Liver fibrosis and type 2 diabetes modulate postprandial incretin and glucagon responses in fatty liver disease.

The study aims to characterize the secretion dynamics of glucagon-related peptides, including GLP-1, GIP, and GLP-2, across different stages of metabolic-associated steatotic liver disease (MASLD), while evaluating the impact of type 2 diabetes (T2D) on these hormonal responses. Thirty-four MASLD subjects were stratified according with the liver transient elastography (TE ≥ 9 kPa) and T2D in NF (no fibrosis, without T2D; n = 12), NFD (no fibrosis, with T2D; n = 8), F (fibrosis, without T2D; n = 5), and FD (fibrosis, with T2D; n = 9) and completed a standardized 3-h meal tolerance test (MTT). The presence of liver fibrosis, regardless of diabetes status, was associated with hyperglycemia, hyperinsulinemia, and greater insulin resistance compared to the non-fibrosis (NF) group. Significant differences in glucagon and GLP-1 response curves were observed across groups. People with T2D showed an elevated peak of glucagon and increased glucagon exposure, as indicated by both the 60-min area under the curve (AUC60') and total AUC during the MTT. In the FD group, fasting and peak GLP-1 levels, as well as AUC60' and total AUC GLP-1, were 1.9-, 1.8-, and 1.9-fold higher, respectively, compared to the NF group. GIP responses were similar across groups, except for elevated fasting levels in NFD (p = 0.002). GLP-2 mirrored GLP-1, with FD showing the highest fasting and postprandial levels. Stepwise regression identified fibrosis and FPG as the main predictors of GLP-1, while glucagon was linked to FPG, HbA1c, and BMI. Liver fibrosis and T2D impact glucagon-related peptides responses in MASLD, revealing important metabolic alterations that may guide therapeutic approaches.