SUN-685 A comparison of the metabolic effects of a long-acting GIPR agonist versus a GIPR antagonist

Abstract Disclosure: I. Davies: None. A. Turland: None. C. Wong: None. H. Tran: None. O. Cahn: None. S.R. Bloom: Zihipp. B. Jones: Metsera, Eli Lilly and Company, Sun Pharma. T. Tan: Zihipp. Introduction: There is significant interest in targeting the glucose dependent insulinotropic polypeptide receptor (GIPR) for the treatment of type 2 diabetes and obesity. However, the optimal method of receptor targeting remains unclear: both activating or inhibiting the GIPR has resulted in metabolic improvement in preclinical models. Moreover, both tirzepatide (a GLP-1R/GIPR dual agonist) and AMG133 (a GLP-1R agonist/ GIPR antagonist) appear to outperform GLP-1R mono-agonists with regards to weight loss in clinical trials. Importantly, there are limited data regarding the comparative metabolic effects of a GIPR agonist versus GIPR antagonist, making valid comparisons between the two pharmacotherapeutic strategies difficult. Aim: Perform an in-depth metabolic comparison of a GIPR agonist (GIP108) versus a GIPR antagonist (NN-GIPR-Ant) in mouse models. Methods: Peptide characterisation was performed in AD293 cells transiently expressing the mouse GIPR, glucagon-like-peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR). cAMP responses using live cell imaging were recorded in mouse pancreatic islets and hypothalamic neurons. Food intake, body weight and blood glucose effects were determined in HFD-induced obese mice. Aversive behaviours were assessed in lean mice. Results: cAMP assessment in GIPR-expressing AD293 cells confirmed the categorisation of GIP108 and NN-GIPR-Ant as a GIPR agonist and antagonist, respectively. Both peptides resulted in minimal cAMP accumulation in cells expressing the mouse GLP-1R or GCGR. GIP108, but not NN-GIPR-Ant, resulted in significant cAMP responses in dispersed mouse pancreatic islets. These findings were mirrored in vivo: while NN-GIPR-Ant displayed no anti-hyperglycaemic efficacy, both single dose and 21-day administration of GIP108 resulted in significant improvements in glucose tolerance in HFD-induced obese mice. We failed to detect a cAMP response in hypothalamic neurons following stimulation with GIP108 or NN-GIPR-Ant, probably due to low GIPR expression. However, acute and chronic administration of GIP108 and NN-GIPR-Ant to HFD-induced obese mice resulted in comparable levels of food intake suppression and body weight reduction. Neither peptide was able to prevent semaglutide-induced aversive behaviours in mice. Conclusion: These results highlight that while both GIPR activation and inhibition result in appetite and body weight reduction, only GIPR activation can significantly improve glucose tolerance - a finding of relevance in the development of GIPR-targeting metabolic therapeutics. Moreover, the observation that GIP108 was unable to prevent GLP-1RA induced emesis, an effect induced by other GIPR agonists, highlights the heterogeneity in CNS responses induced by different GIPR agonists. A comparison of the metabolic effectiveness of both approaches in humans is an important area of future study. Presentation: Sunday, July 13, 2025