Glycaemic and bodyweight effects of GIPR coding variation reflect differences in surface expression and intrinsic functional impairment
File(s)
Author(s)
Jones, Ben
Type
Journal Article
Abstract
The glucose-dependent insulinotropic polypeptide receptor (GIPR) is a major therapeutic target in
type 2 diabetes and obesity. Missense variation in GIPR could confer phenotypic effects through alterations to constitutive activity or functional responses to GIP or pharmacological agonists. In this study we aimed to provide a deep understanding of the molecular mechanisms that underpin the cellular and physiological impacts of GIPR coding variation by studying 30 GIPR coding variants in cellular models and pancreatic islets. Many variants showed impaired GIP-induced cAMP responses, and population-based association analysis highlighted that these loss-of-function variants decrease
BMI but increase glycaemia. In many cases, reduced function was partly driven by reduced expression at the cell surface due to impaired stability and redirection towards proteasomal degradation. Molecular dynamics simulations suggest distinct variant-induced perturbations in inter-and intra-helical interactions which interfere with receptor stability. This study highlights the mechanisms and consequences of GIPR coding variation, which may have implications for the therapeutic targeting of this receptor.
type 2 diabetes and obesity. Missense variation in GIPR could confer phenotypic effects through alterations to constitutive activity or functional responses to GIP or pharmacological agonists. In this study we aimed to provide a deep understanding of the molecular mechanisms that underpin the cellular and physiological impacts of GIPR coding variation by studying 30 GIPR coding variants in cellular models and pancreatic islets. Many variants showed impaired GIP-induced cAMP responses, and population-based association analysis highlighted that these loss-of-function variants decrease
BMI but increase glycaemia. In many cases, reduced function was partly driven by reduced expression at the cell surface due to impaired stability and redirection towards proteasomal degradation. Molecular dynamics simulations suggest distinct variant-induced perturbations in inter-and intra-helical interactions which interfere with receptor stability. This study highlights the mechanisms and consequences of GIPR coding variation, which may have implications for the therapeutic targeting of this receptor.
Date Acceptance
2026-07-22
Citation
Science Advances
ISSN
2375-2548
Publisher
American Association for the Advancement of Science (AAAS)
Journal / Book Title
Science Advances
Copyright Statement
Copyright This paper is embargoed until publication. Once published the Version of Record (VoR) will be available on immediate open access.
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Publication Status
Accepted