The discovery of novel predictive biomarkers and early-stage pathophysiology for the transition from gestational diabetes to type 2 diabetes
Gestational diabetes mellitus (GDM) affects up to 20% of pregnancies, and almost half of the women affected progress to type 2 diabetes later in life, making GDM the most significant risk factor for the development of future type 2 diabetes. An accurate prediction of future type 2 diabetes risk in the early postpartum period after GDM would allow for timely interventions to prevent or delay type 2 diabetes. In addition, new targets for interventions may be revealed by understanding the underlying pathophysiology of the transition from GDM to type 2 diabetes. The aim of this study is to identify both a predictive signature and early-stage pathophysiology of the transition from GDM to type 2 diabetes.
We used a well-characterised prospective cohort of women with a history of GDM pregnancy, all of whom were enrolled at 6–9 weeks postpartum (baseline), were confirmed not to have diabetes via 2 h 75 g OGTT and tested anually for type 2 diabetes on an ongoing basis (2 years of follow-up). A large-scale targeted lipidomic study was implemented to analyse ~1100 lipid metabolites in baseline plasma samples using a nested pair-matched case–control design, with 55 incident cases matched to 85 non-case control participants. The relationships between the concentrations of baseline plasma lipids and respective follow-up status (either type 2 diabetes or no type 2 diabetes) were employed to discover both a predictive signature and the underlying pathophysiology of the transition from GDM to type 2 diabetes. In addition, the underlying pathophysiology was examined in vivo and in vitro.
Machine learning optimisation in a decision tree format revealed a seven-lipid metabolite type 2 diabetes predictive signature with a discriminating power (AUC) of 0.92 (87% sensitivity, 93% specificity and 91% accuracy). The signature was highly robust as it includes 45-fold cross-validation under a high confidence threshold (1.0) and binary output, which together minimise the chance of data overfitting and bias selection. Concurrent analysis of differentially expressed lipid metabolite pathways uncovered the upregulation of α-linolenic/linoleic acid metabolism (false discovery rate [FDR] 0.002) and fatty acid biosynthesis (FDR 0.005) and the downregulation of sphingolipid metabolism (FDR 0.009) as being strongly associated with the risk of developing future type 2 diabetes. Focusing specifically on sphingolipids, the downregulation of sphingolipid metabolism using the pharmacological inhibitors fumonisin B1 (FB1) and myriocin in mouse islets and Min6 K8 cells (a pancreatic beta-cell like cell line) significantly impaired glucose-stimulated insulin secretion but had no significant impact on whole-body glucose homeostasis or insulin sensitivity.
We reveal a novel predictive signature and associate reduced sphingolipids with the pathophysiology of transition from GDM to type 2 diabetes. Attenuating sphingolipid metabolism in islets impairs glucose-stimulated insulin secretion.
KeywordsGestational diabetes mellitus Glucose-stimulated insulin secretion Lipidomic study Machine learning Multiple logistic regression Pathophysiology Predictive biomarker Prospective cohort Sphingolipid metabolism Type 2 diabetes
Branched-chain amino acid
False discovery rate
Fasting plasma glucose
Glucose-stimulated insulin secretion
Kyoto Encyclopedia of Genes and Genomes
Multiple logistic regression
Principal component analysis
Partial least squares-discriminant analysis
Receiver operating characteristic
Study of Women, Infant Feeding and Type 2 Diabetes after GDM
SRK, MBW, EPG, BJC, HM and YL designed the research work. All predictive analytics and bioinformatics were performed by SRK and supervised by MBW and BJC. All in vivo studies were conducted by SRK, HG, HM, YL, DAR, BB and YM. All in vitro studies were conducted by HM, BB and SRK. The manuscript was written by SRK and edited by MBW, EPG, BJC, HM and YL. All authors assisted in reviewing the manuscript and gave final approval of the version to be published. MBW is the guarantor of this work.
These studies are supported by Canadian Institutes of Health Research (CIHR), FRN 143219 (MBW). and National Institute of Child Health and Human Development (NICHD) R01 HD050625 (EPG). SRK is supported by a Diabetes Canada post-doctoral fellowship.
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
- 5.Gunderson EP, Lewis CE, Tsai AL et al (2007) A 20-year prospective study of childbearing and incidence of diabetes in young women, controlling for glycemia before conception: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Diabetes 56(12):2990–2996. https://doi.org/10.2337/db07-1024
- 12.Fadl H, Magnuson A, Östlund I, Montgomery S, Hanson U, Schwarcz E (2014) Gestational diabetes mellitus and later cardiovascular disease: a Swedish population based case-control study. BJOG 121(12):1530–1536. https://doi.org/10.1111/1471-0528.12754
- 16.American Diabetes Association (2016) Management of diabetes in pregnancy. Diabetes Care 39(Suppl 1):S94–S98. https://doi.org/10.2337/dc16-S015
- 22.Russell MA, Phipps MG, Olson CL, Welch HG, Carpenter MW (2006) Rates of postpartum glucose testing after gestational diabetes mellitus. Obstet Gynecol 108(6):1456–1462. https://doi.org/10.1097/01.AOG.0000245446.85868.73 CrossRefPubMedGoogle Scholar
- 27.Chen T, Ni Y, Ma X et al (2016) Branched-chain and aromatic amino acid profiles and diabetes risk in Chinese populations. Sci. Rep. 6:20594. https://doi.org/10.1038/srep20594
- 29.Wang-Sattler R, Yu Z, Herder C et al (2012) Novel biomarkers for pre-diabetes identified by metabolomics. Mol Syst Biol 8:615. https://doi.org/10.1038/msb.2012.43
- 47.Park JW, Park WJ, Kuperman Y, Boura-Halfon S, Pewzner-Jung Y, Futerman AH (2013) Ablation of very long acyl chain sphingolipids causes hepatic insulin resistance in mice due to altered detergent-resistant membranes. Hepatology 57(2):525–532. https://doi.org/10.1002/hep.26015 CrossRefPubMedGoogle Scholar