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.
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Authors | Lianhe 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 |
Journal | Cell chemical biology
(Cell Chem Biol)
Vol. 29
Issue 9
Pg. 1368-1380.e5
(09 15 2022)
ISSN: 2451-9448 [Electronic] United States |
PMID | 35998625
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved. |
Chemical References |
- Incretins
- Tyrosine
- Gastric Inhibitory Polypeptide
- Glucagon-Like Peptide 1
- Glucose
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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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