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. 2024 Jun;30(6):1689-1695.
doi: 10.1038/s41591-024-02936-5. Epub 2024 Apr 16.

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

Marie-France Hivert  1   2   3 , Frédérique White  4 , Catherine Allard  5 , Kaitlyn James  6 , Sana Majid  7 , François Aguet  8 , Kristin G Ardlie  8 , Jose C Florez  9   8   10   11 , Andrea G Edlow  6 , Luigi Bouchard  5   12   13 , Pierre-Étienne Jacques  5   4   14 , S Ananth Karumanchi  15 , Camille E Powe  9   6   8   11
Affiliations

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

Marie-France Hivert et al. Nat Med. 2024 Jun.

Abstract

Reduced insulin sensitivity (insulin resistance) is a hallmark of normal physiology in late pregnancy and also underlies gestational diabetes mellitus (GDM). We conducted transcriptomic profiling of 434 human placentas and identified a 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 gene expression levels in our placenta samples, suggests a placental or decidual source. Higher circulating IGFBP1 levels were associated with greater insulin sensitivity (lesser insulin resistance) at ~26 weeks gestation in the same cohort and in two additional pregnancy cohorts. In addition, low circulating IGFBP1 levels in early pregnancy predicted subsequent GDM diagnosis in two cohorts of pregnant women. These results implicate IGFBP1 in the glycemic physiology of pregnancy and suggest a role for placental IGFBP1 deficiency in GDM pathogenesis.

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Conflict of interest statement

C.E.P. is an Associate Editor of Diabetes Care, receives payments from Wolters Kluwer for UpToDate chapters on diabetes in pregnancy and has received payments for consulting and speaking from Mediflix. M.-F.H. is co-editor of textbook ‘Essentials of Clinical Nutrition in Healthcare’ published by McGraw Hill. F.A. has been an employee of Illumina since 8 November 2021. J.C.F. has received grant funding for an investigator-initiated proposal from Novo Nordisk, a one-time consulting honorarium from AstraZeneca and speaker fees from Merck and Novo Nordisk for scientific presentations over which he had full control of content. J.C.F.’s wife has received a one-time consulting honorarium from Novartis. A.G.E. serves as a consultant for Mirvie and receives research funding from Merck Pharmaceuticals outside of this work. None of these engagements are directly relevant to this work. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Volcano plot showing placenta RNA differential expression in relation to insulin sensitivity (Matsuda, log2 transformed) at 26 weeks gestation in 434 Gen3G participants.
Linear model adjusted for maternal age, gravidity and maternal BMI at first trimester visit, sex of offspring, gestational age at delivery and 37 SVs (from SmartSVA package); gene names identified if P < 1.0 × 10−3. Red dots indicate genes with association P < 1.0 × 10−3 (horizontal dotted line) and absolute log2 fold changes greater than 5 s.d. from the mean (vertical dotted lines).
Fig. 2
Fig. 2. Prediction of GDM diagnosed at a median 26 weeks gestation from first trimester plasma IGFBP1 levels in 837 Gen3G participants (70 GDM cases).
Red line (clinical variables only): ROC curve for GDM diagnosis based on maternal age, gravidity, family history of diabetes, gestational age at V1 and maternal BMI at V1; green line: ROC curve for GDM diagnosis based on all clinical variables plus plasma IGFBP1 levels (measured at a median of 9 weeks of gestation). GDM diagnosed by IADPSG criteria. Shaded areas: 95% CI for each curve (2,000 stratified bootstrap). Comparing AUC values with and without plasma IGFBP1 (Box–Cox transformation) using a two-sided DeLong’s test gave estimates (difference between 2 AUC) = −0.060, 95% CI = −0.104 to −0.015, z = −2.641, P = 0.008.
Fig. 3
Fig. 3. Longitudinal changes in plasma IGFBP1 levels across pregnancy in GDM subtypes and in normal glucose tolerant participants in Gen3G.
Sample size in each group: NGT, n = 767; insulin-resistant GDM, n = 34; insulin-deficient GDM, n = 19; and mixed defect GDM, n = 12. Lines represent the levels of circulating IGFBP1 (not transformed) from the first trimester visit to the late second trimester visit at exact gestational age of the measure, smoothed by a generalized additive model with parameter estimation via restricted maximum likelihood using ‘stat_smooth’ function from the ggplot2 package. Shaded areas represent 95% CIs.
Extended Data Fig. 1
Extended Data Fig. 1. Longitudinal changes in median plasma IGFBP-1 levels across pregnancy and postpartum in normoglycemic SPRING participants (N = 65).
IGFBP1 levels comparison using two-sided Wilcoxon signed-rank test, unadjusted for multiple comparisons. Exact P = 5.08 ×10-15 for differences between V3 (median 9 weeks post-partum) and V1 (median = 13 weeks gestation) and P = 9.18 ×10-19 for differences between V3 and V2 (median= 26 weeks gestation), denoted with *. Blue line is linking median value at each time point. Red bars represent interquartile range at each time point.
Extended Data Fig. 2
Extended Data Fig. 2. Longitudinal changes in median plasma levels of IGFBP-1, insulin, and glucose during 75g-OGTT conducted at median 26 weeks in 27 Gen3G participants.
Panel A: IGFBP1 levels comparison using two-sided Wilcoxon signed-rank test: V = 125, P = 0.13 for differences between 60 min and fasting (0 min); V = 324, P = 0.0007 (denoted with *) for differences between 120 min and fasting (0 min) without adjustment for multiple comparisons. Panel B: insulin levels over three time points of OGTT. Panel C: glucose levels over three time points of OGTT. Blue lines are linking median value between time points. Red bars represent interquartile range at each time point.
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References

    1. Magliano, D., Boyko, E. J. & IDF Diabetes Atlas 10th Edition Scientific Committee. in IDF Diabetes Atlas (eds Boyko, E. J. et al.) Ch. 3, Global picture (International Diabetes Federation, 2021); https://diabetesatlas.org/atlas/tenth-edition/
    1. ElSayed NA, et al. 15. Management of diabetes in pregnancy: standards of care in diabetes—2023. Diabetes Care. 2023;46:S254–S266. - PMC - PubMed
    1. Catalano PM, Kirwan JP, Haugel-de Mouzon S, King J. Gestational diabetes and insulin resistance: role in short- and long-term implications for mother and fetus. J. Nutr. 2003;133:1674S–1683S. - PubMed
    1. Barbour LA, et al. Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes. Diabetes Care. 2007;30:S112–S119. - PubMed
    1. Sun Y, et al. Increasing insulin resistance predicts adverse pregnancy outcomes in women with gestational diabetes mellitus. J. Diabetes. 2020;12:438–446. - PubMed

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