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 () and Amélie Bonnefond ()
Additional contact information
Sarah Meulebrouck: Lille University Hospital
Judith Merrheim: Lille University Hospital
Gurvan Queniat: Lille University Hospital
Cyril Bourouh: Lille University Hospital
Mehdi Derhourhi: Lille University Hospital
Mathilde Boissel: Lille University Hospital
Xiaoyan Yi: Université Libre de Bruxelles
Alaa Badreddine: Lille University Hospital
Raphaël Boutry: Lille University Hospital
Audrey Leloire: Lille University Hospital
Bénédicte Toussaint: Lille University Hospital
Souhila Amanzougarene: Lille University Hospital
Emmanuel Vaillant: Lille University Hospital
Emmanuelle Durand: Lille University Hospital
Hélène Loiselle: Lille University Hospital
Marlène Huyvaert: Lille University Hospital
Aurélie Dechaume: Lille University Hospital
Victoria Scherrer: Lille University Hospital
Piero Marchetti: University of Pisa
Beverley Balkau: 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: Université de Paris
Ronan Roussel: Université de Paris
Raphaël Scharfmann: Université de Paris
Miriam Cnop: Université Libre de Bruxelles
Mickaël Canouil: Lille University Hospital
Morgane Baron: Lille University Hospital
Philippe Froguel: Lille University Hospital
Amélie Bonnefond: Lille University Hospital

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
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DOI: 10.1038/s41467-024-51004-6

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