Nature Communications (Aug 2024)
Functional genetics reveals the contribution of delta opioid receptor to type 2 diabetes and beta-cell function
- Sarah Meulebrouck,
- Judith Merrheim,
- Gurvan Queniat,
- Cyril Bourouh,
- Mehdi Derhourhi,
- Mathilde Boissel,
- Xiaoyan Yi,
- Alaa Badreddine,
- Raphaël Boutry,
- Audrey Leloire,
- Bénédicte Toussaint,
- Souhila Amanzougarene,
- Emmanuel Vaillant,
- Emmanuelle Durand,
- Hélène Loiselle,
- Marlène Huyvaert,
- Aurélie Dechaume,
- Victoria Scherrer,
- Piero Marchetti,
- Beverley Balkau,
- Guillaume Charpentier,
- Sylvia Franc,
- Michel Marre,
- Ronan Roussel,
- Raphaël Scharfmann,
- Miriam Cnop,
- Mickaël Canouil,
- Morgane Baron,
- Philippe Froguel,
- Amélie Bonnefond
Affiliations
- Sarah Meulebrouck
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Judith Merrheim
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Gurvan Queniat
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Cyril Bourouh
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Mehdi Derhourhi
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Mathilde Boissel
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Xiaoyan Yi
- ULB Center for Diabetes Research, Université Libre de Bruxelles
- Alaa Badreddine
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Raphaël Boutry
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Audrey Leloire
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Bénédicte Toussaint
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Souhila Amanzougarene
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Emmanuel Vaillant
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Emmanuelle Durand
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Hélène Loiselle
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Marlène Huyvaert
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Aurélie Dechaume
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Victoria Scherrer
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Piero Marchetti
- Islet Cell Laboratory, Department of Clinical and Experimental Medicine, University of Pisa
- Beverley Balkau
- Paris-Saclay University, Paris-Sud University, UVSQ, Center for Research in Epidemiology and Population Health, Inserm U1018 Clinical Epidemiology
- Guillaume Charpentier
- CERITD (Centre d’Étude et de Recherche pour l’Intensification du Traitement du Diabète)
- Sylvia Franc
- CERITD (Centre d’Étude et de Recherche pour l’Intensification du Traitement du Diabète)
- Michel Marre
- Institut Necker-Enfants Malades, Inserm, Université de Paris
- Ronan Roussel
- Institut Necker-Enfants Malades, Inserm, Université de Paris
- Raphaël Scharfmann
- Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris
- Miriam Cnop
- ULB Center for Diabetes Research, Université Libre de Bruxelles
- Mickaël Canouil
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Morgane Baron
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Philippe Froguel
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- Amélie Bonnefond
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital
- DOI
- https://doi.org/10.1038/s41467-024-51004-6
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 12
Abstract
Abstract Functional genetics has identified drug targets for metabolic disorders. Opioid use impacts metabolic homeostasis, although mechanisms remain elusive. Here, we explore the OPRD1 gene (encoding delta opioid receptor, DOP) to understand its impact on type 2 diabetes. Large-scale sequencing of OPRD1 and in vitro analysis reveal that loss-of-function variants are associated with higher adiposity and lower hyperglycemia risk, whereas gain-of-function variants are associated with lower adiposity and higher type 2 diabetes risk. These findings align with studies of opium addicts. OPRD1 is expressed in human islets and beta cells, with decreased expression under type 2 diabetes conditions. DOP inhibition by an antagonist enhances insulin secretion from human beta cells and islets. RNA-sequencing identifies pathways regulated by DOP antagonism, including nerve growth factor, circadian clock, and nuclear receptor pathways. Our study highlights DOP as a key player between opioids and metabolic homeostasis, suggesting its potential as a therapeutic target for type 2 diabetes.
