Deficiency of transcription factor Nkx6.1 does not prevent insulin secretion in INS-1E cells

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F23%3A00570547" target="_blank" >RIV/67985823:_____/23:00570547 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1038/s41598-023-27985-7" target="_blank" >https://doi.org/10.1038/s41598-023-27985-7</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41598-023-27985-7" target="_blank" >10.1038/s41598-023-27985-7</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Deficiency of transcription factor Nkx6.1 does not prevent insulin secretion in INS-1E cells

Popis výsledku v původním jazyce

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.n

Název v anglickém jazyce

Deficiency of transcription factor Nkx6.1 does not prevent insulin secretion in INS-1E cells

Popis výsledku anglicky

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.n

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30202 - Endocrinology and metabolism (including diabetes, hormones)

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Scientific Reports

ISSN

2045-2322

e-ISSN

2045-2322

Svazek periodika

13

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

13

Strana od-do

683

Kód UT WoS článku

000968670400067

EID výsledku v databázi Scopus

2-s2.0-85146277818