ArticleThe Journal of clinical endocrinology and metabolism2023
Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes.
Article in The Journal of clinical endocrinology and metabolism, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT07019519 (Interplay Between Gut Hormones and Autonomic Postprandial Blood Flow Regulation in Patients With POTS), which is not on this map. Cited by 10 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Interplay Between Gut Hormones and Autonomic Postprandial Blood Flow Regulation in Patients With POTS
Who cites it
10 citing papers in PubMed, 13 citations in OpenAlex.
- RISING STARS: Effects of a GLP-1 receptor polymorphism on responses to liraglutide.The Journal of endocrinology · 2025Trial
- Glycemic and bodyweight effects ofScience advances · 2026Article
- Genetic variants of glucose-dependent insulinotropic polypeptide (GIP) signalling as proxy for body weight reduction and cardiovascular risk.European heart journal · 2026Article
- Targeting of Kaposi's sarcoma-associated herpesvirus by immunotoxins directed against the viral G protein-coupled receptor, ORF74.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2026Article
- GLP-1RA precision medicine in people with type 2 diabetes: current insights and future prospects.The Journal of clinical investigation · 2026Review
- Rare MTNR1B variants causing diminished MT2 signalling associate with elevated HbADiabetologia · 2025Article
- The Expanding Role of GLP-1 Receptor Agonists: Advancing Clinical Outcomes in Metabolic and Mental Health.Current issues in molecular biology · 2025Review
- GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management.Nature metabolism · 2024Review
- Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes.Nature metabolism · 2024Article
- Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes.The Journal of clinical endocrinology and metabolism · 2023Article
Corrections and comments
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Authors and funding
18 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
contextLost glucagon-like peptide 1 receptor (GLP-1R) function affects human physiology.
objectiveThis work aimed to identify coding nonsynonymous GLP1R variants in Danish individuals to link their in vitro phenotypes and clinical phenotypic associations.
methodsWe sequenced GLP1R in 8642 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 cyclic adenosine monophosphate (cAMP) formation and β-arrestin recruitment. We performed a cross-sectional study between the burden of loss-of-signaling (LoS) variants and cardiometabolic phenotypes in 2930 patients with type 2 diabetes and 5712 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 White exome-sequenced participants in the UK Biobank cohort.
resultsWe identified 36 nonsynonymous variants in GLP1R, of which 10 had a statistically significant loss in GLP-1-induced cAMP signaling compared to wild-type. 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 glycated hemoglobin A1c.
conclusionSince no homozygous LoS nor pLoF variants were identified and heterozygous carriers had similar cardiometabolic phenotype as noncarriers, we conclude that GLP-1R may be of particular importance in human physiology, due to a potential evolutionary intolerance of harmful homozygous GLP1R variants.
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