O-17: GLP-1 – C-peptide lag reveals altered incretin – β-cell coupling during MMTT in GCK, HNF1A, HNF4A diabetes patients

Abstract

Introduction: Physiological response and the role of the incretins are well-characterized in healthy individuals. However, there is limited data regarding the incretin-insulin axis in patients with monogenic diabetes (MD). Objectives: Evaluate the timing between GLP-1 and C-peptide peaks during a mixed meal tolerance test (MMTT). By comparing GCK, HNF1A, HNF4A patients vs. healthy controls, we aim to assess β-cell responsiveness and incretin sensitivity across different MD types. Methods: 17 subjects with GCK diabetes (median age 15.3 yrs (IQR 13.6 – 17.8 yrs); 6 - HNF1A, with a median age 20.0 yrs (IQR 15.2 – 23.8 yrs); and two - HNF4A diabetes, aged 24.5 and 25.9 yrs. Control group consisted of 19 subjects (median age 23.2 yrs (IQR 22.6 – 24.6 yrs). C-peptide and GLP-1 levels were measured at 9 time points during a standard MMTT. Area under the curve (AUC) was calculated using the trapezoidal method. An incretin responsiveness index was defined as AUCC-peptide divided AUCGLP-1. GLP-1 – to – C-peptide lag analysis: lag=Tmax (C-peptide) – Tmax (GLP-1). Mann–Whitney U test was used for group comparisons. Results: The incretin responsiveness index was significantly reduced across all MD subtypes. Compared to controls 78.6 [62.4– 96.8], the index was lower in GCK 32.1 [24.7–41.3], p< 0.00001; in HNF1A 27.4 [21.9–33.8, p=0.0004; and in HNF4A 1.08 [0.89–1.27, p=0.0002. GLP-1–to–C-peptide lag differed across groups. Controls demonstrated a median lag of 0 min. (IQR 0–45), while GCK showed marked variability with a wide range including negative values (median 0, IQR −60 to 30). In contrast, HNF1A and HNF4A exhibited a more consistent positive lag (median 30 min.), indicating delayed but preserved temporal coupling. Conclusions: The incretin responsiveness index demonstrated a stepwise impairment in incretin-mediated β-cell responsiveness: Controls->GCK->HNF1A->HNF4A, suggesting the failure of β-cells to respond appropriately in time.