Details

Autor(en) / Beteiligte

• Shen, Weijun
• Taylor, Brandon
• Jin, Qihui
• Nguyen-Tran, Van
• Meeusen, Shelly
• Zhang, You-Qing
• Kamireddy, Anwesh
• Swafford, Austin
• Powers, Andrew F.
• Walker, John
• Lamb, John
• Bursalaya, Badry
• DiDonato, Michael
• Harb, George
• Qiu, Minhua
• Filippi, Christophe M.
• Deaton, Lisa
• Turk, Carolina N.
• Suarez-Pinzon, Wilma L.
• Liu, Yahu
• Hao, Xueshi
• Mo, Tingting
• Yan, Shanshan
• Li, Jing
• Herman, Ann E.
• Hering, Bernhard J.
• Wu, Tom
• Martin Seidel, H.
• McNamara, Peter
• Glynne, Richard
• Laffitte, Bryan

Titel

Inhibition of DYRK1A and GSK3B induces human β-cell proliferation

Ist Teil von

• Nature communications, 2015-10, Vol.6 (1), p.8372, Article 8372

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2015

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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. All forms of diabetes eventually lead to a reduction in insulin-secreting pancreatic β-cells. Here, the authors report aminopyrazine derivatives, which induce proliferation of rodent as well as human β-cells and improve glucose metabolism in a mouse model of type 1 diabetes.