Placental IGFBP1 levels during early pregnancy and the risk of insulin resistance and gestational diabetes

Gestational diabetes mellitus (GDM) affects a significant portion of pregnancies globally and is linked to adverse maternal and offspring health outcomes. A defect in insulin sensitivity, or insulin resistance, is a key contributor to GDM and its associated complications. The placenta plays a crucial role in the marked changes in insulin physiology during pregnancy, including the decline in insulin sensitivity. However, the specific placental factors mediating these changes remain largely unknown. This study aimed to identify novel placental factors involved in the physiological changes in insulin sensitivity during pregnancy and contributing to GDM pathophysiology, focusing on the hypothesis that placental factors may play a significant role in maintaining euglycemia in pregnancy, even amidst the natural decline in insulin sensitivity.

Prior research has established a link between insulin resistance and GDM. Studies have shown that individuals with GDM and the lowest insulin sensitivity face the highest risk of hyperglycemia-associated pregnancy complications. While the placenta is recognized as a major driver of changes in insulin physiology during pregnancy, the specific placental factors involved are not fully understood. Classically implicated pregnancy hormones have shown poor correlation with insulin sensitivity. The variability in insulin sensitivity improvement observed in early pregnancy in several studies highlights the need for further investigation into placental factors that influence insulin sensitivity, both positively and negatively.

This study utilized a multi-cohort approach. A genome-wide RNA sequencing (RNA-seq) study was performed on placental samples (n=434) from the Genetic of Glucose regulation in Gestation and Growth (Gen3G) cohort. The Gen3G cohort is a prospective population-based cohort. Participants underwent a 75g oral glucose tolerance test (OGTT) in the late second trimester to assess insulin sensitivity (Matsuda index). Placental samples were collected at delivery, and RNA was extracted and sequenced. Differential gene expression analysis was performed, adjusting for various covariates. Circulating IGFBP1 protein levels were measured in Gen3G and two additional cohorts: the Study of Pregnancy Regulation of Insulin and Glucose (SPRING) and the Massachusetts General Hospital Obstetrical Maternal Study (MOMS). Correlations between IGFBP1 levels and insulin sensitivity, other metabolic traits, and birth anthropometric measurements were assessed. Logistic regression analyses were conducted to investigate the association between early pregnancy IGFBP1 levels and the subsequent diagnosis of GDM. GDM subtypes were also analyzed based on the underlying physiological defects.

RNA-seq analysis identified *IGFBP1* as the gene most strongly associated with insulin sensitivity in the placenta. Higher placental *IGFBP1* expression correlated with greater insulin sensitivity. Circulating IGFBP1 levels rose during pregnancy and declined postpartum, suggesting a placental or decidual source. Across three cohorts, higher circulating IGFBP1 levels were consistently associated with greater insulin sensitivity. Notably, low circulating IGFBP1 levels in early pregnancy predicted a higher risk of subsequent GDM diagnosis in two cohorts. The association between low first-trimester IGFBP1 levels and subsequent GDM was independent of known clinical risk factors such as maternal BMI. Furthermore, the normal pregnancy rise in IGFBP1 was attenuated in insulin-resistant GDM, suggesting that a defect in placental IGFBP1 release may contribute to this specific GDM subtype. Analyses also showed negative correlations between lower IGFBP1 and higher birth weight z-scores and increased risk of large for gestational age (LGA) birth weight.

This study provides strong evidence implicating IGFBP1 in the regulation of insulin sensitivity during pregnancy and in the pathogenesis of GDM. The consistent findings across multiple cohorts strengthen the reliability of the observed associations. The identification of IGFBP1 as a potential predictor of GDM, independent of traditional risk factors, offers a promising avenue for early detection and preventive interventions. The distinct IGFBP1 trajectories in different GDM subtypes suggest the importance of considering this heterogeneity when investigating GDM pathophysiology and developing targeted therapies. The potential mechanisms by which IGFBP1 influences insulin sensitivity remain to be fully elucidated; however, both direct and indirect effects involving IGF-1 and IGF-2 are plausible explanations. Future research should focus on understanding the precise role of IGFBP1 in placental function and its interactions with other hormonal and metabolic factors involved in pregnancy glucose homeostasis.

This study provides strong evidence that placental IGFBP1 plays a crucial role in maintaining maternal glucose homeostasis during pregnancy and that deficiencies in IGFBP1 are associated with an increased risk of GDM, particularly the insulin-resistant subtype. Low circulating IGFBP1 in early pregnancy may serve as a useful predictor of GDM, offering an opportunity for early intervention. Further investigation into the mechanisms of action and potential therapeutic applications of IGFBP1 is warranted.

The study's observational design limits causal inferences. While the sample sizes were substantial, the number of GDM cases, particularly those within specific subtypes, was relatively modest. The use of bulk placental samples prevents precise identification of the cellular source of IGFBP1. Finally, the generalizability of the findings might be limited due to the predominantly white ethnicity of the Gen3G cohort.