Functional genetics reveals the contribution of delta opioid receptor to type 2 diabetes and beta-cell function

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.

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Publication Details

Journal
Nature Communications
Published
2024-08-05
DOI
https://doi.org/10.1038/s41467-024-51004-6
Citations
12
Primary Topic
Pancreatic function and diabetes
Type
article
Field-Weighted Citation Impact
6.87

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article

Functional genetics reveals the contribution of delta opioid receptor to type 2 diabetes and beta-cell function

Piero Marchetti, Raphaël Scharfmann, Philippe Froguel, Aurélie Dechaume et al.
12 citations
Nature Communications
Pancreatic function and diabetes
6.87
article

Functional genetics reveals the contribution of delta opioid receptor to type 2 diabetes and beta-cell function

Piero Marchetti, Raphaël Scharfmann, Philippe Froguel, Aurélie Dechaume, Amélie Bonnefond, Audrey Leloire, Victoria Scherrer, Mickaël Canouil, Gurvan Quéniat, Xiaoyan Yi, Cyril Bourouh, Sylvia Franc, Alaa Badreddine, Miriam Cnop, Ronan Roussel, Beverley Balkau, Souhila Amanzougarene, Judith Merrheim, Raphaël Boutry, Emmanuel Vaillant, Guillaume Charpentier, Mathilde Boissel, Morgane Baron, Sarah Meulebrouck, Bénédicte Toussaint, Marlène Huyvaert, Hélène Loiselle, Michel Marre, Mehdi Derhourhi, Emmanuelle Durand
article en
12 citations

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.

Nature CommunicationsVol. 15(1)
Université Claude Bernard Lyon 1 (FR), Université Paris-Sud (FR), University of Pisa (IT), Centre National de la Recherche Scientifique (FR), Université Libre de Bruxelles (BE), Inserm (FR), Université de Versailles Saint-Quentin-en-Yvelines (FR), Université Paris Cité (FR), Université de Lille (FR), Université Paris-Saclay (FR), Institut Pasteur de Lille (FR), Erasmus Hospital (BE), Centre Hospitalier Universitaire de Lille (FR), Institut Necker Enfants Malades (FR), Sorbonne Paris Cité (FR), Assistance Publique – Hôpitaux de Paris (FR), Centre de recherche en Epidémiologie et Santé des Populations (FR), Centre Hospitalier Sud Francilien (FR), Genopole (France) (FR), Institut Cochin (FR), Hôpital Bichat-Claude-Bernard (FR), Clinique Ambroise Paré (FR), Centre d'Etudes et de Recherches pour l'Intensification du Traitement du Diabète (FR), European Genomic Institute for Diabetes (FR), (Epi)génomique fonctionnelle métabolique et des dysfonctions dans le diabète de type 2 et des maladies associées (FR), Imperial College London (GB)
Eli Lilly and Company, European Commission, European Foundation for the Study of Diabetes, Agence Nationale de la Recherche, Fonds De La Recherche Scientifique - FNRS, Novo Nordisk, China Scholarship Council, Conseil Régional Hauts-de-France, CHIST-ERA
Good health and well-being
Openalex Percentile: Top 2%
Pancreatic function and diabetes
6.87
DOIOpen Access PDFOpenAlex
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