GLP1 receptor mutations in humans affect metabolic control and modify the effectiveness of GLP1 receptor-based treatments against type 2 diabetes and obesity

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A collaborative study carried out by the team "Functional Pharmacology and Physiopathology of Membrane Receptors" led by Dr Ralf Jockers, and published in Nature Metab., shows that mutations of the gene encoding the receptor of glucagon-like peptide 1 (GLP1R) affect metabolic traits such as glucose and body weight management and modulates the effectiveness of GLP1R agonists clinically used to treat diabetic and/or obese patients.

Glucagon-like peptide 1 (GLP1) is a hormone primarily released from the gastrointestinal tract in response to food intake which controls insulin secretion and body weight through activation of its receptor (GLP1R) located in both pancreatic β cells and in several brain nuclei. GLP1R agonists such as liraglutide and semaglutide are widely used to restore normal blood glucose levels in patients with type 2 diabetes (T2D) and to manage body weight in individuals with obesity. Until now, there has been a contradiction between the importance of this major target for anti-diabetic and anti-obesity drugs, and the importance of mutations in this target gene in humans. Indeed, the consequences of naturally occurring mutations in GLP1R gene on receptor function and metabolic traits related to T2D and obesity, as well as the responsiveness to current GLP1R-based treatments had not been clearly established.

The team of Ralf Jockers in collaboration with the team of Dr Amélie Bonnefond from the European Genomic Institute for Diabetes (EGID, Lille, France), the Huazhong University of Science and Technology (Wuhan, China), the Baylor College of Medicine (Houston, USA) and Imperial College Lonodon (UK) performed a large-scale functional genetics analysis of 60 rare GLP1R mutations. 56 of them showed an unexpectedly high impact on receptor function. Our results indicate that GLP1R mutations in humans lead to defective cell surface expression and impaired activation of the cAMP pathway, resulting in major defects in insulin secretion. Rescue of defective insulin secretion has been achieved by two pharmacological paradigms: high agonist concentrations or a combination of low agonist concentration and positive allosteric modulators (PAMs) for some mutants. Human GLP1R loss-of-function (LoF) mutations found among participants of the large UK Biobank cohort (200,000 participants), were associated with impaired glucose homeostasis and increased adiposity. The consortium also found that loss-of-function (LoF) mutations in the β-arrestin pathway could improve metabolic traits. This supports the concept that β-arrrestin-dependent trafficking of GLP1R limits the action of GLP1R activation on insulin secretion.

Our study indicates that GLP1R LoF mutants, in particular those with impaired GLP1R cell surface expression or cAMP activation, are linked to defective insulin secretion in vitro and to impaired glucose homeostasis and adiposity of patients in the 200K participants of the UK Biobank. These findings are of high relevance for personalized medicine approaches. Risk allele carriers might not only benefit from the latest generations of GLP1R agonists including dual GLP1R/GIPR agonists, but also from recently developed GLP1R PAMs or Gs/cAMP pathway-biased ligands. The impact of defective GLP1R cell surface expression suggests that pharmacological chaperons, molecules known to facilitate proper export of proteins to the cell surface, might be of therapeutic relevance for mutation carriers, as already shown for other important metabolic receptors such as melanocortin MC4 receptor. Our study is likely to trigger a diversification of treatment options targeting GLP1R. They might not only be beneficial for GLP1R LoF carriers but also for obese and diabetics patients that are either resistant to current GLP1R agonists treatments or are suffering from serious adverse effects.


Gao W, Liu L, Huh E, Gbahou F, Cecon E, Oshima M, Houzé L, Katsonis P, Hegron A, Fan Z, Hou G, Charpentier G, Boissel M, Derhourhi M, Marre M, Balkau B, Froguel P, Scharfmann R, Lichtarge O, Dam J, Bonnefond A, Liu J, Jockers R. Human GLP1R variants affecting GLP1R cell surface expression are associated with impaired glucose control and increased adiposityNat Metab (2023).


 This study has been funded by: :

Fondation de la Recherche Médicale (Equipe FRM DEQ20130326503 to R.J.), Agence Nationale de la Recherche (ANR-2011-BSV1-012-01 “MLT2D”, ANR-2011-META “MELA-BETES, ANR-21-CE18-0023 “alloGLP1R”) and the “Who am I?” laboratory of excellence No.ANR-11-LABX-0071 funded by the French Government through its “Investments for the Future” program operated by The French National Research Agency under grant No.ANR-11-IDEX-0005-01 to R.J.. This work was supported by grants from the European Union’s Horizon Europe Research and Innovation Program under grant agreement 101080465 to A.B., P.F., R.J., J.D. and the Ministry of Science and Technology (grant number 2018YFA0507003 and 2021ZD0203302 to J. L.), the National Natural Science Foundation of China (NSFC) (grant numbers 81720108031, 81872945 and 31721002 to J. L.). This study was further funded by the French National Research Agency (ANR-10-LABX-46 [European Genomics Institute for Diabetes]) to A.B. and P.F., the French National Research Agency (ANR-10-EQPX-07-01 [LIGAN-PM]) to A.B. and P.F., the European Research Council (ERC GEPIDIAB – 294785 to P.F.; ERC Reg-Seq – 715575 to A.B.), “France Génomique” consortium (ANR-10-INBS-009) and the National Center for Precision Diabetic Medicine – PreciDIAB to A.B. and P.F., which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001), by the European Union (FEDER), by the Hauts-de-France Regional Council and by the European Metropolis of Lille (MEL), Inserm, CNRS, China Scholarship Council.
O.L. gratefully acknowledges support from NIH GM066099.

This research has been conducted using the UK Biobank Application #67575 (A.B.)


Ralf Jockers

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