introduction
Gestational diabetes mellitus (GDM) and insulin resistance are two key issues in modern pregnancy medicine research, affecting the health of millions of pregnant women worldwide. GDM can have long-term health effects not only on mothers, but also on the next generation. With the deepening of the medical community's understanding of metabolic pathology during pregnancy, more and more research is focused on exploring the link between placental function and metabolic diseases during pregnancy. Insulin-like Growth Factor Binding Protein 1 (IGFBP1) is a protein produced primarily by the liver and secreted into the bloodstream, which plays a key role in regulating the activity of insulin-like growth factor (IGF). Early studies have shown an association between IGFBP1 and insulin sensitivity, but its specific role and mechanism in pregnancy are unclear. The study "Placental IGFBP1 levels during early pregnancy and the risk of insulin resistance and gestational diabetes" published in Nature Medicine on April 16 through multiple international cohorts during pregnancy, as well as rigorous experimental design and extensive data collection, To further explore how IGFBP1 expression in the placenta affects insulin sensitivity from the first trimester to the third trimester and its potential impact on GDM. High-throughput RNA sequencing (RNA-seq) technology was used to quantitatively analyze the expression of IGFBP1 in placental tissues and compare it with the level of IGFBP1 in maternal plasma. The results of the study showed that high levels of placental IGFBP1 expression were associated with higher insulin sensitivity during pregnancy and may reduce the risk of GDM through this mechanism. In addition, the analysis included the Gen3G, the Study of Pregnancy Regulation of Insulin and Glucose (SPRING), and the Massachusetts General Hospital Obstetrical Maternal Study. MOMS), further validating this finding. The significance of this study is that it not only reveals the potential role of IGFBP1 in regulating insulin sensitivity and preventing GDM during pregnancy, but also provides a new idea for early intervention on metabolic health during pregnancy. With a better understanding of IGFBP1 function, new strategies for the prevention and treatment of GDM may be developed in the future to improve the health of pregnant women and their offspring
Highlights
Association between placental IGFBP1 expression and insulin sensitivityThis study analyzed the expression of IGFBP1 (Insulin-like Growth Factor Binding Protein 1) in placental tissue in detail by high-throughput RNA sequencing (RNA-seq) technology. The study found that high expression levels of placental IGFBP1 were strongly associated with higher insulin sensitivity during pregnancy. This finding provides a new perspective on the role of placental function in regulating insulin sensitivity during pregnancy.
跨队列的验证与统一结果研究团队不仅在Gen3G队列中观察到上述现象，还在孕期胰岛素与葡萄糖调节研究（Study of Pregnancy Regulation of Insulin and Glucose, SPRING）和麻省总医院妇产科研究（Massachusetts General Hospital Obstetrical Maternal Study, MOMS）这两个独立的队列中复现了这一结果。 这种跨队列的统一结果增强了研究发现的可靠性和普适性。
The potential to predict gestational diabetes mellitus (GDM) has been demonstrated by the IGFBP1 assay in early pregnancy, which has demonstrated its potential in predicting the risk of GDM. After multivariate adjustment, the risk of GDM was significantly reduced in pregnant women with higher IGFBP1 levels in the first trimester, suggesting the possibility of early prediction of GDM by blood markers.
Clinical and public health implicationsThis study not only improves our understanding of the relationship between placental function and metabolic disease during pregnancy, but may also have implications for public health strategies. Early identification of high-risk groups allows early interventions to be implemented to reduce the incidence of GDM and its impact on maternal and child health.
Strategies
The study aimed to explore the association between placenta-specific transcripts and insulin sensitivity during pregnancy through genome-wide transcriptomic analysis of human placental tissue. In the study, 434 human placental samples were collected and gene expression was quantified using RNA sequencing technology. First, the research team enrolled participants in the first trimester (average gestational age of about 9 weeks) and performed an oral glucose tolerance test (75g-OGTT) in the second trimester (average gestational week of about 26 weeks) to assess insulin sensitivity. Insulin sensitivity was estimated using the Matsuda index, which has been shown to be in good agreement with the euglycemic technique during pregnancy. After data processing and quality control (QC), the differential expression of 15,202 genes in placental RNA expression data was analyzed to explore the relationship between these expressions and the Matsuda index. Transcripts associated with insulin sensitivity were screened using multivariate linear regression models, taking into account technique, exact variables (e.g., gestational age at delivery, fetal sex), and potential confounders (e.g., gestational size, maternal age, and body mass index). In addition, the study measured the protein levels of insulin-like growth factor-binding protein 1 (IGFBP1) in the plasma of these pregnant women and explored its association with placental IGFBP1 gene expression. IGFBP1 is a binding protein produced primarily by the liver and is commonly associated with the risk of insulin resistance and type 2 diabetes (T2D) outside of pregnancy. The findings suggest that higher circulating IGFBP1 levels are associated with higher insulin sensitivity, a finding that was validated in three different pregnancy cohorts. This study reveals the possible role of placenta-specific genes in changes in insulin sensitivity during pregnancy, providing potential biomarkers and targets for early identification of gestational diabetes risk and the development of new therapeutic strategies
Behind the Scenes
Gestational Diabetes Mellitus (GDM)Gestational diabetes refers to varying degrees of impaired glucose tolerance first identified or diagnosed during pregnancy. This is usually detected in the third trimester, especially when an oral glucose tolerance test (OGTT) is performed at 24 to 28 weeks' gestation.
According to the International Diabetes Federation (IDF), the global incidence of gestational diabetes is about 7% to 13%, and this proportion varies significantly among different countries and regions and different ethnicities. For example, the incidence is higher in Southeast Asia and the Pacific, while it is relatively low in Europe and North America. The occurrence of gestational diabetes is not only related to genetic, environmental and lifestyle factors, but also closely related to factors such as maternal age, weight and family history of diabetes.
Effects on maternal and infant healthGestational diabetes can pose a range of health risks to both mother and baby. For mothers, gestational diabetes increases the risk of gestational hypertension, preeclampsia, dystocia, and may develop type 2 diabetes mellitus (T2DM) after childbirth. For newborns, they may have macrosomia, neonatal hypoglycemia, jaundice and breathlessness, and in the long term, these babies are at relatively high risk of diabetes and obesity in the future.
The role of the placenta in gestational diabetesThe placenta is a key organ in pregnancy, responsible for the exchange of nutrients and oxygen, and is also the center of production of several hormones and biologically active substances. These substances are essential for the metabolic state of the mother and the development of the fetus. During pregnancy, the placenta causes significant changes in insulin resistance through the secretion of hormones such as human chorionic gonadotropin (hCG), human placental lactogen (hPL), and placental growth hormone (GH). Although these hormones are the traditional blamers of insulin resistance in pregnancy, studies have shown that they correlate poorly with insulin sensitivity.
IGFBP1 regulates insulin sensitivity and diabetes risk outside of pregnancyInsulin-like growth factor-binding protein 1 (IGFBP1) is mainly produced by the liver and plays an important role in regulating insulin sensitivity. Low levels of IGFBP1 have been shown to be strongly associated with insulin resistance and a predictor of the risk of type 2 diabetes (T2D). For example, the study of Hagström et al. showed that IGFBP1 is associated with advanced liver fibrosis, which is often associated with insulin resistance.
Insulin Regulation: The expression of IGFBP1 is negatively regulated by insulin. That is, when insulin levels rise, IGFBP1 expression is inhibited. This regulatory mechanism has been studied in liver cells. Insulin reduces the expression of the IGFBP1 gene by inhibiting its transcription, a mechanism that reflects the complex interaction between IGFBP1 and insulin sensitivity.
Association with Metabolic and Growth RegulationIGFBP1 not only regulates insulin sensitivity, but also participates in the regulation of growth and metabolism by binding to insulin-like growth factors (IGFs). IGFBP1 is able to bind to IGF-1 and IGF-2, two growth factors that play a key role in growth and metabolism in the body. According to Bae et al., IGFBP1 is able to modulate its biological effects by enhancing or inhibiting the activity of IGF, depending on the physiological environment.
Potential IGF-Independent ActionsIn addition to being an IGF-binding protein, IGFBP1 may also have IGF-independent physiological effects. Studies have shown that IGFBP1 can directly activate the PI3K/AKT signaling pathway associated with insulin signaling, suggesting that it may have potential applications in the treatment of diabetes and other metabolic diseases. For example, studies in mice have found that injection of the active IGFBP1 peptide improves insulin sensitivity in diet-induced obese mice.
Changes in IGFBP1 levels during pregnancy Changes in IGFBP1 levels in the first to second trimester: Studies have shown that lower levels of IGFBP1 (insulin-like growth factor-binding protein 1) during the first trimester predicts the risk of subsequent gestational diabetes mellitus (GDM). For example, in the Gen3G cohort, the median IGFBP1 in the first trimester (first trimester) was 66,610 pg/ml, while at 24 to 32 weeks' gestation, the level rose to 79,379 pg/ml. This increase suggests that IGFBP1 may be predominantly produced by the placenta and has important endocrine functions during pregnancy. Change in IGFBP1 levels in the third trimester: however, IGFBP1 levels in the third trimester (immediately postpartum) drop dramatically, for example, to 16,588 pg/ml in the first postpartum trimester. This significant decline may reflect a decrease in placental production of IGFBP1 and a change in pregnancy status.
Placental expression of IGFBP1 in the context of pregnancy is significantly associated with insulin sensitivity: in the placenta, IGFBP1 expression is significantly correlated with insulin sensitivity during pregnancy. The expression level of IGFBP1 gene in the placenta was found to be positively correlated with insulin sensitivity (β = 0.43; P = 2.5 × 10^-5）。 This suggests that IGFBP1 may affect maternal metabolic status by modulating insulin-like growth factor activity of the placenta. Association of IGFBP1 with gestational diabetes: low IGFBP1 levels in early pregnancy are associated with an increased risk of GDM in later pregnancy. For example, in the Gen3G cohort, the risk of GDM was reduced by more than 50% for each standard deviation increase in IGFBP1 levels in the first trimester (OR = 0.44; IQR = 0.30–0.64; P < 0.001）。 This highlights the possible importance of monitoring IGFBP1 levels in the first trimester of pregnancy for the prevention of GDM. Correlation with insulin-resistant GDM: Among the different physiological subtypes of GDM, IGFBP1 levels were delayed in the second trimester of pregnancy in insulin-resistant GDM, while IGFBP1 levels were similar to those in the normal glucose tolerance (NGT) group in insulin-deficient GDM. This suggests that IGFBP1 may have different physiological pathways in different types of GDMs.
The study of the predictive ability of IGFBP1 level and GDM diagnosis in early pregnancy showed that the Receiver Operating Characteristic Area Under the Curve (ROC AUC) was 0.66 for the diagnosis of gestational diabetes using only clinical variables (such as maternal age, gestational frequency, etc.). When the IGFBP1 level of early pregnancy was added to the model, the predictive ability increased to ROC AUC=0.72 (P=0.008), indicating that IGFBP1 level has important value in predicting gestational diabetes.
IGFBP1 deletion and the pathogenesis of gestational diabetes suggest that the loss of placental IGFBP1 may be part of the pathogenesis of GDM. IGFBP1 is predominantly expressed by the liver in the nonpregnant state, and its production is regulated by insulin. During pregnancy, IGFBP1 is not only expressed in placental cells and Hofbauer cells of the placenta, but may also be released by endometrial decidualized cells, which are involved in regulating insulin sensitivity during pregnancy, thereby affecting the nutritional balance of the mother and fetus.
Correlation between IGFBP1 level and placental function during pregnancyPlacental IGFBP1 expression and secretion Placental IGFBP1 expression and secretion Throughout pregnancy, the level of insulin-like growth factor binding protein 1 (IGFBP1) expressed by placental cells was significantly higher than that in non-pregnancy. This phenomenon may be closely related to the contribution of placental and/or decidual cells. In the study, it was found that the expression level of IGFBP1 was 103.4 in millions of transcripts on average, indicating its high expression status in the placenta. In addition, decidual cells and Hofbauer cells were also observed to express IGFBP1.
Physiological Functions of IGFBP1 in the PlacentaPlacental IGFBP1 not only enhances secretion during pregnancy, but may also be involved in fetal growth and metabolic regulation by regulating the activity of insulin-like growth factors (IGFs). IGFBP1 is able to modulate the biological activity of these growth factors by binding to IGF-1 and IGF-2. This role is particularly important during pregnancy, as IGF-1 and IGF-2 are key factors in regulating fetal growth.
Variation of IGFBP1 levels during pregnancyIn the first trimester, circulating levels of IGFBP1 predict the risk of gestational diabetes mellitus (GDM) in later trimester. For example, in the Gen3G study, the average concentration of IGFBP1 in the first trimester was 66,610 pg/ml, while at 24 to 32 weeks' gestation, the concentration increased to 79,379 pg/ml. This change reflects the close association of IGFBP1 levels with placental function and suggests that the placenta may be the main source of high circulating IGFBP1 levels during pregnancy.
Potential LimitationsSample Size LimitationsThe study only performed placental transcriptomic analysis in 434 participants and may not fully reflect biomarker expression in the broader population. In addition, this sample size may limit the statistical power of the findings, making it difficult to find small or moderate-sized associations.
Study Design LimitationsThis study used an observational study design and could not prove causation. Although multivariate regression models were used to adjust for confounders, there was a risk that unobserved confounders could affect the results.
特定人群的适用性(Specific Population Generalizability)研究样本可能主要来源于某一特定地区或种族,研究结果的普适性(generalizability)可能受限。 如果胎盘 IGFBP1(Insulin-like Growth Factor Binding Protein 1)水平在不同人群中表现出显著的异质性,那么研究结果可能无法推广到所有孕妇。
Measurement LimitationsWhile the use of RNA sequencing (RNA-seq) provides detailed data on gene expression, these data can be affected by sample processing, storage, and sequencing platforms. In addition, the measurement of IGFBP1 relies on enzyme-linked immunosorbent assay (ELISA), which, while highly specific, may be limited by antibody specificity and cross-reactivity.
Biological Mechanism Interpretation LimitationsAlthough studies have revealed an association between IGFBP1 and insulin sensitivity in pregnancy, its biological mechanism is still not fully understood. The effect of IGFBP1 on IGF-1 and IGF-2 (Insulin-like Growth Factor 1 and 2) mentioned in the study may depend on a variety of factors, and these complex interactions may vary in different physiological and pathological states.
Cross-sectional Analysis LimitationsAlthough studies have measured the relationship between IGFBP1 levels and insulin sensitivity at different time points, this cross-sectional analysis is not effective in explaining causal relationships over time. In addition, cross-sectional studies are often more difficult to exclude confounders.
Potential research directions: Detailed functional studies of placental IGFBP1: To further explore the specific biological functions and mechanisms of placental IGFBP1 during pregnancy, especially how it affects insulin sensitivity by regulating the balance of fetal and maternal nutrient needs. IGFBP1 expression in pathological conditions: changes in IGFBP1 expression in GDM and other pregnancy complications can be of interest, which may help determine the specific aspects of GDM pathogenesis and its role in other pregnancy-related metabolic problems. Exploration of the clinical application of IGFBP1: to explore how IGFBP1 levels in the first trimester can be used as a biomarker to predict GDM, as well as possible preventive measures, such as regulating IGFBP1 levels through nutritional or pharmacological interventions to reduce the risk of GDM. Gene editing and animal model research: Verify the function of IGFBP1 through gene editing technology and animal models, and observe the effects of its deletion or overexpression on the pregnancy process and fetal development, so as to better understand its physiological and pathological effects.
Link to original article
Hivert MF, White F, Allard C, James K, Majid S, Aguet F, Ardlie KG, Florez JC, Edlow AG, Bouchard L, Jacques PÉ, Karumanchi SA, Powe CE. Placental IGFBP1 levels during early pregnancy and the risk of insulin resistance and gestational diabetes. Nat Med. 2024 Apr 16. doi: 10.1038/s41591-024-02936-5. Epub ahead of print. PMID: 38627562.
https://www.nature.com/articles/s41591-024-02936-5
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