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 language | English (US) |
|---|---|
| Article number | 2542 |
| Journal | International Journal of Molecular Sciences |
| Volume | 19 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2018 |
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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
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 journal › Article
}
TY - JOUR
T1 - Isx9 regulates calbindin D28K expression in pancreatic β cells and promotes β cell survival and function
AU - Pujol, Julien B.
AU - Heikkila, Eija
AU - Savoia, Claudia
AU - Hajibeigi, Asghar
AU - De Marchi, Umberto
AU - Battiprolu, Pavan K.
AU - Öz, Orhan K.
AU - Dioum, El Hadji M.
PY - 2018/9/1
Y1 - 2018/9/1
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Calbindin-D28K
KW - Calcineurin
KW - Calcium homeostasis
KW - Inflammation
KW - Isx9
KW - NFAT transcription factor
KW - Serum deprivation
KW - β cell function
UR - http://www.scopus.com/inward/record.url?scp=85052522126&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052522126&partnerID=8YFLogxK
U2 - 10.3390/ijms19092542
DO - 10.3390/ijms19092542
M3 - Article
C2 - 30150605
AN - SCOPUS:85052522126
VL - 19
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 9
M1 - 2542
ER -