/mL, p = 0.003) and the adiponectin/TNF-α ratio (4.31 ± 0.05 vs. 4.80 ± 0.07, p < 0.001) than normal pregnant women.…”

Section: Resultsmentioning

confidence: 99%

Gestational Diabetes Mellitus—Recent Literature Review

Modzelewski

Stefanowicz-Rutkowska

Matuszewski

et al. 2022

JCM

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Gestational diabetes mellitus (GDM), which is defined as a state of hyperglycemia that is first recognized during pregnancy, is currently the most common medical complication in pregnancy. GDM affects approximately 15% of pregnancies worldwide, accounting for approximately 18 million births annually. Mothers with GDM are at risk of developing gestational hypertension, pre-eclampsia and termination of pregnancy via Caesarean section. In addition, GDM increases the risk of complications, including cardiovascular disease, obesity and impaired carbohydrate metabolism, leading to the development of type 2 diabetes (T2DM) in both the mother and infant. The increase in the incidence of GDM also leads to a significant economic burden and deserves greater attention and awareness. A deeper understanding of the risk factors and pathogenesis becomes a necessity, with particular emphasis on the influence of SARS-CoV-2 and diagnostics, as well as an effective treatment, which may reduce perinatal and metabolic complications. The primary treatments for GDM are diet and increased exercise. Insulin, glibenclamide and metformin can be used to intensify the treatment. This paper provides an overview of the latest reports on the epidemiology, pathogenesis, diagnosis and treatment of GDM based on the literature.

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Placental proteome abnormalities in women with gestational diabetes and large-for-gestational-age newborns

Cited by 19 publications

References 34 publications

Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2

Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2

Effect of the interaction between advanced maternal age and pre-pregnancy BMI on pre-eclampsia and GDM in Central China

Gestational Diabetes Mellitus—Recent Literature Review

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