In vivo functional profiling and structural characterization of the human GLP1R A316T variant.

Liliane El Eid; Yusman Manchanda; Gregory Austin; Kieran Deane-Alder; Roxana-Maria Rujan; Zamara Mariam; Affiong I Oqua; Matthew J Belousoff; Jorge Bernardino de la Serna; Kyle W Sloop; Guy A Rutter; Alex Montoya; Dominic J Withers; Steven J Millership; Karim Bouzakri; Ben Jones; Christopher A Reynolds; Patrick M Sexton; Denise Wootten; Giuseppe Deganutti; Alejandra Tomas

doi:10.1126/sciadv.adw0899

In vivo functional profiling and structural characterization of the human GLP1R A316T variant.

Liliane El Eid
, Yusman Manchanda
, Gregory Austin
, Kieran Deane-Alder
, Roxana-Maria Rujan
, Zamara Mariam
, Affiong I Oqua
, Matthew J Belousoff
, Jorge Bernardino de la Serna
, Kyle W Sloop
, Guy A Rutter
, Alex Montoya
, Dominic J Withers
, Steven J Millership
, Karim Bouzakri
, Ben Jones
, Christopher A Reynolds
, Patrick M Sexton
, Denise Wootten
, Giuseppe Deganutti

Alejandra Tomas

Imperial College London
Monash University
Eli Lilly and Company
University of Montréal
Nanyang Technological University
MRC Laboratory of Medical Sciences
Centre Européen d'Étude du Diabète
University of Essex

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

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Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective therapies for type 2 diabetes (T2D) and obesity, yet patient responses are variable, with GLP1R gene variation potentially linked to therapeutic outcomes. A GLP1R natural missense variant, A316T, protects against T2D and cardiovascular disease. Here, we generated and characterized a human GLP1R A316T mouse model. Human GLP1R A316T/A316T mice displayed lower fasting blood glucose versus wild-type littermates even under metabolic stress, as well as slower weight gain and alterations in islet cytoarchitecture, glucagon secretion, and liver metabolism under a high-fat, high-sucrose diet. This was however associated with blunted responses to pharmacological GLP-1RAs in vivo. Further investigations in β cell models demonstrated that human GLP1R A316T exhibits characteristics of constitutive activation but dampened GLP-1RA responses. Results are further supported by cryo-EM analyses and molecular dynamics simulations of GLP-1R A316T structure, collectively demonstrating that the A316T variant governs basal GLP-1R activity and pharmacological responses to GLP-1R-targeting therapies.

Original language	English
Article number	eadw0899
Number of pages	28
Journal	Science advances
Volume	12
Issue number	6
Early online date	4 Feb 2026
DOIs	https://doi.org/10.1126/sciadv.adw0899
Publication status	Published - 6 Feb 2026

Bibliographical note

Copyright © 2026 the authors; exclusive licensee American Association for the Advancement of Science subject to British Crown copyright, © British Crown Copyright, 2026, Met Office. Distributed under a Creative Commons Attribution 4.0 (CC BY).

Funding

this work was supported by the diabetes UK Phd Studentship grant 19/0006094 to A.t. and a Society for Endocrinology Research Grant to A.t. and l.E.E. the A.t. group is additionally funded by an MRc Project Grant [MR/X021467/1, with B.J. as co- investigator (co- i)] and a Wellcome trust discovery Award (301619/Z/23/Z, with B.J. and J.B.S. as co- is). J.B.S. also acknowledges funding from BBSRc (BB/ v019791/1) and MRc (MR/W024985/1). B.J. is further supported by MRc clinician Scientist Fellowship MR/Y00132X/1 and a Project Grant from diabetes UK. the Section of Endocrinology at imperial college london is funded by grants from the MRc, nihR and is supported by the nihR Biomedical Research centre Funding Scheme and the nihR/imperial clinical Research Facility. the views expressed are those of the author(s) and not necessarily those of the nhS, the nihR, or the department of health. G.A.R. was supported by a Wellcome trust investigator Award (Wt212625/Z/18/Z), MRc Programme Grant (MR/R022259/1), nih- niddK Project Grant (R01dK135268), cihR- JdRF team Grant (cihR- iRSc tdP- 186358 and JdRF 4- SRA- 2023- 1182- S- n), cRchUM start- up funds, and an innovation canada John R. Evans leader Award (cFi 42649). d.J.W. acknowledges support from the MRc (Mc- A654- 5QB40). S.J.M. was supported by a Wellcome trust iSSF Fellowship (204834/Z/16/Z, award no. RSRO_67869), Society for Endocrinology Early career and Small Equipment Grants, and a diabetes Research & Wellness Foundation Pump Priming Grant. d.W. and P.M.S. are leadership Fellows of the national health and Medical Research council of Australia (nhMRc) (grant ids 2026300 and 2025694, respectively). their work was also supported by an nhMRc ideas grant to d.W. (id: 1184726)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Glucagon-Like Peptide-1 Receptor/genetics
Humans
Animals
Mice
Diabetes Mellitus, Type 2/genetics
Molecular Dynamics Simulation
Glucagon-Like Peptide-1 Receptor Agonists
Blood Glucose
Disease Models, Animal
Insulin-Secreting Cells/metabolism
Cryoelectron Microscopy
Male

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Rujan2026VoRFinal published version, 7.57 MBLicence: CC BY

Cite this

El Eid, L., Manchanda, Y., Austin, G., Deane-Alder, K., Rujan, R.-M., Mariam, Z., Oqua, A. I., Belousoff, M. J., de la Serna, J. B., Sloop, K. W., Rutter, G. A., Montoya, A., Withers, D. J., Millership, S. J., Bouzakri, K., Jones, B., Reynolds, C. A., Sexton, P. M., Wootten, D., ... Tomas, A. (2026). In vivo functional profiling and structural characterization of the human GLP1R A316T variant. Science advances, 12(6), Article eadw0899. https://doi.org/10.1126/sciadv.adw0899

El Eid, L, Manchanda, Y, Austin, G, Deane-Alder, K, Rujan, R-M, Mariam, Z, Oqua, AI, Belousoff, MJ, de la Serna, JB, Sloop, KW, Rutter, GA, Montoya, A, Withers, DJ, Millership, SJ, Bouzakri, K, Jones, B, Reynolds, CA, Sexton, PM, Wootten, D, Deganutti, G & Tomas, A 2026, 'In vivo functional profiling and structural characterization of the human GLP1R A316T variant.', Science advances, vol. 12, no. 6, eadw0899. https://doi.org/10.1126/sciadv.adw0899

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title = "In vivo functional profiling and structural characterization of the human GLP1R A316T variant.",

abstract = "Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective therapies for type 2 diabetes (T2D) and obesity, yet patient responses are variable, with GLP1R gene variation potentially linked to therapeutic outcomes. A GLP1R natural missense variant, A316T, protects against T2D and cardiovascular disease. Here, we generated and characterized a human GLP1R A316T mouse model. Human GLP1R A316T/A316T mice displayed lower fasting blood glucose versus wild-type littermates even under metabolic stress, as well as slower weight gain and alterations in islet cytoarchitecture, glucagon secretion, and liver metabolism under a high-fat, high-sucrose diet. This was however associated with blunted responses to pharmacological GLP-1RAs in vivo. Further investigations in β cell models demonstrated that human GLP1R A316T exhibits characteristics of constitutive activation but dampened GLP-1RA responses. Results are further supported by cryo-EM analyses and molecular dynamics simulations of GLP-1R A316T structure, collectively demonstrating that the A316T variant governs basal GLP-1R activity and pharmacological responses to GLP-1R-targeting therapies. ",

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AU - Mariam, Zamara

AU - Oqua, Affiong I

AU - Belousoff, Matthew J

AU - de la Serna, Jorge Bernardino

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AU - Rutter, Guy A

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AU - Withers, Dominic J

AU - Millership, Steven J

AU - Bouzakri, Karim

AU - Jones, Ben

AU - Reynolds, Christopher A

AU - Sexton, Patrick M

AU - Wootten, Denise

AU - Deganutti, Giuseppe

AU - Tomas, Alejandra

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N2 - Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective therapies for type 2 diabetes (T2D) and obesity, yet patient responses are variable, with GLP1R gene variation potentially linked to therapeutic outcomes. A GLP1R natural missense variant, A316T, protects against T2D and cardiovascular disease. Here, we generated and characterized a human GLP1R A316T mouse model. Human GLP1R A316T/A316T mice displayed lower fasting blood glucose versus wild-type littermates even under metabolic stress, as well as slower weight gain and alterations in islet cytoarchitecture, glucagon secretion, and liver metabolism under a high-fat, high-sucrose diet. This was however associated with blunted responses to pharmacological GLP-1RAs in vivo. Further investigations in β cell models demonstrated that human GLP1R A316T exhibits characteristics of constitutive activation but dampened GLP-1RA responses. Results are further supported by cryo-EM analyses and molecular dynamics simulations of GLP-1R A316T structure, collectively demonstrating that the A316T variant governs basal GLP-1R activity and pharmacological responses to GLP-1R-targeting therapies.

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ER -

In vivo functional profiling and structural characterization of the human GLP1R A316T variant.

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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