Glycemic and bodyweight effects of GIPR coding variation reflect differences in surface expression and intrinsic functional impairment.

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 cyclic adenosine monophosphate responses, and population-based association analysis highlighted that these loss-of-function variants decrease body mass index but increase glycemia. In many cases, reduced function was partly driven by reduced expression at the cell surface due to impaired stability and redirection toward proteasomal degradation. Molecular dynamics simulations suggest distinct variant-induced perturbations in inter- and intrahelical 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.