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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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
Externally publishedYes

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Homeostasis
Cell Death
Cytokines
Calcium
Thioredoxins
Endoplasmic Reticulum
Endoplasmic Reticulum Stress
Type 1 Diabetes Mellitus
Proteins
Calcium Compounds
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Dantrolene
Inflammation Mediators
Apoptosis Regulatory Proteins
Calpain
Enzymes

ASJC Scopus subject areas

  • General

Cite this

Clark, A. L., Kanekura, K., Lavagnino, Z., Spears, L. D., Abreu, D., Mahadevan, J., ... 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

Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death. / Clark, Amy L.; Kanekura, Kohsuke; Lavagnino, Zeno; Spears, Larry D.; Abreu, Damien; Mahadevan, Jana; Yagi, Takuya; Semenkovich, Clay F.; Piston, David W.; Urano, Fumihiko.

In: Scientific Reports, Vol. 7, No. 1, 5611, 01.12.2017.

Research output: Contribution to journalArticle

Clark, AL, Kanekura, K, Lavagnino, Z, Spears, LD, Abreu, D, Mahadevan, J, Yagi, T, Semenkovich, CF, Piston, DW & Urano, F 2017, 'Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death', Scientific Reports, vol. 7, no. 1, 5611. https://doi.org/10.1038/s41598-017-05935-4
Clark AL, Kanekura K, Lavagnino Z, Spears LD, Abreu D, Mahadevan J et al. Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death. Scientific Reports. 2017 Dec 1;7(1). 5611. https://doi.org/10.1038/s41598-017-05935-4
Clark, Amy L. ; Kanekura, Kohsuke ; Lavagnino, Zeno ; Spears, Larry D. ; Abreu, Damien ; Mahadevan, Jana ; Yagi, Takuya ; Semenkovich, Clay F. ; Piston, David W. ; Urano, Fumihiko. / Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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