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

1 Scopus citations

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

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

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    Pujol, J. B., Heikkila, E., Savoia, C., Hajibeigi, A., De Marchi, U., Battiprolu, P. K., Öz, O. 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