January 2022

ENDOCRINOLOGY

P2Y1 PURINERGIC RECEPTOR IDENTIFIED AS A DIABETES TARGET IN A SMALL-MOLECULE SCREEN TO REVERSE CIRCADIAN β-CELL FAILURE

Featuring: Joseph Bass, MD, PhD
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​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-cells. We validated hit compounds in primary mouse islets and identified known modulators of ligand-gated ion channels and
​G-protein- coupled receptors, including the antihelmintic ivermectin. Single-cell  electrophysiology in circadian mutant mouse and human cadaveric islets revealed ivermectin as a glucose-dependent secretagogue.

Genetic, genomic, and pharmacological analyses established the P2Y1 receptor as a clock-controlled mediator of the insulinotropic activity of ivermectin. These findings identify the P2Y1 purinergic receptor as a diabetes target based upon a genetically sensitized phenotypic screen.

Editor's Evaluation
Circadian disruption is widespread in our modern 24/7 society, leading to an increased prevalence of common diseases including type 2 diabetes. The authors conducted an unbiased screen for small-molecule compounds that can restore the attenuated insulin secretion from pancreatic β-cells caused by a disrupted circadian clock. They identified ivermectin and its clock-controlled target, the P2Y1 receptor, which regulate glucose-stimulated ca2+ influx and insulin secretion in β-cells. This discovery represents an important advance in our understanding of regulatory mechanisms of insulin secretion
by cell-autonomous clocks in mouse and human β-cells and is of fundamental clinical importance in context of novel therapeutic targets for diabetes management.​
Joseph Bass, MD, PhD, the Charles F. Kettering Professor of Medicine, director of the Center for Diabetes and Metabolism and chief of Endocrinology in the Department of Medicine.​

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