학술논문
Exploring the role of purinergic receptor P2RY1 in type 2 diabetes risk and pathophysiology: Insights from human functional genomics.
Document Type
Academic Journal
Author
Dance A; Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Université de Lille, Lille, France.; Fernandes J; Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Université de Lille, Lille, France.; Toussaint B; Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Université de Lille, Lille, France.; Vaillant E; Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Université de Lille, Lille, France.; Boutry R; Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Université de Lille, Lille, France.; Baron M; Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Université de Lille, Lille, France.; Loiselle H; Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Université de Lille, Lille, France.; Balkau B; Paris-Saclay University, Paris-Sud University, UVSQ, Center for Research in Epidemiology and Population Health, Inserm U1018 Clinical Epidemiology, Villejuif, France.; Charpentier G; CERITD (Centre d'Étude et de Recherche pour l'Intensification du Traitement du Diabète), Evry, France.; Franc S; CERITD (Centre d'Étude et de Recherche pour l'Intensification du Traitement du Diabète), Evry, France; Department of Diabetes, Sud-Francilien Hospital, Paris-Sud University, Corbeil-Essonnes, France.; Ibberson M; Vital-IT Group, Swiss Institute of Bioinformatics, Lausanne, Switzerland.; Marre M; Institut Necker-Enfants Malades, Inserm, Université de Paris, Paris, France; Clinique Ambroise Paré, Neuilly-sur-Seine, France.; Gernay M; Department of Diabetology, Nutrition and Metabolic Diseases, Sart Tilman University Hospital Center, Liège, Belgium.; Fadeur M; Department of Diabetology, Nutrition and Metabolic Diseases, Sart Tilman University Hospital Center, Liège, Belgium.; Paquot N; Department of Diabetology, Nutrition and Metabolic Diseases, Sart Tilman University Hospital Center, Liège, Belgium.; Vaxillaire M; Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Université de Lille, Lille, France.; Boissel M; Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Université de Lille, Lille, France.; Amanzougarene S; Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Université de Lille, Lille, France.; Derhourhi M; Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Université de Lille, Lille, France.; Khamis A; Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Université de Lille, Lille, France; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom.; Froguel P; Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Université de Lille, Lille, France; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom. Electronic address: philippe.froguel@cnrs.fr.; Bonnefond A; Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Université de Lille, Lille, France; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom. Electronic address: amelie.bonnefond@inserm.fr.
Source
Publisher: Elsevier GmbH Country of Publication: Germany NLM ID: 101605730 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2212-8778 (Electronic) Linking ISSN: 22128778 NLM ISO Abbreviation: Mol Metab Subsets: MEDLINE
Subject
Language
English
Abstract
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.
Competing Interests: Declaration of competing interest Authors declare that they have no competing interests.
(Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)
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.
Competing Interests: Declaration of competing interest Authors declare that they have no competing interests.
(Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)