Inhibition of DYRK1A and GSK3B induces human β-cell proliferation.
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.
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Weijun
W
Shen
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Brandon
B
Taylor
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Qihui
Q
Jin
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Van
V
Nguyen-Tran
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Shelly
S
Meeusen
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
You-Qing
YQ
Zhang
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Anwesh
A
Kamireddy
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Austin
A
Swafford
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Andrew F
AF
Powers
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
John
J
Walker
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
John
J
Lamb
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Badry
B
Bursalaya
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Michael
M
DiDonato
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
George
G
Harb
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Minhua
M
Qiu
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Christophe M
CM
Filippi
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Lisa
L
Deaton
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Carolina N
CN
Turk
Department of Surgery and Schulze Diabetes Institute, University of Minnesota, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA.
Wilma L
WL
Suarez-Pinzon
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Yahu
Y
Liu
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Xueshi
X
Hao
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Tingting
T
Mo
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Shanshan
S
Yan
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Jing
J
Li
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Ann E
AE
Herman
Department of Surgery and Schulze Diabetes Institute, University of Minnesota, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA.
Bernhard J
BJ
Hering
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Tom
T
Wu
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
H
H
Martin Seidel
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Peter
P
McNamara
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Richard
R
Glynne
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Bryan
B
Laffitte
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D015536:Down-Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology; D000097603:Dyrk Kinases
D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011724:Pyridazines; D000097603:Dyrk Kinases; C513630:aminopyridazine; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse