Loss of Function Glucose-Dependent Insulinotropic Polypeptide Receptor Variants Are Associated With Alterations in BMI, Bone Strength and Cardiovascular Outcomes

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) and its receptor (GIPR) are involved in multiple physiological systems related to glucose metabolism, bone homeostasis and fat deposition. Recent research has surprisingly indicated that both agonists and antagonists of GIPR may be useful in the treatment of obesity and type 2 diabetes, as both result in weight loss when combined with GLP-1 receptor activation. To understand the receptor signaling related with weight loss, we examined the pharmacological properties of two rare missense GIPR variants, R190Q (rs139215588) and E288G (rs143430880) linked to lower body mass index (BMI) in carriers. At the molecular and cellular level, both variants displayed reduced G protein coupling, impaired arrestin recruitment and internalization, despite maintained high GIP affinity. The physiological phenotyping revealed an overall impaired bone strength, increased systolic blood pressure, altered lipid profile, altered fat distribution combined with increased body impedance in human carriers, thereby substantiating the role of GIP in these physiological processes.

The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection

“…This is highlighted by the fact that both agonists and antagonists at the GIPR could provide valuable modes of action in the treatment of T2D and obesity ( 90 ). Recently, two GIPR mutations have been shown to link to lower BMI in carriers ( 37 ). Following a deep molecular characterization both mutations displayed reduced Gα s protein coupling as well as impaired β-arrestin 2 recruitment and internalization.…”

“…We focused on the 41 genetic variants found in GIP(1-42) to dissect different peptide regions as they exhibit differential features with respect to receptor interaction. Taking the twodomain binding mechanism into account (35), GIP(1-42) was divided into three segments: a N-terminal segment (residue 1-15), a core segment (residue 16-30), and a C-terminal segment (residue [31][32][33][34][35][36][37][38][39][40][41][42].…”

“…In the core segment (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), the hydrophobic positions 22,23,26, and 27, complementing a binding groove in the GIPR (57), showed the highest degree of conservation (CS < -1.328). The C-terminal segment (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) represents the C-terminal tail, which is unique for GIP(1-42) and structurally less ordered than the closely related class B1 peptides (58). Positions in this segment showed the lowest degree of conservation, except positions 32 and 33, located in the PC2 cleavage motif (G31; K32; K33) (59) (Figure 4A).…”

“…Recently, two naturally occurring missense variants in the GIPR gene were described to be associated with a lower body mass index (BMI) in human carriers. In vitro studies indicate that these GIPR variants result in reduced G protein coupling and impaired β-arrestin 2 recruitment, conceivably providing a molecular explanation for the reduced body weight phenotype ( 37 ). However, to date, no systematic investigations of human variants in the proGIP gene or the region encoding GIP (1-42) have been conducted.…”

Editorial: Cell Biology, Physiology and Molecular Pharmacology of G Protein Coupled Receptors

“…The authors in this paper highlight the biology and paracrine roles of GLP-1, GIP, and GLP-2 in integrating the response to food intake with the maintenance of the structure and function of the gut as it relates to nutrient absorption. A thought-provoking paper included in this research topic is by Kizilkaya et al (2021) on incretin receptor GIPR. The authors functionally characterized two missense GIPR variants, R190Q (rs139215588) and E288G (rs143430880) that are associated with lower body mass index (BMI).…”