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

• Published in: Nature communications Vol. 15; no. 1; pp. 6627 - 12
• Main Authors: Meulebrouck, Sarah, Merrheim, Judith, Queniat, Gurvan, Bourouh, Cyril, Derhourhi, Mehdi, Boissel, Mathilde, Yi, Xiaoyan, Badreddine, Alaa, Boutry, Raphaël, Leloire, Audrey, Toussaint, Bénédicte, Amanzougarene, Souhila, Vaillant, Emmanuel, Durand, Emmanuelle, Loiselle, Hélène, Huyvaert, Marlène, Dechaume, Aurélie, Scherrer, Victoria, Marchetti, Piero, Balkau, Beverley, Charpentier, Guillaume, Franc, Sylvia, Marre, Michel, Roussel, Ronan, Scharfmann, Raphaël, Cnop, Miriam, Canouil, Mickaël, Baron, Morgane, Froguel, Philippe, Bonnefond, Amélie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 14/1; 49/23; 49/47; 49/91; 631/208/191; 692/163/2743; 692/308/2056; 96/44; 96/95; Addicts; Adipose tissue; Adult; Beta cells; Biochemistry, Molecular Biology; Circadian rhythms; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Drug abuse; Endocrinology and metabolism; Female; Gene expression; Gene sequencing; Genetics; Genomics; Growth factors; Health risks; Homeostasis; Human genetics; Human health and pathology; Humanities and Social Sciences; Humans; Hyperglycemia; Insulin - metabolism; Insulin secretion; Insulin Secretion - drug effects; Insulin Secretion - genetics; Insulin-Secreting Cells - metabolism; Life Sciences; Male; Metabolic disorders; Metabolism; Middle Aged; multidisciplinary; Narcotics; Nerve growth factor; Opioid receptors (type delta); Oprd1 gene; Receptors; Receptors, Opioid, delta - genetics; Receptors, Opioid, delta - metabolism; Risk analysis; Science; Science (multidisciplinary); Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51004-6

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. Opioid use impacts metabolic homeostasis, although the mechanisms remain elusive. Here, the authors explore the OPRD1 gene (encoding the delta opioid receptor, DOP) to understand its impact on type 2 diabetes and highlight DOP as a key player between opioids and metabolic homeostasis.