Rare heterozygous loss-of-function variants in the human GLP-1 receptor do not associate with cardiometabolic phenotypes

Josefine U Melchiorsen, Kimmie V Sørensen, Jette Bork-Jensen, Hüsün S Kizilkaya, Lærke S Gasbjerg, Alexander S Hauser, Jørgen Rungby, Henrik T Sørensen, Allan Vaag, Jens S Nielsen, Oluf Pedersen, Allan Linneberg, Bolette Hartmann, Anette P Gjesing, Jens J Holst, Torben Hansen, Mette M Rosenkilde, Niels Grarup

Research output: Contribution to journalJournal articleResearchpeer-review


CONTEXT: Impact of lost GLP-1 receptor function in human physiology.

OBJECTIVE: Identify coding nonsynonymous GLP1R variants in Danish individuals to link their in vitro phenotypes and clinical phenotypic associations.

METHODS: We sequenced GLP1R in 8,642 Danish individuals with type 2 diabetes or normal glucose tolerance and examined the ability of nonsynonymous variants to bind GLP-1 and to signal in transfected cells via cAMP formation and beta-arrestin recruitment. We performed a cross-sectional study between the burden of loss-of-signalling (LoS) variants and cardiometabolic phenotypes in 2,930 patients with type 2 diabetes and 5,712 participants in a population-based cohort. Furthermore, we studied the association between cardiometabolic phenotypes and the burden of the LoS variants and 60 partly overlapping predicted loss-of-function (pLoF) GLP1R variants found in 330,566 unrelated Caucasian exome-sequenced participants in the UK Biobank cohort.

RESULTS: We identified 36 nonsynonymous variants in GLP1R of which 10 had a statistically significant loss in GLP-1-induced cAMP signalling compared to wildtype. However, no association was observed between the LoS variants and type 2 diabetes, although LoS variant carriers had a minor increased fasting plasma glucose level. Moreover, pLoF variants from the UK Biobank also did not reveal substantial cardiometabolic associations, despite a small effect on HbA1c.

CONCLUSION: Since no homozygous LoS nor pLoF variants were identified and heterozygous carriers had similar cardiometabolic phenotype as non-carriers, we conclude that GLP-1R may be of particular importance in human physiology, due to a potential evolutionary intolerance of harmful homozygous GLP1R variants.

Original languageEnglish
JournalThe Journal of clinical endocrinology and metabolism
Publication statusE-pub ahead of print - 26. May 2023

Bibliographical note

© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.


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