What question did this study set out to answer?

The study aims to develop a humanized mouse model for evaluating obesity and diabetes therapies.

June 7, 2026

2542-P: Generation of Humanized GCGR, GIPR, and GLP-1R Mice for Obesity and Diabetes Preclinical Research

Key Points

The study aims to develop a humanized mouse model for evaluating obesity and diabetes therapies.
Three individual humanized mouse models (GCGR, GIPR, GLP-1R) were created and crossed to generate B-hGCGR/hGIPR/hGLP1R mice.
Expression of human receptors confirmed via RT-PCR and immunohistochemistry.
In vivo efficacy tested with a high-fat diet followed by treatments with Semaglutide and analogs.
Humanized mice only expressed human GCGR, GIPR, and GLP1R, with no mouse receptor expression detected.
Treatment with Semaglutide and analogs significantly reduced body weight and food intake in HFD-induced mice.
Only wild-type mice showed mouse Gcgr and Gipr expression.

Abstract

Introduction and Objective: The two major incretin hormones, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are secreted from the intestine on the intake of glucose or nutrients to induce insulin secretion. GIP and GLP-1 exert their regulatory effects through binding to their specific GIP receptor (GIPR) and GLP-1 receptor (GLP-1R), respectively—receptors that fall under the G-protein coupled receptor family. The Glucagon Receptor (GCGR) plays a critical role in glucose metabolism and energy homeostasis. GCGR transduces the biological effects of glucagon.To support preclinical research on obesity and diabetes, Biocytogen developed a triple humanized mouse model (B-hGCGR/hGIPR/hGLP1R) for in vivo evaluation. Methods: Three single humanized mouse models were first generated: GCGR humanized mice, GIPR humanized mice, and GLP1R humanized mice. Further, by crossing these mice to obtain B-hGCGR/hGIPR/hGLP1R mice.mRNA and protein expression of human receptors were validated by RT-PCR and immunohistochemistry.For the in vivo efficacy study, mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity, followed by treatment with Semaglutide, Orforglipron-analog, Tirzepatide-analog, or Retatrutide-analog. Results: Mouse Gcgr, Gipr were only detectable in wild-type C57BL/6JNifdc mice. Human GCGR, GIPR, and GLP1R were only detectable in humanized mice.human GLP1R protein was detected only in humanized mice, with no mouse GLP1R expression observed.Semaglutide, Orforglipron-analog, Tirzepatide-analog, and Retatrutide-analog could reduce body weight and food intake in a high-fat diet (HFD) induced B-hGCGR/hGIPR/hGLP1R mice. Conclusion: B-hGCGR/hGIPR/hGLP1R mice can successfully express human but not mouse GCGR, GIPR, and GLP1R. Based on in vivo efficacy data, this model is suitable for preclinical studies of obesity and diabetes. Disclosure H. Horton: None. J. Ma: None. J. Huo: None. Y. Li: None. Z. Chen: None. Y. Zhou: None. Y. Zhou: None. X. Zhou: None.

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