Impaired Glucagon Suppression Accompanied by Liver Fat Accumulation Mediated Worse Blood Glucose Control in Patients With T2D

Abstract

Context: Metabolic dysfunction-associated steatotic liver disease is prevalent in type 2 diabetes (T2D) and exacerbates hyperglycemia, but its impact on postprandial glucagon suppression remains unclear.

Objective: To investigate the association between hepatic steatosis and impaired glucagon suppression during oral glucose tolerance tests (OGTTs), and to evaluate the mediating role of glucagon dysregulation in linking liver fat to glycemic control.

Methods: In this cross-sectional study, 604 patients with T2D underwent liver fat quantification via the FibroScan Pro controlled attenuation parameter (CAP) and liver ultrasound. Postprandial glucagon suppression was assessed during 180-minute OGTTs (0, 30, 60, 120, 180 minutes), with continuous glucose monitoring (CGM) in 287 participants. Glucagon suppression was calculated for early (0-30 minutes), late (30-180 minutes), and overall (0-180 minutes) phases. Multivariable regression and mediation analyses tested associations between CAP, glucagon dynamics, and CGM-derived glycemic profiles.

Results: Patients with T2D with MASLD (CAP ≥238 dB/m, n = 414) exhibited significantly impaired glucagon suppression compared to non-MASLD controls (n = 190) across all phases (all P < .05). Each 1-SD CAP increase independently predicted attenuated dose-dependent suppression in all phases (standardized β = 0.183-0.303, P < .001). Males showed greater suppression impairment than females and stronger CAP-associated dysregulation. Mediation analysis revealed that glucagon suppression mediated 14.9% to 33.9% of the adverse effects of liver fat on hyperglycemia.

Conclusion: Liver fat accumulation in T2D is strongly associated with defective postprandial glucagon suppression, particularly in males, which mediates nearly one-third of its detrimental impact on glycemic control. Targeting hepatic steatosis and glucagon signaling may offer novel therapeutic strategies for T2D management.

Keywords: continuous glucose monitoring; glucagon suppression; liver–α axis; metabolic dysfunction–associated steatotic liver disease; type 2 diabetes.