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[Preprint]. 2023 Oct 27:rs.3.rs-3464151.
doi: 10.21203/rs.3.rs-3464151/v1.

Placental RNA sequencing implicates IGFBP1 in insulin sensitivity during pregnancy and in gestational diabetes

Marie-France Hivert  1 , Frederique White  2 , Catherine Allard  2 , Kaitlyn James  3 , Sana Majid  1 , François Aguet  4 , Kristin Ardlie  5 , Andrea Edlow  6 , Jose Florez  3 , Luigi Bouchard  7 , Pierre-Etienne Jacques  2 , S Karumanchi  8 , Camille Powe  9
Affiliations

Placental RNA sequencing implicates IGFBP1 in insulin sensitivity during pregnancy and in gestational diabetes

Marie-France Hivert et al. Res Sq. .

Update in

Abstract

Reduced insulin sensitivity (or greater insulin resistance) is a hallmark of normal physiology in late pregnancy and also underlies gestational diabetes mellitus (GDM) pathophysiology. We conducted transcriptomic profiling of 434 human placentas and identified a strong positive association between insulin-like growth factor binding protein 1 gene (IGFBP1) expression in the placenta and insulin sensitivity at ~ 26 weeks' gestation. Circulating IGFBP1 protein levels rose over the course of pregnancy and declined postpartum, which together with high placental gene expression levels, suggests a placental source. Higher circulating IGFBP1 levels were strongly associated with greater insulin sensitivity (lesser insulin resistance) at ~ 26 weeks' gestation in the same cohort and two additional pregnancy cohorts. In addition, low circulating IGFBP1 levels in early pregnancy predicted subsequent GDM diagnosis in two cohorts. These results implicate IGFBP1 in the glycemic physiology of pregnancy and suggest a role for placental IGFBP1 deficiency in GDM pathogenesis.

Keywords: Insulin Growth Factors (IGF); RNA sequencing; gestational diabetes mellitus; insulin sensitivity; placenta; prediction; pregnancy; transcriptomics.

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Figures

Figure 1
Figure 1. Volcano plot showing placenta RNA differential expression in relation to insulin sensitivity (Matsuda, log2 transformed) at 26 weeks’ gestation in 434 Gen3G participants
model adjusted for maternal age, gravidity, maternal BMI at first trimester visit, sex of offspring, and gestational age at delivery, and 37 SVs (from SmartSVA package); gene names identified if P-values <1.0 × 10−3
Figure 2
Figure 2. Prediction of GDM diagnosed at a median 26 weeks’ gestation from 1 st trimester plasma IGFBP1 levels in 837 Gen3G participants (70 GDM cases)
Red line (clinical variables only) = maternal age, gravidity, family history of diabetes, gestational age at V1, and maternal BMI at V1. Green line: all clinical variables plus plasma IGFBP1 levels (measured a median of 9 weeks of gestation). GDM diagnosed by International Association of the Diabetes in Pregnancy Study Groups (IADPSG) criteria. Shaded area: 95% CI for each curve (2000 stratified bootstrap). Comparing Area under the curve (AUC) values with and without plasma IGFBP1 (box-cox transformation): P-value = 0.008
Figure 3
Figure 3. Longitudinal changes in plasma IGFBP1 levels across pregnancy in GDM subtypes and in normal glucose tolerant participants in Gen3G
Abbreviations: normal glucose tolerance (NGT); Gestational Diabetes Mellitus (GDM). Sample size in each group: NGT n=767; Insulin-resistant GDM n=34; Insulin-deficient GDM n=19; Mixed defect GDM n=12.
See this image and copyright information in PMC

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