Target Background

The gastric inhibitory polypeptide receptor (GIPR), also known as the glucose-dependent insulinotropic polypeptide receptor, is a class B G-protein-coupled receptor (GPCR) that mediates the actions of the incretin hormone GIP. GIPR is highly expressed in pancreatic β-cells and adipose tissue, with additional expression in the gastrointestinal tract, bone, adrenal cortex, and central nervous system. This distribution underlies its diverse physiological functions in glucose regulation, lipid metabolism, and bone remodeling.

Upon nutrient ingestion, GIP is secreted from intestinal K-cells and activates GIPR, leading to coupling with Gs proteins, stimulation of adenylate cyclase, and elevation of intracellular cAMP. In pancreatic β-cells, this signaling enhances glucose-dependent insulin secretion and promotes β-cell proliferation and survival. In adipocytes, GIPR activation facilitates lipid uptake and storage, while in bone it contributes to anabolic effects on osteoblasts. Recent studies also suggest a role for GIPR in appetite regulation and energy expenditure through central mechanisms.

Pharmacologically, GIPR has emerged as an important target in metabolic disease. While early efforts to develop GIPR agonists showed modest effects in type 2 diabetes, the development of dual GLP-1R/GIPR agonists such as tirzepatide has demonstrated superior efficacy in improving glycemic control and inducing weight loss compared to GLP-1R agonists alone. Conversely, GIPR antagonism is under exploration for obesity and insulin resistance, highlighting the complex biology of this receptor. With its multifaceted influence on insulin secretion, adiposity, and skeletal health, GIPR remains a significant focus of incretin-based drug discovery and translational research.