Imperial College London
Professor Philippe Froguel

ProfessorPhilippeFroguel

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Chair in Genomic Medicine
 
 
 
//

Contact

 

+44 (0)20 7594 6520p.froguel

 
 
//

Assistant

 

Mrs Patricia Murphy +44 (0)20 7594 1603

 
//

Location

 

E306Burlington DanesHammersmith Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Dance:2024:10.1016/j.molmet.2023.101867,
author = {Dance, A and Fernandes, J and Toussaint, B and Vaillant, E and Boutry, R and Baron, M and Loiselle, H and Balkau, B and Charpentier, G and Franc, S and Ibberson, M and Marre, M and Gernay, M and Fadeur, M and Paquot, N and Vaxillaire, M and Boissel, M and Amanzougarene, S and Derhourhi, M and Khamis, A and Froguel, P and Bonnefond, A},
doi = {10.1016/j.molmet.2023.101867},
journal = {Mol Metab},
title = {Exploring the role of purinergic receptor P2RY1 in type 2 diabetes risk and pathophysiology: Insights from human functional genomics.},
url = {http://dx.doi.org/10.1016/j.molmet.2023.101867},
volume = {79},
year = {2024}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - OBJECTIVE: Human functional genomics has proven powerful in discovering drug targets for common metabolic disorders. Through this approach, we investigated the involvement of the purinergic receptor P2RY1 in type 2 diabetes (T2D). METHODS: P2RY1 was sequenced in 9,266 participants including 4,177 patients with T2D. In vitro analyses were then performed to assess the functional effect of each variant. Expression quantitative trait loci (eQTL) analysis was performed in pancreatic islets from 103 pancreatectomized individuals. The effect of P2RY1 on glucose-stimulated insulin secretion was finally assessed in human pancreatic beta cells (EndoCβH5), and RNA sequencing was performed on these cells. RESULTS: Sequencing P2YR1 in 9,266 participants revealed 22 rare variants, seven of which were loss-of-function according to our in vitro analyses. Carriers, except one, exhibited impaired glucose control. Our eQTL analysis of human islets identified P2RY1 variants, in a beta-cell enhancer, linked to increased P2RY1 expression and reduced T2D risk, contrasting with variants located in a silent region associated with decreased P2RY1 expression and increased T2D risk. Additionally, a P2RY1-specific agonist increased insulin secretion upon glucose stimulation, while the antagonist led to decreased insulin secretion. RNA-seq highlighted TXNIP as one of the main transcriptomic markers of insulin secretion triggered by P2RY1 agonist. CONCLUSION: Our findings suggest that P2RY1 inherited or acquired dysfunction increases T2D risk and that P2RY1 activation stimulates insulin secretion. Selective P2RY1 agonists, impermeable to the blood-brain barrier, could serve as potential insulin secretagogues.
AU  - Dance,A
AU  - Fernandes,J
AU  - Toussaint,B
AU  - Vaillant,E
AU  - Boutry,R
AU  - Baron,M
AU  - Loiselle,H
AU  - Balkau,B
AU  - Charpentier,G
AU  - Franc,S
AU  - Ibberson,M
AU  - Marre,M
AU  - Gernay,M
AU  - Fadeur,M
AU  - Paquot,N
AU  - Vaxillaire,M
AU  - Boissel,M
AU  - Amanzougarene,S
AU  - Derhourhi,M
AU  - Khamis,A
AU  - Froguel,P
AU  - Bonnefond,A
DO  - 10.1016/j.molmet.2023.101867
PY  - 2024///
TI  - Exploring the role of purinergic receptor P2RY1 in type 2 diabetes risk and pathophysiology: Insights from human functional genomics.
T2  - Mol Metab
UR  - http://dx.doi.org/10.1016/j.molmet.2023.101867
UR  - https://www.ncbi.nlm.nih.gov/pubmed/38159881
VL  - 79
ER  -
Download