The glucose-dependent insulinotropic polypeptide receptor (GIPR) is the target of several approved and investigational drugs for type 2 diabetes and obesity. Missense coding variation in GIPR could confer phenotypic effects through altered constitutive or functional responses to GIP or alter the efficacy of pharmacological agents targeting this receptor. We aimed to provide a deep understanding of the cellular and physiological impacts of individual GIPR coding variants and the mechanisms underpinning these effects. By studying a panel of the 30 highest prevalence GIPR coding variants in HEK293 cells, INS-1 β-cells and pancreatic islets, we found that many show impaired cAMP responses to physiological GIP stimulation. Population-based association analysis highlighted that these loss-of-function GIPR variants decrease BMI but increase glycaemia. In many cases, reduced function was at least partly driven by reduced variant expression at the cell surface due to impaired stability and redirection towards proteasomal degradation pathway. Molecular dynamics simulations suggest distinct variant-induced perturbations in inter- and intra-helical interactions within the transmembrane region which interfere with receptor stability and signalling. This study highlights the mechanisms and consequences of GIPR coding variation, which may have implications for the therapeutic targeting of this receptor in metabolic disease.

This work was supported by an LRAP award to A.T., B.J. and K.W.S. B.J. has received grant funding and is a consultant for Metsera Inc. A.T. has received funding from Sun Pharmaceuticals. J.R.B.P. and E.J.G. are employees and shareholders of Insmed Inc. R.D., K.K.O. and N.J.W. receive research funding from Eli Lilly. J.R.B.P. receives research funding from GSK.

This work was supported by an LRAP award to A.T., B.J. and K.W.S. B.J. is supported by an MRC Clinician Scientist Fellowship (MR/Y00132X/1). The A.T. group is funded by grants from Diabetes UK (19/0006094), the MRC (MR/X021467/1), and the Wellcome Trust (301619/Z/23/Z), the latter two in collaboration with B.J. E.J.G., J.R.B.P., K.K.O. and N.J.W. acknowledge funding from the Medical Research Council (Unit Programmes: MC_UU_00006/1 and MC_UU_00006/2) and the NIHR Cambridge Biomedical Research Centre (NIHR203312). The Section of Endocrinology at Imperial College London is funded by grants from the MRC, NIHR and is supported by the NIHR Biomedical Research Centre Funding Scheme and the NIHR/Imperial Clinical Research Facility.

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The UK Biobank operates under approval from the North West Multi-centre Research Ethics Committee (REC reference 13/NW/0157) as a Research Tissue Bank (RTB), with informed consent obtained from all participants. This approval allows researchers to conduct studies without requiring separate ethical clearance, as they are covered by the RTB approval. Initially granted in 2011, this approval is renewed every five years, with successful renewals completed in 2016 and 2021. The work described for this analysis was approved by the UK Biobank through resource application number 9905.

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All experimental data from wet laboratory experiments are included in the Supporting Data Values file. The UKBB phenotype and WES data used in this study are accessible to registered researchers via the UKBB data access protocol. Details on how to register for data access can be found at https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access. Data for this study were obtained under Resource Application Number: 9905.