B6-hGIPR/hGLP-1R Mouse

The Glucagon-like peptide 1 receptor (GLP1R) gene encodes a protein that belongs to the glucagon receptor subfamily of the G protein-coupled receptor B cluster ^[1]. This cell surface receptor protein is widely expressed in tissues such as the brain, small intestine, heart, and lungs, and plays a crucial role in insulin secretion signaling cascades by responding to GLP-1 and GLP-1 analogs. Animal model data also suggest that it has neuroprotective effects. Polymorphisms of this gene are closely associated with diabetes, making the GLP-1R protein an important drug target for the treatment of type 2 diabetes and stroke ^[2-3]. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are novel anti-diabetic drugs that activate GLP-1R to enhance insulin secretion, inhibit glucagon secretion, delay gastric emptying, and reduce food intake through central appetite suppression, thereby achieving blood sugar reduction and weight loss ^[4].

The GIPR gene encodes a G-protein-coupled receptor for gastric inhibitory polypeptide (GIP), secreted by intestinal K cells after food intake. GIP was initially discovered in intestinal extracts to inhibit gastric acid secretion and gastrin release, but it was later found to stimulate insulin release in the presence of elevated glucose levels. GIPR activation stimulates pancreatic β-cells to secrete insulin and mediates fat deposition by increasing lipoprotein lipase activity, adipogenesis, and fatty acid and glucose uptake in adipocytes. GIPR is primarily expressed in EBV-transformed lymphocytes, the stomach, and visceral adipose tissue ^[6]. Knockout mice for this gene exhibit elevated blood glucose levels and impaired initial insulin response following oral glucose load. Mice with disrupted Gipr expression show resistance to diet-induced obesity ^[7]. A deficiency in the GIPR gene is associated with type 2 diabetes and obesity. Research suggests that one of the core strategies for the next generation of T2D drugs is the production of single-peptide agonists, targeting both GLP-1R activity and the glucose-dependent insulinotropic polypeptide receptor (GIPR). GIPR involvement enhances the weight-loss effects of GLP-1-based therapies. This approach improves glycemic control and weight loss in T2D patients, highlighting the GIPR signaling axis as a promising and effective co-target ^[8].

The B6-hGIPR/hGLP-1R mouse is a dual humanized model for the Gipr and Glp1r genes. Using gene-editing technology, a partial coding sequence (CDS) of the human GIPR gene was inserted into the mouse Gipr gene sequence in B6-hGLP-1R mice (Catalog No.: C001421). This model expresses the functional region of the human GIPR protein while preserving the mouse signal peptide. It can be used to study the pathogenic mechanisms of metabolic diseases such as obesity and type 2 diabetes, and the development of GIPR/GLP-1R dual agonist drugs. The homozygotes are viable and fertile.