Metabolic Profiling of Pregnant Women with Obesity: An Exploratory Study in Women at Greater Risk of Gestational Diabetes

Abstract

Gestational diabetes mellitus (GDM) is one of the most prevalent obstetric conditions, particularly among women with obesity. Pathways to hyperglycaemia remain obscure and a better understanding of the pathophysiology would facilitate early detection and targeted intervention. Among obese women from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), we aimed to compare metabolic profiles early and mid-pregnancy in women identified as high-risk of developing GDM, stratified by GDM diagnosis. Using a GDM prediction model combining maternal age, mid-arm circumference, systolic blood pressure, glucose, triglycerides and HbA1c, 231 women were identified as being at higher-risk, of whom 119 women developed GDM. Analyte data (nuclear magnetic resonance and conventional) were compared between higher-risk women who developed GDM and those who did not at timepoint 1 (15+0–18+6 weeks) and at timepoint 2 (23+2–30+0 weeks). The adjusted regression analyses revealed some differences in the early second trimester between those who developed GDM and those who did not, including lower adiponectin and glutamine concentrations, and higher C-peptide concentrations (FDR-adjusted p < 0.005, < 0.05, < 0.05 respectively). More differences were evident at the time of GDM diagnosis (timepoint 2) including greater impairment in β-cell function (as assessed by HOMA2-%B), an increase in the glycolysis-intermediate pyruvate (FDR-adjusted p < 0.001, < 0.05 respectively) and differing lipid profiles. The liver function marker γ-glutamyl transferase was higher at both timepoints (FDR-adjusted p < 0.05). This exploratory study underlines the difficulty in early prediction of GDM development in high-risk women but adds to the evidence that among pregnant women with obesity, insulin secretory dysfunction may be an important discriminator for those who develop GDM.

Multigenerational diabetes mellitus

“…Increased ketone bodies in GDM inhibit proteolysis and reduce BCAA and ketogenic acid oxidation in skeletal muscle ( 72 ). BCAAs are consistently associated with GDM, particularly leucine/isoleucine and valine, as well as several carnitine esters of BCAA metabolites, and the BCAA metabolic by-product glutamate/glutamine ( 49 , 51 , 54 , 58 , 60 ). Glycine has also been implicated in diabetes development and is an excitatory neurotransmitter of N-methyl-D-aspartate receptors in beta cells, which accelerates their dysfunction and hyperglycaemia-induced apoptosis ( 54 ).…”

“…FFAs, phosphatidylcholines (PCs) and lysophosphatidylcholines have strong positive relationships with the risk of GDM development ( 72 ), however their utility as diagnostic markers wanes as pregnancy progresses ( 50 ). Interestingly, secondary analysis of high-risk women from the UPBEAT trial reported consistent association of both second and third trimester phospholipids and free cholesterol in small HDL with GDM ( 51 ), highlighting their potential use as biomarkers, particularly in high-risk individuals. Maternal serum triglyceride levels are notably the strongest predictor of macrosomia and are positively related to insulin resistance ( 59 ).…”

Glycolysis: A fork in the path of normal and pathological pregnancy

“…This may be due to increased glucose metabolism or a reduction in mitochondrial transfer or metabolism. 207 In addition, a study examined metabolites in blood samples from 755 women spanning early, mid, and late pregnancy. The results showed that compared with non-obese controls without GDM, the differences in glycolysis-related measures were more pronounced in obese women with GDM than in non-obese women with GDM.…”

“…Recently, a study based on serum samples found that the concentration of pyruvate was elevated in women with GDM than in those at high risk but without GDM. This may be due to increased glucose metabolism or a reduction in mitochondrial transfer or metabolism 207 . In addition, a study examined metabolites in blood samples from 755 women spanning early, mid, and late pregnancy.…”