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Deficiency of transcription factor Nkx6.1 does not prevent insulin secretion in INS-1E cells
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SYSNO ASEP 0570547 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Deficiency of transcription factor Nkx6.1 does not prevent insulin secretion in INS-1E cells Author(s) Pavluch, Vojtěch (FGU-C) RID, ORCID
Engstová, Hana (FGU-C) RID, ORCID
Špačková, Jitka (FGU-C) RID, ORCID
Ježek, Petr (FGU-C) RID, ORCIDArticle number 683 Source Title Scientific Reports. - : Nature Publishing Group - ISSN 2045-2322
Roč. 13, č. 1 (2023)Number of pages 13 s. Language eng - English Country DE - Germany Keywords Nkx6.1 ; pancreatic-beta-cells ; GLUT2 ; pyruvate carboxylase ; glucose-stimulated insulin secretion OECD category Endocrinology and metabolism (including diabetes, hormones) R&D Projects LX22NPO5104 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GA20-00408S GA ČR - Czech Science Foundation (CSF) Method of publishing Open access Institutional support FGU-C - RVO:67985823 UT WOS 000968670400067 EID SCOPUS 85146277818 DOI 10.1038/s41598-023-27985-7 Annotation Pancreatic-beta-cell-specifying transcription factor Nkx6.1, indispensable for embryonic development of the pancreatic epithelium and commitment to beta-cell lineage, directly controls the expression of a glucose transporter (Glut2), pyruvate carboxylase (Pcx), and genes for insulin processing (endoplasmic reticulum oxidoreductase-1 beta, Ero1lb, zinc transporter-8, Slc30a8). The Nkx6.1 decline in aging diabetic Goto-Kakizaki rats contributes to beta-cell trans-differentiation into delta-cells. Elucidating further Nkx6.1 roles, we studied Nkx6.1 ablation in rat INS-1E cells, prepared by CRISPR/Cas9 gene editing from single colonies. INS-1E(Nkx6.1-/-) cells exhibited unchanged glucose-stimulated insulin secretion (GSIS), moderately decreased phosphorylating/non-phosphorylating respiration ratios at high glucose, unchanged but delayed ATP-elevation responses to glucose, delayed uptake of fluorescent glucose analog, but slightly improved cytosolic Ca2+-oscillations, induced by glucose, despite approximately halved Glut2, Pcx, Ero1lb, and Slc30a8 expression, and reduced nuclear receptors Nr4a1 and Nr4a3. Thus, ATP synthesis was time-compensated, despite the delayed GLUT2-mediated glucose uptake and crippled pyruvate-malate redox shuttle (owing to the PCX-deficiency) in INS-1E(Nkx6.1-/-) cells. Nkx6.1 thus controls the expression of genes that are not essential for acute insulin secretion, the function of which can be compensated for. Considerations that Nkx6.1 deficiency is an ultimate determinant of beta-cell pathology beyond cell trans-(de-)differentiation or beta-cell identity are not supported by our results.
Workplace Institute of Physiology Contact Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Year of Publishing 2024 Electronic address https://doi.org/10.1038/s41598-023-27985-7
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