Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death

Amy L. Clark, Kohsuke Kanekura, Zeno Lavagnino, Larry D. Spears, Damien Abreu, Jana Mahadevan, Takuya Yagi, Clay F. Semenkovich, David W. Piston, Fumihiko Urano

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Abstract

Pro-inflammatory cytokines are important mediators of islet inflammation, leading to beta cell death in type 1 diabetes. Although alterations in both endoplasmic reticulum (ER) and cytosolic free calcium levels are known to play a role in cytokine-mediated beta cell death, there are currently no treatments targeting cellular calcium homeostasis to combat type 1 diabetes. Here we show that modulation of cellular calcium homeostasis can mitigate cytokine- and ER stress-mediated beta cell death. The calcium modulating compounds, dantrolene and sitagliptin, both prevent cytokine and ER stress-induced activation of the pro-apoptotic calcium-dependent enzyme, calpain, and partly suppress beta cell death in INS1E cells and human primary islets. These agents are also able to restore cytokine-mediated suppression of functional ER calcium release. In addition, sitagliptin preserves function of the ER calcium pump, sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), and decreases levels of the pro-apoptotic protein thioredoxin-interacting protein (TXNIP). Supporting the role of TXNIP in cytokine-mediated cell death, knock down of TXNIP in INS1-E cells prevents cytokine-mediated beta cell death. Our findings demonstrate that modulation of dynamic cellular calcium homeostasis and TXNIP suppression present viable pharmacologic targets to prevent cytokine-mediated beta cell loss in diabetes.

Original languageEnglish
Article number5611
JournalScientific reports
Volume7
Issue number1
DOIs
Publication statusPublished - 2017 Dec 1

ASJC Scopus subject areas

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    Clark, A. L., Kanekura, K., Lavagnino, Z., Spears, L. D., Abreu, D., Mahadevan, J., Yagi, T., Semenkovich, C. F., Piston, D. W., & Urano, F. (2017). Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death. Scientific reports, 7(1), [5611]. https://doi.org/10.1038/s41598-017-05935-4