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GIPR (Gastric Inhibitory Polypeptide Receptor)

Summary

Gastric inhibitory polypeptide receptor (GIPR), also known as glucose-dependent insulinotropic polypeptide receptor, is a G-protein coupled receptor that mediates the insulinotropic effects of GIP. In conjunction with GLP1R, it is targeted by dual-agonist therapies such as tirzepatide for weight management and glycemic control. A GWAS conducted by the Auton Lab identified a missense variant in GIPR (rs1800437, p.Glu354Gln) that modulates the risk of vomiting specifically in patients treated with tirzepatide.

Biological Role and Disease Association

  • Incretin System: GIPR is expressed in pancreatic islets, adipose tissue, and the central nervous system. Its activation promotes insulin secretion in response to oral glucose, regulates lipid metabolism in adipose tissue, and acts synergistically with GLP1 signaling in the brain to reduce food intake and buffer aversive side effects like nausea and vomiting.
  • Synergistic Targeting: GIPR activation combined with GLP1R activation leads to enhanced metabolic efficacy compared to selective GLP1R agonists, which forms the basis for dual-agonist therapies like tirzepatide.

Pharmacogenetics and Genetic Variants

  • rs1800437 (p.Glu354Gln): A missense variant in the GIPR gene. The G (effect) allele is protective against vomiting, whereas the C allele is associated with a higher risk of vomiting side effects (odds ratio = 1.83, $P = 5.1 \times 10^{-9}$ as of 2026-04-08). This association is restricted to patients treated with the dual agonist tirzepatide and is not observed in those treated with semaglutide. The p.Glu354Gln variant behaves as a partial loss-of-function mutation, which may impair the ability of GIP signaling to buffer GLP1-mediated nausea and vomiting.

Citations