The gastric inhibitory peptide receptor (GIPR) is a receptor for glucose-dependent insulinotropic polypeptide (GIP) and belongs to the G protein-coupled receptor (GPCR) family. The activity of this receptor is mediated by G proteins that activate adenylate cyclase. GIPR plays a crucial role in regulating insulin secretion, blood glucose, and lipid metabolism, and is crucial for maintaining normal metabolic status.
GIPR expression distribution
GIPR is primarily expressed in glandular epithelial cells, neurons, glial cells, and endocrine cells. GIPR is widely distributed in the body and expressed in the pancreas, stomach, small intestine, adipose tissue, heart, and brain, with the highest expression in pancreatic β cells.
(Data source: Uniprot)
(Data source: Uniprot)
Structure of GIPR
GIPR is a transmembrane protein composed of 466 amino acids. The receptor contains a large extracellular N-terminal domain involved in ligand recognition and binding. Seven transmembrane α-helices (TM1-TM7) form the receptor core and participate in signal transduction. Intracellular loops (ICL1-ICL3) are involved in binding to Gs protein, activating downstream signaling pathways. GIPR activated by GIP directs signaling through binding to the heterotrimeric Gs (αβγ) complex.
(Data source: Cong Z, et al. Cell Discov. 2024)
GIPR signaling pathway and regulation
GIPRs primarily couple to Gs proteins, leading to the separation of the α and βγ subunits of the Gs protein. This activates adenylate cyclase (AC), increasing intracellular cAMP levels. cAMP, acting as a second messenger, activates protein kinase A (PKA) and cAMP exchange protein Epac, which in turn regulates various cellular functions, including insulin secretion and cell survival.
(Data source: Shilleh AH, et al. Peptides. 2024)
GIPR-targeted therapy
GIPR-targeted therapy is an emerging therapeutic strategy primarily used for metabolic diseases such as type 2 diabetes and obesity. Currently, drugs targeting GIPRs primarily include small molecule drugs, synthetic peptides, fusion proteins, antibodies, and biclonal antibodies.
Tirzepatide is a dual agonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R), approved for marketing in 2022. Tirzepatide stimulates insulin secretion through both the GLP-1R and GIPR in β-cells. It binds to the GIPR receptor, similar to native GIP, acting as a full agonist, signaling through the Gs/cAMP and β-arrestin (βarr) pathways. On the other hand, tirzepatide engages the GLP-1R in a biased manner, favoring Gs/cAMP signaling over β-arrestin. Tirzepatide also stimulates glucagon secretion from α-cells through the GIPR through an unclear mechanism.
(Data source: Campbell JE, et al. Cell Metab. 2023)
GMA-106, developed by Hongyun Huaning, is a bispecific antibody targeting both GIPR and GLP-1R, reducing appetite and body fat accumulation by modulating these two pathways. Due to its extended half-life, GMA106 may enable a better dosing schedule (weekly or monthly) and higher patient compliance. In preclinical studies, GMA106 demonstrated excellent efficacy in reducing body weight, particularly body fat content, and may become a highly effective treatment for obesity, non-alcoholic fatty liver disease (NASH), and type 2 diabetes mellitus (T2DM).
