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In vivo drug discovery for increasing incretin-expressing cells identifies DYRK inhibitors that reinforce the enteroendocrine system.

Abstract
Analogs of the incretin hormones Gip and Glp-1 are used to treat type 2 diabetes and obesity. Findings in experimental models suggest that manipulating several hormones simultaneously may be more effective. To identify small molecules that increase the number of incretin-expressing cells, we established a high-throughput in vivo chemical screen by using the gip promoter to drive the expression of luciferase in zebrafish. All hits increased the numbers of neurogenin 3-expressing enteroendocrine progenitors, Gip-expressing K-cells, and Glp-1-expressing L-cells. One of the hits, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitor, additionally decreased glucose levels in both larval and juvenile fish. Knock-down experiments indicated that nfatc4, a downstream mediator of DYRKs, regulates incretin+ cell number in zebrafish, and that Dyrk1b regulates Glp-1 expression in an enteroendocrine cell line. DYRK inhibition also increased the number of incretin-expressing cells in diabetic mice, suggesting a conserved reinforcement of the enteroendocrine system, with possible implications for diabetes.
AuthorsLianhe Chu, Michishige Terasaki, Charlotte L Mattsson, Romain Teinturier, Jérémie Charbord, Ercument Dirice, Ka-Cheuk Liu, Michael G Miskelly, Qiao Zhou, Nils Wierup, Rohit N Kulkarni, Olov Andersson
JournalCell chemical biology (Cell Chem Biol) Vol. 29 Issue 9 Pg. 1368-1380.e5 (09 15 2022) ISSN: 2451-9448 [Electronic] United States
PMID35998625 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.
Chemical References
  • Incretins
  • Tyrosine
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1
  • Glucose
Topics
  • Animals
  • Diabetes Mellitus, Experimental
  • Diabetes Mellitus, Type 2
  • Drug Discovery
  • Gastric Inhibitory Polypeptide (metabolism, therapeutic use)
  • Glucagon-Like Peptide 1 (genetics, metabolism, therapeutic use)
  • Glucose (metabolism)
  • Incretins (metabolism, therapeutic use)
  • Mice
  • Tyrosine
  • Zebrafish (metabolism)

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