Diabetologia. 2017 Oct;60(10):1903-1912. doi: 10.1007/s00125-017-4380-6.

Metabolic profiling of gestational diabetes in obese women during pregnancy.

White SL1, Pasupathy D2, Sattar N3, Nelson SM4, Lawlor DA5,6, Briley AL2, Seed PT2, Welsh P3, Poston L2; UPBEAT Consortium.

1 Division of Women‘s Health, King’s College London, 10th floor North Wing, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, UK. sara.white@kcl.ac.uk.
2 Division of Women‘s Health, King’s College London, 10th floor North Wing, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, UK.
3 Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
4 School of Medicine, University of Glasgow, Glasgow, UK.
5 MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Bristol, UK.
6 School of Social and Community Medicine, University of Bristol, Bristol, UK.

Abstract

AIMS/HYPOTHESIS:

Antenatal obesity and associated gestational diabetes (GDM) are increasing worldwide. While pre-existing insulin resistance is implicated in GDM in obese women, the responsible metabolic pathways remain poorly described. Our aim was to compare metabolic profiles in blood of obese pregnant women with and without GDM 10 weeks prior to and at the time of diagnosis by OGTT.

METHODS:

We investigated 646 women, of whom 198 developed GDM, in this prospective cohort study, a secondary analysis of UK Pregnancies Better Eating and Activity Trial (UPBEAT), a multicentre randomised controlled trial of a complex lifestyle intervention in obese pregnant women. Multivariate regression analyses adjusted for multiple testing, and accounting for appropriate confounders including study intervention, were performed to compare obese women with GDM with obese non-GDM women. We measured 163 analytes in serum, plasma or whole blood, including 147 from a targeted NMR metabolome, at time point 1 (mean gestational age 17 weeks 0 days) and time point 2 (mean gestational age 27 weeks 5 days, at time of OGTT) and compared them between groups.

RESULTS:

Multiple significant differences were observed in women who developed GDM compared with women without GDM (false discovery rate corrected p values <0.05). Most were evident prior to diagnosis. Women with GDM demonstrated raised lipids and lipoprotein constituents in VLDL subclasses, greater triacylglycerol enrichment across lipoprotein particles, higher branched-chain and aromatic amino acids and different fatty acid, ketone body, adipokine, liver and inflammatory marker profiles compared with those without GDM.

CONCLUSIONS/INTERPRETATION:

Among obese pregnant women, differences in metabolic profile, including exaggerated dyslipidaemia, are evident at least 10 weeks prior to a diagnosis of GDM in the late second trimester.

KEYWORDS:

Biomarkers; Gestational diabetes; Lipids; Obesity; Pregnancy; Targeted metabolome

PMID: 28766127

 

Supplement

Antenatal obesity and associated gestational diabetes (GDM) are increasing worldwide. In this article we explore the biochemical differences during pregnancy between obese women who develop GDM and those who do not, utilising conventional platforms and nuclear magnetic resonance (NMR) spectroscopy.

Metabolic adaptations occurring during pregnancy aid the growth of a healthy fetus and prepare mother and baby for the post-partum. These changes include a physiologically beneficial increase in insulin resistance. In contrast, pre-pregnancy insulin resistance, which is often observed in obese women, is linked with an increased risk of GDM and complications for the baby.

It is known that the metabolic adaptation to pregnancy in obese women differs from that occurring in normal weight; elucidation of the metabolic pathways leading to GDM in this subset of women would be useful as fewer than one third of obese pregnant women actually develop GDM. Indeed, no distinction is currently made in clinical practice and all are categorised as high risk.

The UK Pregnancies Better Eating and Activity Trial (UPBEAT) was a study designed to prevent GDM in obese women and reduce the incidence for large-for-gestational age infants, via a dietary and physical activity intervention. As there were no differences in primary outcomes between intervention arms, the trial women were treated as a cohort for these analyses. Our metabolomics study is a secondary analysis of UPBEAT data, covering 646 pregnant women with a BMI of ≥ 30kg/m2, of whom 198 (30.6%) developed GDM (IADPSG criteria). Blood samples were taken early in gestation (15 – 18+6 gestational weeks; time point 1) and again at the time of oral glucose tolerance testing (OGTT, 23+2 – 30+0 gestational weeks; time point 2).

The metabolic profiles were obtained by evaluating 163 analytes from a high-throughput targeted NMR metabolomics platform and conventional laboratory analyses. The NMR platform allows a detailed analysis of lipoproteins (very low density lipoprotein; VLDL, low density lipoprotein; LDL, intermediate density lipoprotein; IDL, high density lipoprotein; HDL, each of varying sizes) and their constituents (non-esterified cholesterol, cholesteryl esters, phospholipid, triacylglycerol), amino acids, glycolysis-related metabolites, ketones and inflammatory markers. A number of other markers linked with Type 2 diabetes, insulin resistance or GDM were measured with conventional laboratory assays.

Analysis of the data collected showed that there were many differences in the metabolic profiles of obese GDM and obese non-GDM women, many of which were present at least 10 weeks prior to diagnostic testing at the end of the second trimester. GDM women had higher total lipids in all VLDL subclasses (apart from very small) at both measurement times than non-GDM women, as well as numerous other lipid differences. Glycemic markers (insulin, C-Peptide, fructosamine) and low grade inflammatory markers were raised at both time points. Branched chain (isoleucine, leucine and valine) and aromatic amino acids (phenylalanine and tyrosine) were higher in GDM women and fatty acid measures differed between groups. Adiponectin and sex hormone binding globulin (SHBG) were lower in GDM women both before and at the time of diagnosis.

Overall there was a marked similarity in the differential patterns found between GDM and non-GDM women both pre-diagnosis and at diagnosis. As with insulin resistance observed in non-pregnant individuals, the metabolome showed a complex change in metabolic profile. As well as dysregulation of glucose metabolism, there was also an exaggerated dyslipidaemia, shedding light on how insulin resistance affects lipid metabolism in obese pregnant women.

This is the first longitudinal assessment of a whole range of metabolites associated with GDM amongst a large cohort of obese pregnant women. It is also the first time that a targeted NMR approach has been applied to the study of GDM in obese women. Defining biochemical differences is relevant, as at present, all obese pregnant women are treated as if they have equal risk of developing the condition. Indeed, this new study shows that the metabolic perturbations of exaggerated insulin resistance predate the diagnosis of GDM by many weeks, supporting the recent observation that excessive fetal growth also predates the conventional diagnosis of GDM. Thus, a diagnostic approach based upon a wider range of metabolic abnormalities, as detailed here, might improve treatment and outcomes in pregnancy. The findings also strongly support diagnosis of GDM, particularly in obese women, earlier in pregnancy than is done currently.