1. Inhibition of DYRK1A and GSK3B induces human β-cell proliferation.
- Author
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Shen W, Taylor B, Jin Q, Nguyen-Tran V, Meeusen S, Zhang YQ, Kamireddy A, Swafford A, Powers AF, Walker J, Lamb J, Bursalaya B, DiDonato M, Harb G, Qiu M, Filippi CM, Deaton L, Turk CN, Suarez-Pinzon WL, Liu Y, Hao X, Mo T, Yan S, Li J, Herman AE, Hering BJ, Wu T, Martin Seidel H, McNamara P, Glynne R, and Laffitte B
- Subjects
- Animals, Cell Division drug effects, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Experimental genetics, Diabetes Mellitus, Experimental metabolism, Diabetes Mellitus, Experimental physiopathology, Down-Regulation drug effects, Glycogen Synthase Kinase 3 metabolism, Glycogen Synthase Kinase 3 beta, Humans, Insulin-Secreting Cells drug effects, Insulin-Secreting Cells enzymology, Male, Mice, Mice, Transgenic, Protein Serine-Threonine Kinases metabolism, Protein-Tyrosine Kinases metabolism, Pyridazines pharmacology, Dyrk Kinases, Cell Proliferation drug effects, Glycogen Synthase Kinase 3 genetics, Insulin-Secreting Cells cytology, Protein Serine-Threonine Kinases genetics, Protein-Tyrosine Kinases genetics
- 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.
- Published
- 2015
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