Associations of maternal BMI and insulin resistance with the maternal metabolome and newborn outcomes

Abstract

Aims/hypothesis Maternal obesity increases the risk for large-for-gestational-age birth and excess newborn adiposity, which are associated with adverse long-term metabolic outcomes in offspring, probably due to effects mediated through the intrauterine environment. We aimed to characterise the maternal metabolic milieu associated with maternal BMI and its relationship to newborn birthweight and adiposity. Methods Fasting and 1 h serum samples were collected from 400 European-ancestry mothers in the Hyperglycaemia and Adverse Pregnancy Outcome Study who underwent an OGTT at ~28 weeks gestation and whose offspring had anthropometric measurements at birth. Metabolomics assays were performed using biochemical analyses of conventional clinical metabolites, targeted MS-based measurement of amino acids and acylcarnitines and non-targeted GC/MS. Results Per-metabolite analyses demonstrated broad associations with maternal BMI at fasting and 1 h for lipids, amino acids and their metabolites together with carbohydrates and organic acids. Similar metabolite classes were associated with insulin resistance with unique associations including branched-chain amino acids. Pathway analyses indicated overlapping and unique associations with maternal BMI and insulin resistance. Network analyses demonstrated collective associations of maternal metabolite subnetworks with maternal BMI and newborn size and adiposity, including communities of acylcarnitines, lipids and related metabolites, and carbohydrates and organic acids. Random forest analyses demonstrated contribution of lipids and lipid-related metabolites to the association of maternal BMI with newborn outcomes. Conclusions/interpretation Higher maternal BMI and insulin resistance are associated with broad-based changes in maternal metabolites, with lipids and lipid-related metabolites accounting, in part, for the association of maternal BMI with newborn size at birth.

Metabolic profiling of gestational diabetes in obese women during pregnancy

“…These included elevated pyruvate and alanine (both substrates of carbohydrate metabolism), raised acetoacetate (likely secondary to unregulated fatty acid oxidation and/or increased metabolism of BCAA) and higher citrate (an early intermediate of the TCA cycle). The observed increase in alanine concurs with previous metabolomic studies of mild hyperglycaemia in pregnant women of heterogeneous BMI from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort [8,9].…”

“…As described in weight-heterogeneous GDM women [34] and in recent studies [35] including HAPO [8,9], BCAA were higher in GDM women, implicating a predominant influence of insulin resistance as opposed to obesity. Whether elevation of BCAA reflects cause or effect is unclear; the mechanism may relate to reduced branch-chain α-ketoacid dehydrogenase activity as implicated in insulin resistance in non-pregnant states, although multiple pathological processes may be involved [36][37][38].…”

“…It adds to observations in which the metabolome as measured by mass spectrometry was investigated in mildly hyperglycaemic women from the HAPO study (BMI 29.0 kg/m 2 ; SD 4.89, at OGTT) [8]. In the present study, we have defined differences in the metabolic profile of GDM specific to obese women.…”

“…There was a marked similarity in differential patterns found pre-diagnosis of GDM and at the time of diagnosis. Of the few previous reports of dysglycaemia in pregnancy in which the serum/plasma metabolome has been described, none has previously addressed GDM confined to obese women and recent reports have focused on moderate hyperglycaemia [8,9]. As anticipated and in line with the diagnosis of GDM, obese women had raised dysglycaemic markers, including HbA 1c , fructosamine and insulin, and these were raised before diagnosis.…”

“…Two recent metabolomic studies of normal pregnancy have described widespread metabolic perturbations that extend beyond the traditional boundaries of insulin resistance to encompass pathways including amino acids, lipoproteins and inflammatory markers [3,4]. GDM has also been the focus of some recent metabolomic studies, although to date all have included participants from across the maternal weight spectrum, which is itself known to affect the maternal metabolome [5][6][7][8][9]. None has addressed the metabolome in obese women prior to and at the time of GDM diagnosis.…”