Inhibition of DYRK1A and GSK3B induces human β-cell proliferation

Insufficient pancreatic beta-cell mass or function results in diabetes mellitus. While significant progress has been made in regulating insulin secretion from beta-cells in diabetic patients, no pharmacological agents have been described that increase beta-cell replication in humans. Here we report aminopyrazine compounds that stimulate robust beta-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 beta-cell proliferation, increases beta-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 beta-cell mass, and highlights a tractable pathway for future drug discovery efforts.