The attenuated incretin effect is associated with glucose intolerance in patients with hepatitis B-related acute-on-chronic liver failure

Objective The pathogenesis of glucose homeostasis disturbance in acute-on-chronic liver failure (ACLF) remains poorly defined. This study aimed to investigate the association between incretin effect (IE) and glucose intolerance in patients with hepatitis B virus-related ACLF (HBV-ACLF). Methods In this prospective study, 25 patients with HBV-ACLF were stratified by glucose tolerance: normal glucose tolerance (NGT, n=7), pre-diabetes (pre-DM, n=9), and diabetes mellitus (DM, n=9). All participants underwent paired oral (OGTT) and intravenous glucose tolerance test (IVGTT) within 72 hours of admission. Dynamic profiles of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and insulin were analyzed. The IE, calculated from insulin area under the curve (AUC) differences, was compared across groups. Results Patients with pre-DM and DM exhibited significantly reduced insulin sensitivity and early-phase insulin secretion, alongside elevated insulin resistance, compared to the NGT group. While GLP-1 and GIP responses post-OGTT remained significantly higher than post-IVGTT across all groups, the GIP secretory response was markedly blunted in DM patients compared to those with NGT. Critically, the incremental insulin response during OGTT versus IVGTT was abolished in DM patients but preserved in pre-DM and NGT. Consequently, IE was progressively and significantly reduced from NGT (58.5 ± 9.2%) to pre-DM (44.5 ± 7.5%) to DM (25.8 ± 8.7%) ( P < 0.01). These differences remained statistically significant after adjustment for age, sex, body mass index, Model for End-Stage Liver Disease-Sodium score and C-reactive protein. Conclusion The attenuated IE is associated with the severity of glucose intolerance, and the development of DM is associated with a blunted GIP secretory response in patients with HBV-ACLF.