Introduction and Objective: Gestational diabetes mellitus (GDM) increases the risk of early-onset prediabetes (<40 years). We hypothesized that biological pathways mediating the transition from pregnancy to early-onset prediabetes one year postpartum differ between women with prior GDM and those with normoglycemic (NG) pregnancies, using stratified longitudinal analyses with deep metabolic phenotyping.Methods: In the prospective, multicenter PREG study, we evaluated 181 women (56 GDM; 125 NG) at 24+0-31+6 weeks gestation and again at one year postpartum. Assessments included anthropometrics, OGTT-based indices of insulin resistance (IR) and secretion, hormonal analyses including incretins, MRI/¹H-MRS-based body fat distribution, and untargeted metabolomics.Results: Early-onset prediabetes occurred in 35% of women with prior GDM and 24% of women with NG pregnancies. Among NG women, progression to prediabetes was mainly driven by increasing IR, predominantly hepatic, alongside greater hepatic and visceral fat accumulation compared with NG women who remained normoglycemic. In contrast, among women with GDM, those transitioning to prediabetes versus those regressing to normoglycemia showed similar trajectories of whole-body IR and hepatic/visceral fat but uniquely failed to increase beta-cell function from pregnancy to one year postpartum. Beta-cell function increased postpartum in all groups except the prior-GDM group. Pregnancy metabolomics identified elevated triglyceride-rich lipoproteins and VLDL particles as predictors of early-onset prediabetes independent of GDM status.Conclusion: Early-onset prediabetes within one year postpartum is common after both GDM and NG pregnancies but arises via distinct mechanisms: persistent beta-cell dysfunction after GDM and rising IR with hepatic and visceral fat accumulation after NG pregnancies. These findings support stringent postpartum screening and mechanism-tailored prevention strategies.
J. Sbierski-Kind: None. M. Ganslmeier: None. Y. Kober: None. A. Vosseler: None. L. Semeia: None. S. Kullmann: None. M. Roden: Advisory Panel; Current; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Madrigal Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Echosens. M. Bluher: Consultant; Current; Amgen Inc. Speaker’s Bureau; Current; Abbott. Consultant; Current; Bayer AG, Boehringer Ingelheim International GmbH. Speaker’s Bureau; Current; Daiichi Sankyo. Consultant; Current; Eli Lilly and Company, Novo Nordisk. Speaker’s Bureau; Current; Merck Sharp & Dohme Corp., Sanofi, Novartis AG. M. Schulze: None. N. Stefan: Speaker’s Bureau; Current; AstraZeneca. Advisory Panel; Ended; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Ended; Boehringer Ingelheim International GmbH. Advisory Panel; Ended; Lilly. Speaker’s Bureau; Current; Lilly. Advisory Panel; Ended; Pfizer Inc., Madrigal Pharmaceuticals, Inc. Speaker’s Bureau; Ended; Madrigal Pharmaceuticals, Inc. Research Support; Ended; Sanofi. Speaker’s Bureau; Current; Sanofi. R.J. von Schwartzenberg: None. A. Fritsche: None. C. Trautwein: None. P. Hubert: None. A.L. Birkenfeld: None.
The PREG study is supported in part by a grant from the Federal Ministry of Education and Research 397 (BMBF) (01GI0925) to the German Center for Diabetes Research (DZD). We also thank the Joachim Herz Foundation for supporting L.S. through an Add-on Fellowship. J.S.K. is supported by the Medical Faculty of the University of Tuebingen, the German Diabetes Association (DDG), and the DZD. In addition to funding by the BMBF, RJvS was funded by the Funding Program: Helmholtz Young Investigators Groups. Project ID No.: VH-NG-1619 and the Cluster of Excellence EXC-2124 under the Project Number 03.007. Quantitative NMR spectroscopy analysis was supported by Bruker BioSpin GmbH & Co. KG Ettlingen, Germany. The study was additionally funded by a grant from the German Research Foundation (DFG) to ALB (GRK2816).
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