Work

Genetic GHSR deficiency and LEAP2 treatment enhance the glucose-lowering effects of liraglutide in male mice in a metabolic state-dependent manner

Year: 2026

Type: article

Abstract: Aims Liraglutide is a glucagon-like peptide-1 receptor (GLP-1R) agonist that lowers glycemia and is used to treat type 2 diabetes (T2D) and obesity. Activation of the growth hormone secretagogue receptor (GHSR) increases glycemia. We aimed to determine whether GHSR inhibition enhances the glucose-lowering effects of liraglutide. Materials and methods We investigated the acute glucose-lowering effects of liraglutide in mice with genetic GHSR deletion or pharmacological GHSR blockade under fed, fasting, and postprandial conditions. We also examined the potential cellular basis of this interaction in murine islets using transcriptomic and immunolabeling approaches and in human pancreatic tissue using a publicly available transcriptomic dataset. Key findings Liraglutide similarly reduced glycemia in ad libitum-fed GHSR-null and control mice. Following food deprivation, liraglutide more effectively attenuated postprandial increases in glycemia in male, but not female, GHSR-null mice than in control mice. Liraglutide reduced glycemia in fasted GHSR-null male mice but not in WT males. In male mice, pretreatment with a LEAP2 (liver-expressed antimicrobial peptide 2) analog, an endogenous GHSR antagonist and inverse agonist, enhanced the glucose-lowering effects of liraglutide under postprandial and fasting conditions. GHSR and GLP-1R showed limited co-expression in murine islets. In human islets, their co-expression was also limited and enriched in δ-cells, but was also detected in β-cells, where the proportion of GHSR + /GLP-1R + cells was higher in donors with T2D. Significance GHSR inhibition enhances liraglutide's glucose-lowering effects in a sex-dependent manner, highlighting GHSR as a potential target to improve GLP-1R agonist efficacy.

Source: Life Sciences

DOI: 10.1016/j.lfs.2026.124754