Early Pregnancy-Associated Plasma Protein A Concentrations Are Associated With Third Trimester Insulin Sensitivity

Abstract

Context:First or early second trimester pregnancy-associated plasma protein A (PAPP-A) concentrations have previously been shown to be lower in women who subsequently develop gestational diabetes mellitus (GDM) and gestational hypertension.Objective:We therefore sought to investigate why circulating PAPP-A concentrations are related to the subsequent risk of GDM and gestational hypertension.Patients, Design, and Setting:We measured serum PAPP-A concentrations around week 15 of pregnancy and related these to indices derived from week 28 oral glucose tolerance tests and blood pressures across pregnancy in the Cambridge Baby Growth Study cohort.Results:Increased PAPP-A concentrations were associated with reduced GDM risk [odds ratio 0.623 (0.453, 0.856), P = 3.5 × 10−3, n = 777] and reduced mean arterial blood pressures (β = −0.202 to −0.177, P = 1.7 to 6.9 × 10−3, n = 347 to 355). They were also negatively associated with week 28 fasting (β = −0.149, P = 6.6 × 10−4, n = 777) and 60-minute (β = −0.188, P = 1.5 × 10−5, n = 777) oral glucose tolerance test glucose concentrations. These associations were underpinned by the strong associations between increased week 15 PAPP-A concentrations and decreased week 28 insulin resistance (homeostasis model assessment of insulin resistance: β = −0.319, P = 1.7 × 10−13, n = 768), as well as increased insulin secretion relative to insulin sensitivity (insulin disposition index: β = 0.202, P = 6.5 × 10−6, n = 731).Conclusions:These results suggest that links between PAPP-A concentrations in early pregnancy and subsequent glucose concentrations and blood pressures may be mediated by changes in insulin sensitivity (and secretion).

Quantitative Proteomics by SWATH‐MS Suggest an Association Between Circulating Exosomes and Maternal Metabolic Changes in Gestational Diabetes Mellitus

“…On the other hand, PAPP‐A was downregulated in GDM exosomes compared with exosomes from NGT. Low levels of circulating PAPP‐A in maternal plasma has been associated with GDM and high levels of CAMK2 in skeletal muscle from GDM have been associated with decrease in insulin sensitive . Therefore, PAPP‐A and CAMK2β were chosen for the validation of the proteomic data in an independent cohort of women with NGT and GDM using ELISA kits.…”

“…Low maternal circulating concentrations of PAPP‐A is correlated with adverse pregnancy outcomes including GDM . Notably, PAPP‐A levels in the first trimester is associated with insulin resistance later in pregnancy . Likewise, in this study, we found that PAPP‐A expression is lower in GDM exosomes compared to NGT exosomes.…”

Temporal Trends without Seasonal Effects on Gestational Diabetes Incidence Relate to Reductions in Indices of Insulin Secretion: The Cambridge Baby Growth Study

“…At a median (inter-quartile range) of 28.4 (28.1-28.7) weeks gestation 1,074 of the CBGS mothers underwent a 75g oral glucose tolerance test (OGTT) after fasting overnight. 27 Venous blood was collected just prior to and 60 min. after the glucose load was administered for the measurement of plasma glucose, insulin and c-peptide concentrations.…”

GDF15 Concentrations in Maternal Serum Associated with Vomiting in Pregnancy: the Cambridge Baby Growth Study

“…The prospective Cambridge Baby Growth Study recruited 2,229 mothers (and their partners and offspring) attending antenatal ultrasound clinics during early pregnancy at the Rosie Maternity Hospital, Cambridge, United Kingdom, between 2001 and 2009 [17]. All mothers were over 16 years of age.…”