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Exploring the role of purinergic receptor P2RY1 in type 2 diabetes risk and pathophysiology: Insights from human

Arnaud Dance1, Justine Fernandes1, Bénédicte Toussaint1

  • 1Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Université de Lille, Lille, France.

Molecular Metabolism
|December 30, 2023
PubMed
Abstract

Insights

Dysfunctional purinergic receptor P2RY1 increases type 2 diabetes risk. Activating P2RY1 stimulates insulin secretion, suggesting P2RY1 agonists as potential treatments for type 2 diabetes.

Area of Science:

  • Genetics
  • Metabolic Disorders
  • Pharmacology

Background:

  • Human functional genomics aids in identifying drug targets for metabolic disorders.
  • The purinergic receptor P2RY1's role in type 2 diabetes (T2D) warrants investigation.

Purpose of the Study:

  • To investigate the involvement of the purinergic receptor P2RY1 in type 2 diabetes (T2D).
  • To assess the potential of P2RY1 agonists as insulin secretagogues.

Main Methods:

  • Sequencing of P2RY1 in 9,266 participants (4,177 with T2D).
  • In vitro functional analysis of P2RY1 variants.
  • Expression quantitative trait loci (eQTL) analysis in human pancreatic islets.
  • Assessment of P2RY1's effect on glucose-stimulated insulin secretion in human pancreatic beta cells (EndoCβH5) and RNA sequencing.

Main Results:

  • 22 rare P2RY1 variants identified; 7 were loss-of-function.
  • Carriers of loss-of-function variants showed impaired glucose control.
  • P2RY1 variants in a beta-cell enhancer were linked to increased expression and reduced T2D risk.
  • P2RY1 activation stimulated insulin secretion; TXNIP identified as a key transcriptomic marker.

Conclusions:

  • Inherited or acquired P2RY1 dysfunction increases T2D risk.
  • P2RY1 activation stimulates insulin secretion.
  • Selective P2RY1 agonists may serve as potential insulin secretagogues for T2D treatment.

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