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

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

  • Cell Chem Biol. 2022 Sep 15;29(9):1368-1380.e5. doi: 10.1016/j.chembiol.2022.08.001.
Lianhe Chu 1,  Michishige Terasaki 1,  Charlotte L Mattsson 1,  Romain Teinturier 1,  Jérémie Charbord 1,  Ercument Dirice 2,  Ka-Cheuk Liu 1,  Michael G Miskelly 3,  Qiao Zhou 4,  Nils Wierup 3,  Rohit N Kulkarni 5,  Olov Andersson 6
Affiliations

Affiliations

  • 1 Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
  • 2 Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
  • 3 Department of Clinical Sciences, Lund University Diabetes Centre, Malmö 20502, Sweden.
  • 4 Division of Regenerative Medicine & Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
  • 5 Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Harvard Stem Cell Institute, Boston, MA 02215, USA.
  • 6 Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. Electronic address: olov.andersson@ki.se.
PMID: 35998625 DOI: 10.1016/j.chembiol.2022.08.001
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.

Keywords

DYRK; GIP; GLP-1; chemical screen; diabetes; enteroendocrine cells; incretin hormones; mouse; zebrafish.

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