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

Chu, Lianhe ; Terasaki, Michishige ; Mattsson, Charlotte L. ; Teinturier, Romain ; Charbord, Jérémie ; Dirice, Ercument ; Liu, Ka Cheuk ; Miskelly, Michael G. LU ; Zhou, Qiao and Wierup, Nils LU , et al. (2022) In Cell Chemical Biology 29(9). p.5-1380
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
chemical screen, diabetes, DYRK, enteroendocrine cells, GIP, GLP-1, incretin hormones, mouse, zebrafish
in
Cell Chemical Biology
volume
29
issue
9
pages
5 - 1380
publisher
Elsevier
external identifiers
  • pmid:35998625
  • scopus:85137623611
ISSN
2451-9456
DOI
10.1016/j.chembiol.2022.08.001
language
English
LU publication?
yes
id
a24637ff-9fda-4d70-859f-9001652ddc25
date added to LUP
2022-11-30 09:23:41
date last changed
2024-04-16 14:20:55
@article{a24637ff-9fda-4d70-859f-9001652ddc25,
  abstract     = {{<p>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<sup>+</sup> 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.</p>}},
  author       = {{Chu, Lianhe and Terasaki, Michishige and Mattsson, Charlotte L. and Teinturier, Romain and Charbord, Jérémie and Dirice, Ercument and Liu, Ka Cheuk and Miskelly, Michael G. and Zhou, Qiao and Wierup, Nils and Kulkarni, Rohit N. and Andersson, Olov}},
  issn         = {{2451-9456}},
  keywords     = {{chemical screen; diabetes; DYRK; enteroendocrine cells; GIP; GLP-1; incretin hormones; mouse; zebrafish}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{9}},
  pages        = {{5--1380}},
  publisher    = {{Elsevier}},
  series       = {{Cell Chemical Biology}},
  title        = {{In vivo drug discovery for increasing incretin-expressing cells identifies DYRK inhibitors that reinforce the enteroendocrine system}},
  url          = {{http://dx.doi.org/10.1016/j.chembiol.2022.08.001}},
  doi          = {{10.1016/j.chembiol.2022.08.001}},
  volume       = {{29}},
  year         = {{2022}},
}