Human GLP1R variants affecting GLP1R cell surface expression contribute to impaired glucose control and increased adiposity

Abstract

The glucagon-like peptide 1 receptor (GLP1R) is a major drug target with several agonists being prescribed in patients with type 2 diabetes (T2D) and obesity. The impact of genetic variability of the GLP1R gene on receptor function and its association with metabolic traits are unclear. Here, functional profiling of 59 rare and one common GLP1R variant across four signaling pathways reveals an unexpected diversity of phenotypes ranging from defective cell surface expression to complete or pathway-specific gain- and loss-of-functions. Defective insulin secretion of loss-of-function GLP1R variants was rescued by allosteric GLP1R ligands or high exendin-4 concentrations in INS-1 823/3 cells. Genetic association studies in 200K participants from UK Biobank show that impaired GLP1R cell surface expression contributes to impaired glucose control and increased adiposity with increased HbA1c, BMI and diastolic blood pressure. This study defines impaired GLP-1R cell surface expression as a risk factor for T2D- and obesity-associated traits.

Individualized Pharmacotherapy Utilizing Genetic Biomarkers and Novel In Vitro Systems As Predictive Tools for Optimal Drug Development and Treatment

“…In vitro models have been a long-standing research tool for the evaluation of pharmacogenomic associations, as well as for drug testing. In vitro evaluation of the effects of pharmacogenetic candidate variants using recombinant expression systems have been highly successful in confirming the functional effect of variants in drug metabolizing enzymes (Muroi et al, 2014;Shrestha et al, 2018;Siamoglou et al, 2022) and drug transporters (Seitz et al, 2015, Russell et al, 2020, as well as for determining the molecular and structural basis of drug resistance (Zhou et al, 2021, Gao et al, 2023. However, these models require overexpression of candidate variants or the knock-out/knockdown of gene products of interest.…”

Glucagon‐like‐peptide 1 receptor agonism and attempted suicide: A Mendelian randomisation study to assess a potential causal association

“…The first comprised a low-frequency missense variant (rs10305492, NP_002053.3:p.Ala316Thr MAF $1.5% in European ancestries), $0.85% in Latin American ancestries and <0.5% in other ancestries) (dbSNP: https://www.ncbi.nlm.nih.gov/snp/rs10305492# frequency_tab, date accessed 30 August 2023), which is associated with reduced fasting glucose and haemoglobin A1c (HbA1c) at genome-wide significance (GWS) along with in vitro evidence of increased Gs/cAMP signalling and calcium mobilisation. 25,26,29 rs1042044 (pLeu260Phe) was used to proxy the effect of GLP1RA on BMI: the A allele is associated with lower BMI at exome widesignificance in European participants in the UK Biobank ((https:// azphewas.com/, 470 K v5, 30 ). The A allele of rs1042044 is in LD with the A allele of rs877446 in European ancestries (D 1 1.0, R 2 .97, https://ldlink.nih.gov/?var=rs1042044&pop=GBR&genome_build= grch37&r2_d=r2&window=500000&collapseTranscript=true&annotate= forge&tab=ldproxy, date accessed 15 December 2023) and is associated with lower BMI at genome-wide significance.…”

Variation in responses to incretin therapy: Modifiable and non-modifiable factors

“…The GLP-1R has itself several LoF variants including R380C, shown by two independent groups to have normal surface expression but reduced affinity for Exenatide (Wootten et al, 2016;Hegron et al, 2023). Another LoF variant, R421W, displays reduced coupling to mini-Gα s proteins in response to various endogenous and clinical agonists (Lagou et al, 2021).…”

“…Patients heterozygous for R131Q secrete at least double the amount of insulin in response to GLP-1 during a hyperglycaemic clamp (Sathananthan et al, 2010). Another GoF variant, A316T, shows a 2-fold increase in cAMP accumulation (Hegron et al, 2023), and increased Ca 2+ mobilization (which is essential for insulin secretion). Furthermore, A316T shows enhanced recruitment of Gα s and endocytosis in response to oxyntomodulin, GLP-1, Semaglutide and Tirzepatide, but not Exenatide (Lagou et al, 2021).…”