Isx9 regulates calbindin D28K expression in pancreatic β cells and promotes β cell survival and function

Julien B. Pujol, Eija Heikkila, Claudia Savoia, Asghar Hajibeigi, Umberto De Marchi, Pavan K. Battiprolu, Orhan K. Öz, El Hadji M. Dioum

Research output: Contribution to journalArticle

Abstract

Pancreatic β-cell dysfunction and death contribute to the onset of diabetes, and novel strategies of β-cell function and survival under diabetogenic conditions need to be explored. We previously demonstrated that Isx9, a small molecule based on the isoxazole scaffold, drives neuroendocrine phenotypes by increasing the expression of genes required for β-cell function and improves glycemia in a model of β cell regeneration. We further investigated the role of Isx9 in β-cell survival. We find that Isx9 drives the expression of Calbindin-D28K (D28K), a key regulator of calcium homeostasis, and plays a cytoprotective role through its calcium buffering capacity in β cells. Isx9 increased the activity of the calcineurin (CN)/cytoplasmic nuclear factor of the activated T-cells (NFAT) transcription factor, a key regulator of D28K, and improved the recruitment of NFATc1, cAMP response element-binding protein (CREB), and p300 to the D28K promoter. We found that nutrient stimulation increased D28K plasma membrane enrichment and modulated calcium channel activity in order to regulate glucose-induced insulin secretion. Isx9-mediated expression of D28K protected β cells against chronic stress induced by serum withdrawal or chronic inflammation by reducing caspase 3 activity. Consequently, Isx9 improved human islet function after transplantation in NOD-SCID mice in a streptozotocin-induced diabetes model. In summary, Isx9 significantly regulates expression of genes relevant to β cell survival and function, and may be an attractive therapy to treat diabetes and improve islet function post-transplantation.

Original languageEnglish (US)
Article number2542
JournalInternational Journal of Molecular Sciences
Volume19
Issue number9
DOIs
StatePublished - Sep 1 2018

Fingerprint

Calbindin 1
Cell Survival
Cells
Medical problems
Calcium
cells
calcium
transplantation
Transplantation
regulators
NFATC Transcription Factors
Isoxazoles
TCF Transcription Factors
Gene Expression
Cyclic AMP Response Element-Binding Protein
genes
Inbred NOD Mouse
Genes
SCID Mice
Experimental Diabetes Mellitus

Keywords

  • Apoptosis
  • Calbindin-D28K
  • Calcineurin
  • Calcium homeostasis
  • Inflammation
  • Isx9
  • NFAT transcription factor
  • Serum deprivation
  • β cell function

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Pujol, J. B., Heikkila, E., Savoia, C., Hajibeigi, A., De Marchi, U., Battiprolu, P. K., ... Dioum, E. H. M. (2018). Isx9 regulates calbindin D28K expression in pancreatic β cells and promotes β cell survival and function. International Journal of Molecular Sciences, 19(9), [2542]. https://doi.org/10.3390/ijms19092542

Isx9 regulates calbindin D28K expression in pancreatic β cells and promotes β cell survival and function. / Pujol, Julien B.; Heikkila, Eija; Savoia, Claudia; Hajibeigi, Asghar; De Marchi, Umberto; Battiprolu, Pavan K.; Öz, Orhan K.; Dioum, El Hadji M.

In: International Journal of Molecular Sciences, Vol. 19, No. 9, 2542, 01.09.2018.

Research output: Contribution to journalArticle

Pujol, Julien B. ; Heikkila, Eija ; Savoia, Claudia ; Hajibeigi, Asghar ; De Marchi, Umberto ; Battiprolu, Pavan K. ; Öz, Orhan K. ; Dioum, El Hadji M. / Isx9 regulates calbindin D28K expression in pancreatic β cells and promotes β cell survival and function. In: International Journal of Molecular Sciences. 2018 ; Vol. 19, No. 9.
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