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

Abstract

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. 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. 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). 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.