Functional genetics reveals the contribution of delta opioid receptor to type 2 diabetes and beta-cell function.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
05 Aug 2024
05 Aug 2024
Historique:
received:
23
01
2024
accepted:
29
07
2024
medline:
6
8
2024
pubmed:
6
8
2024
entrez:
5
8
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39103322
doi: 10.1038/s41467-024-51004-6
pii: 10.1038/s41467-024-51004-6
doi:
Substances chimiques
Receptors, Opioid, delta
0
OPRD1 protein, human
0
Insulin
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6627Informations de copyright
© 2024. The Author(s).
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