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

Author

Listed:
  • 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)
    Paris-Sud University)

  • Michel Marre

    (Université de Paris
    Clinique Ambroise Paré)

  • Ronan Roussel

    (Université de Paris
    Hôpital Bichat, DHU FIRE, Assistance Publique Hôpitaux de Paris)

  • Raphaël Scharfmann

    (Université de Paris)

  • Miriam Cnop

    (Université Libre de Bruxelles
    Université Libre de Bruxelles)

  • Mickaël Canouil

    (Lille University Hospital)

  • Morgane Baron

    (Lille University Hospital)

  • Philippe Froguel

    (Lille University Hospital
    Imperial College London)

  • Amélie Bonnefond

    (Lille University Hospital
    Imperial College London)

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.

Suggested Citation

  • Sarah Meulebrouck & Judith Merrheim & Gurvan Queniat & Cyril Bourouh & Mehdi Derhourhi & Mathilde Boissel & Xiaoyan Yi & Alaa Badreddine & Raphaël Boutry & Audrey Leloire & Bénédicte Toussaint & Souhi, 2024. "Functional genetics reveals the contribution of delta opioid receptor to type 2 diabetes and beta-cell function," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51004-6
    DOI: 10.1038/s41467-024-51004-6
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    References listed on IDEAS

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