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Isx9 Regulates Calbindin D28K Expression in Pancreatic ? Cells and Promotes ? Cell Survival and Function.


ABSTRACT: Pancreatic ?-cell dysfunction and death contribute to the onset of diabetes, and novel strategies of ?-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 ?-cell function and improves glycemia in a model of ? cell regeneration. We further investigated the role of Isx9 in ?-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 ? 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 ? 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 ? cell survival and function, and may be an attractive therapy to treat diabetes and improve islet function post-transplantation.

SUBMITTER: Pujol JB 

PROVIDER: S-EPMC6165483 | BioStudies | 2018-01-01

REPOSITORIES: biostudies

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