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Nat Commun. 2015 Oct 26;6:8372. doi: 10.1038/ncomms9372.

Inhibition of DYRK1A and GSK3B induces human β-cell proliferation.

Author information

1
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
2
Department of Surgery and Schulze Diabetes Institute, University of Minnesota, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA.

Abstract

Insufficient pancreatic β-cell mass or function results in diabetes mellitus. While significant progress has been made in regulating insulin secretion from β-cells in diabetic patients, no pharmacological agents have been described that increase β-cell replication in humans. Here we report aminopyrazine compounds that stimulate robust β-cell proliferation in adult primary islets, most likely as a result of combined inhibition of DYRK1A and GSK3B. Aminopyrazine-treated human islets retain functionality in vitro and after transplantation into diabetic mice. Oral dosing of these compounds in diabetic mice induces β-cell proliferation, increases β-cell mass and insulin content, and improves glycaemic control. Biochemical, genetic and cell biology data point to Dyrk1a as the key molecular target. This study supports the feasibility of treating diabetes with an oral therapy to restore β-cell mass, and highlights a tractable pathway for future drug discovery efforts.

PMID:
26496802
PMCID:
PMC4639830
DOI:
10.1038/ncomms9372
[Indexed for MEDLINE]
Free PMC Article

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