1471-P: Impaired Delta Opioid Receptor Function Protects against Type 2 Diabetes and Results in Enhanced Insulin Secretion—A Functional Genetic Study

Introduction & Objective: Human genetics has proven powerful to pinpoint novel drug targets for metabolic disorders. While the influence of opioids on metabolic homeostasis has been largely acknowledged, the underlying mechanisms remain unclear. We used functional genomics focusing on OPRD1 encoding delta opioid receptor (DOP), aiming to unravel its effects on type 2 diabetes (T2D).

Methods: OPRD1 was sequenced in 7K participants from the French RaDiO study followed by functional investigation of rare and frequent variants. Association analyses between OPRD1 variants and metabolic traits were performed in RaDiO and confirmed in up to 222K individuals. Glucose-stimulated insulin secretion assays were done in human beta cells and islets utilizing DOP agonist or DOP antagonist. RNA-sequencing was done in human beta cells upon DOP antagonist treatment and in human islets subjected to various diabetogenic treatments.

Results: Loss-of-function OPRD1 variants were associated with higher adiposity and lower hyperglycemia risk, while gain-of-function variants were associated with lower adiposity and higher T2D risk. OPRD1 is expressed in human pancreatic islets and beta cells, but not in rodents, and this expression is decreased when exposed to diabetogenic conditions. DOP activation in human beta cells inhibited insulin secretion while DOP inhibition by a specific antagonist strongly enhanced insulin secretion in human islets and beta cells. We identified several pathways regulated by DOP antagonism in human beta cells, including nerve growth factor, circadian clock and nuclear receptor pathways.

Conclusion: Our study highlights the delta opioid receptor as a major link between opioids and metabolic homeostasis in humans, which directly modulates insulin secretion. A peripherally acting DOP antagonist unable to cross the blood-brain barrier might represent a new drug to restore optimal insulin secretion in response to glucose.