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Inhibition of the NFAT kinases, GSK3beta and Dyrk1a, increases human beta cell proliferation and islet mass

Laffitte, Bryan and Shen, Weijun and Glynne, Richard and Mcnamara, Peter (2016) Inhibition of the NFAT kinases, GSK3beta and Dyrk1a, increases human beta cell proliferation and islet mass. Nature Communications.

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 glycemic 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.

Item Type: Article
Date Deposited: 28 Oct 2015 00:45
Last Modified: 28 Oct 2015 00:45
URI: https://oak.novartis.com/id/eprint/20997

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