P2Y1 purinergic receptor identified as a diabetes target in a small-molecule screen to reverse circadian β-cell failure.

ABSTRACT: The mammalian circadian clock drives daily oscillations in physiology and behavior through an autoregulatory transcription feedback loop present in central and peripheral cells. Ablation of the core clock within the endocrine pancreas of adult animals impairs the transcription and splicing of genes involved in hormone exocytosis and causes hypoinsulinemic diabetes. Here, we developed a genetically sensitized small-molecule screen to identify druggable proteins and mechanistic pathways involved in circadian β-cell failure. Our approach was to generate β-cells expressing a nanoluciferase reporter within the proinsulin polypeptide to screen 2640 pharmacologically active compounds and identify insulinotropic molecules that bypass the secretory defect in CRISPR-Cas9-targeted clock mutant β-cell

SUBMITTER: Marcheva B 

PROVIDER: S-EPMC8860442 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature