Dynamic OGTT-derived C-peptide trajectories for metabolic heterogeneity and adverse pregnancy outcomes in gestational diabetes mellitus: a nested case‒control study

Background: Existing diagnostic criteria for gestational diabetes mellitus (GDM) rely solely on glucose thresholds, which are insufficient to capture metabolic heterogeneity. We aimed to evaluate the role of C-peptide measured during the oral glucose tolerance test (OGTT) in assisting the development of stratified treatment strategies and predicting the risk of adverse pregnancy outcomes. Methods: This nested case–control study conducted within the Xi’an Longitudinal Mother–Child Cohort included 1014 pregnant women with GDM and 1014 without GDM (non-GDM) who delivered singleton live-born infants between January 1, 2017, and December 31, 2018. C-peptide levels were measured at three intervals during the OGTT. Latent class trajectory modeling was used to identify distinct C-peptide trajectories, and logistic regression was used to assess their associations with adverse fetal and maternal outcomes. Results: Two principal C-peptide trajectories were identified in GDM despite similar glucose profiles. GDM Class 1 (771, 76.04%) presented a delayed 120-min C-peptide peak and poorer beta-cell secretion, whereas GDM Class 2 (243, 23.96%) presented a sharp 60-min peak followed by a decline and significantly increased insulin resistance, with greater risks of delivering large for gestational age (LGA) (adjusted odds ratio (aOR), 1.52; 95% confidence interval (CI), 1.07–2.15) and macrosomia (aOR, 1.83; 95% CI, 1.13–2.97). Surprisingly, 21.7% (220) of the non-GDM group had a high C-peptide response associated with elevated preeclampsia risk (aOR, 2.91; 95% CI, 1.25–6.74). Conclusions: Dynamic OGTT-derived C-peptide trajectories revealed clinically significant metabolic subgroups of GDM that were obscured by glucose-only diagnostics, with the predominantly insulin-resistant Class being at higher risk of fetal overgrowth.