Keywords: GIPR, Glucose-Dependent Insulinotropic Polypeptide Receptor, Incretin, cAMP Signaling, Obesity, Type 2 Diabetes, Tirzepatide

The Glucose-Dependent Insulinotropic Polypeptide Receptor (GIPR) is a key member of the B1 class of G protein-coupled receptors (GPCRs), forming a core receptor network with GLP-1R and GCGR to regulate glucose homeostasis and energy metabolism. The endogenous ligand of GIPR is GIP (Glucose-Dependent Insulinotropic Polypeptide), secreted by intestinal K cells after nutrient intake. GIPR is widely expressed in pancreatic β-cells, adipose tissue, the central nervous system, bones, and other tissues, playing an indispensable role in regulating postprandial insulin secretion, lipid metabolism, and energy balance.

In recent years, with the breakthrough clinical efficacy of dual-target agonists like tirzepatide (GLP-1R/GIPR), GIPR has evolved from a classical incretin receptor to a core target in metabolic disease drug development. Meanwhile, GIPR's unique signaling regulatory properties—including its abundant splice variants, complex transport mechanisms, and central nervous system functions—make it a critical entry point for understanding multi-target synergistic therapy. This article systematically analyzes the biological basis and clinical translation prospects of GIPR from the perspectives of molecular structure, signal transduction, tissue distribution, physiological functions, and drug development.

GIPR belongs to the B1 class secretin/glucagon subfamily of GPCRs. Its protein structure consists of an extracellular N-terminus, seven transmembrane helices (TM1-TM7), and an intracellular C-terminus. The GIPR protein contains a signal peptide (amino acids 1-21), which is cleaved during maturation.

In 2021, a team led by Wang Mingwei, Yang Dehua, and Xu Huaqiang from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, resolved the high-resolution cryo-EM structure (2.9 Å) of the human GIPR in complex with GIP and the Gs protein, revealing the molecular mechanism of ligand recognition and signal transduction. The structure shows that the N-terminus of GIP inserts into the transmembrane domain of GIPR, while the C-terminus of the ligand tightly connects with extracellular loop 1. Compared to GLP-1R and GCGR, GIPR's extracellular loop 1 extends upward toward the center of the transmembrane domain, causing GIP to shift 2.7 Å and 3.3 Å relative to GLP-1 and glucagon in their respective receptors. All three receptors share conserved amino acid residues for binding common ligand regions, while selective recognition of their endogenous ligands relies on non-conserved residues.

GIPR primarily couples with the Gαs protein. When GIP binds to the extracellular domain of GIPR, the receptor undergoes conformational changes, prompting the replacement of GDP with GTP on the G protein α subunit. The GTP-bound α subunit dissociates from the trimer and activates adenylate cyclase, generating cAMP. cAMP then activates protein kinase A (PKA), which triggers a phosphorylation cascade, promoting cell membrane depolarization, opening voltage-gated Ca²⁺ channels, and inducing Ca²⁺ influx to fuse insulin vesicles with the plasma membrane and release insulin. Elevated Ca²⁺ levels also enhance insulin gene transcription, increasing β-cell insulin content.

However, GIPR's signaling regulation is far more complex than the classical Gαs-cAMP-PKA pathway, exhibiting the following unique features:

Abundant Splice Variants: Unlike the other two incretin receptors, GIPR has at least 13 reported splice variants, over half of which exhibit sequence variations in the N- or C-terminus. A 2023 PNAS study revealed the function of two N-terminal-altered splice variants (SV1 and SV2): they neither bind ligands nor transmit signals alone but inhibit wild-type GIPR's ligand binding and cAMP accumulation in a ligand-independent manner when co-expressed. Cryo-EM structures show that SV1 and SV2 exhibit abnormal inward folding of transmembrane helix 6 and extracellular loop 3, locking the receptor in a "ligand-binding pocket occupied" conformation. This constitutive biased signaling mechanism expands the understanding of GPCR signaling bias.

Unique Receptor Transport Regulation: GIPR's internalization and desensitization do not fully rely on the classical β-arrestin pathway. A 2025 study found that GIPR recruits the cytoskeletal motor protein myosin VI via its C-terminal PDZ-binding motif to drive receptor internalization. β-arrestin binding to phosphorylated residues enhances myosin VI recruitment and activation, converging at the receptor's C-terminus to cooperatively regulate GIPR internalization and signal desensitization. Blocking myosin VI activity enhances insulin release in β-cells.

Species Differences and Clinical Translation Challenges: Studies show that human GIPR undergoes internalization more readily than rodent GIPR. Although human and mouse GIPR exhibit similar agonist affinity and Gαs activation potency, mouse GIPR shows significantly reduced receptor desensitization, internalization, and β-arrestin recruitment. "Tail-swap" experiments confirm that human GIPR's desensitization depends on its C-terminal tail—replacing the human C-terminus with rat or mouse tails abolishes β-arrestin 2 recruitment. This species difference is a critical consideration for GIPR-targeted drug translation from animal models to clinical applications.

Beyond pancreatic β-cells, GIPR is widely distributed in adipocytes, intestinal epithelial cells, the adrenal cortex, bones, the heart, and multiple brain regions, including the cerebral cortex, pituitary, hippocampus, olfactory bulb, and hypothalamus. This broad distribution underpins GIPR's multisystem physiological functions.

Pancreas: In β-cells, GIPR promotes glucose-dependent insulin secretion. Under hypoglycemic conditions, GIP also stimulates α-cells to release glucagon, acting as a bifunctional hormone to maintain glucose homeostasis.

Adipose Tissue: GIPR promotes lipid accumulation in adipocytes. GIPR knockout mice show partial resistance to high-fat diet-induced obesity, attributed to slightly reduced food intake and intact β-adrenergic receptor-mediated lipolysis in white adipocytes.

Central Nervous System: Central GIPR plays a key role in weight regulation. Studies show that GIPR-blocking peptide-antibody conjugates (GIPR-Ab/GLP-1) require simultaneous central GIPR and GLP-1R signaling for maximal weight loss. These conjugates are detectable in circumventricular organs and activate c-FOS in appetite-regulating nuclei.

Bone: GIP signaling inhibits bone resorption, suggesting a potential role in bone metabolism regulation.

GIPR exhibits a "state-dependent" dual role in metabolic regulation, profoundly influencing drug development strategies.

Under normoglycemic conditions, GIPR signaling promotes lipid storage in adipose tissue. GIPR knockout mice show partial resistance to high-fat diet-induced obesity, and GIPR antagonists can prevent weight gain by reducing food intake. These findings suggest that GIPR antagonism may have value in obesity treatment.

However, under hyperglycemic conditions, GIPR promotes glucose-dependent insulin secretion in β-cells. Clinically, GIPR agonist strategies like tirzepatide, combined with GLP-1R agonism, have achieved over 20% weight loss in obese and type 2 diabetes patients.

The seemingly contradictory strategies of GIPR agonism and antagonism both yield metabolic benefits, rooted in GIPR's differential signaling outputs across tissues and metabolic states—promoting lipid storage in adipose tissue while regulating appetite in the CNS—and its complex synergy with GLP-1R signaling.

5.1 GLP-1R/GIPR Dual-Target Agonists

Tirzepatide is the first globally approved GLP-1R/GIPR dual-target agonist, simultaneously binding both receptors. In the SURMOUNT-1 Phase III trial, the 15 mg dose group achieved 20.9% weight loss. Dual-target agonists synergistically regulate food intake, energy expenditure, and lipid metabolism, further improving metabolic outcomes. Hengrui's HRS9531 is China's first domestically developed GLP-1/GIP dual-target agonist under regulatory review, with Phase III data showing 19.2% weight loss. Ascletis' ASC35 exhibits ~4x stronger in vitro agonism for GLP-1R and GIPR than tirzepatide, with an extended half-life supporting monthly subcutaneous dosing. Viking Therapeutics' oral dual agonist VK2735 has entered Phase II trials.

5.2 GIPR Antagonist Strategies

Antagonistic anti-GIPR antibodies combined with GLP-1R agonists have shown weight loss and insulin resistance improvement in preclinical obesity and diabetes models. GIPR-Ab/GLP-1 is a peptide-antibody conjugate linking a fully human anti-GIPR antagonistic antibody to two GLP-1 analogs via an amino acid linker, exerting weight loss effects by blocking GIPR while activating GLP-1R.

5.3 Multi-Target Expansion

GIPR is also integrated into more complex multi-target designs. GLP-1R/GIPR/GCGR triple agonists (e.g., retatrutide) simultaneously regulate food intake, energy expenditure, and lipid metabolism, showing greater weight loss potential in clinical trials. Additionally, innovative molecules like anti-GIPR antibody-FGF21 fusion proteins are under development.

As a GPCR target with both classical incretin functions and complex signaling networks, GIPR's molecular structure, splice variant regulation, unique internalization mechanisms, and species differences have been progressively elucidated. GIPR's differential functional outputs in pancreatic islets, adipose tissue, and the CNS allow it to serve as both an agonistic target (synergizing with GLP-1R for glucose-lowering and weight loss) and an antagonistic target (blocking fat storage and central appetite regulation for weight loss)—a rare "dual-nature" feature among metabolic targets. With tirzepatide's clinical success and the advancement of more dual- and triple-target molecules, GIPR will continue to drive the evolution from single-target agonism to multi-target synergy as a core regulator of metabolic therapy.