Insulin; Glucose; P2RY1 protein, human; Receptors, Purinergic P2Y1; Humans; Insulin/metabolism; Genomics; Glucose/metabolism; Receptors, Purinergic P2Y1/genetics; Receptors, Purinergic P2Y1/metabolism; Diabetes Mellitus, Type 2/genetics; Diabetes Mellitus, Type 2/metabolism; Islets of Langerhans/metabolism; Diabetes Mellitus, Type 2; Islets of Langerhans; Molecular Biology; Cell Biology
Abstract :
[en] [en] 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.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Dance, Arnaud; 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, Justine; 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, Bénédicte; 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, Emmanuel; 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, Raphaël; 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, Morgane; 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, Hélène; 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, Beverley; Paris-Saclay University, Paris-Sud University, UVSQ, Center for Research in Epidemiology and Population Health, Inserm U1018 Clinical Epidemiology, Villejuif, France
Charpentier, Guillaume; CERITD (Centre d'Étude et de Recherche pour l'Intensification du Traitement du Diabète), Evry, France
Franc, Sylvia; 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, Mark; Vital-IT Group, Swiss Institute of Bioinformatics, Lausanne, Switzerland
Marre, Michel; Institut Necker-Enfants Malades, Inserm, Université de Paris, Paris, France, Clinique Ambroise Paré, Neuilly-sur-Seine, France
GERNAY, Marie-Marie ; Centre Hospitalier Universitaire de Liège - CHU > > Service de diabétologie, nutrition, maladies métaboliques
Fadeur, Marjorie ; Centre Hospitalier Universitaire de Liège - CHU > > Service de diabétologie, nutrition, maladies métaboliques
Paquot, Nicolas ; Université de Liège - ULiège > Département des sciences cliniques > Diabétologie, nutrition et maladies métaboliques
Vaxillaire, Martine; 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, Mathilde; 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, Souhila; 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, Mehdi; 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, Amna; 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, Philippe; 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, Amélie; 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
ERC - European Research Council ANR - French National Research Agency
Funding text :
We thank “France Génomique” consortium (ANR-10-INBS-009). This work was supported by grants from the French National Research Agency (ANR-10-LABX-46 [European Genomics Institute for Diabetes] and ANR-10-EQPX-07-01 [LIGAN-PM]), from the European Research Council ( ERC OπO – 101,043,671, to AB), and from the National Center for Precision Diabetic Medicine – PreciDIAB, which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001), by the European Union ( FEDER ), by the Hauts-de-France Regional Council and by the European Metropolis of Lille (MEL).
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