Folate deficiency triggers an oxidative-nitrosative stress-mediated apoptotic cell death and impedes insulin biosynthesis in RINm5F pancreatic islet β-cells: Relevant to the pathogenesis of diabetes

Hung Chih Hsu, Jeng Fong Chiou, Yu Huei Wang, Chia Hui Chen, Shin Yi Mau, Chun Te Ho, Pey Jium Chang, Tsan Zon Liu, Ching Hsein Chen

Research output: Contribution to journalArticle

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Abstract

It has been postulated that folic acid (folate) deficiency (FD) may be a risk factor for the pathogenesis of a variety of oxidative stress-triggered chronic degenerative diseases including diabetes, however, the direct evidence to lend support to this hypothesis is scanty. For this reason, we set out to study if FD can trigger the apoptotic events in an insulin-producing pancreatic RINm5F islet β cells. When these cells were cultivated under FD condition, a time-dependent growth impediment was observed and the demise of these cells was demonstrated to be apoptotic in nature proceeding through a mitochondria-dependent pathway. In addition to evoke oxidative stress, FD condition could also trigger nitrosative stress through a NF-κB-dependent iNOS-mediated overproduction of nitric oxide (NO). The latter compound could then trigger depletion of endoplasmic reticulum (ER) calcium (Ca2+) store leading to cytosolic Ca2+ overload and caused ER stress as evidence by the activation of CHOP expression. Furthermore, FD-induced apoptosis of RINm5F cells was found to be correlated with a time-dependent depletion of intracellular gluthathione (GSH) and a severe down-regulation of Bcl-2 expression. Along the same vein, we also demonstrated that FD could severely impede RINm5F cells to synthesize insulin and their abilities to secret insulin in response to glucose stimulation were appreciably hampered. Even more importantly, we found that folate replenishment could not restore the ability of RINm5F cells to resynthesize insulin. Taken together, our data provide strong evidence to support the hypothesis that FD is a legitimate risk factor for the pathogenesis of diabetes. Copyright:

Original languageEnglish
Article numbere77931
JournalPLoS One
Volume8
Issue number11
DOIs
Publication statusPublished - Nov 4 2013

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Oxidative stress
Biosynthesis
islets of Langerhans
Cell death
Medical problems
Islets of Langerhans
Folic Acid
folic acid
diabetes
cell death
Oxidative Stress
Cell Death
oxidative stress
insulin
pathogenesis
biosynthesis
Insulin
calcium
endoplasmic reticulum
cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Folate deficiency triggers an oxidative-nitrosative stress-mediated apoptotic cell death and impedes insulin biosynthesis in RINm5F pancreatic islet β-cells : Relevant to the pathogenesis of diabetes. / Hsu, Hung Chih; Chiou, Jeng Fong; Wang, Yu Huei; Chen, Chia Hui; Mau, Shin Yi; Ho, Chun Te; Chang, Pey Jium; Liu, Tsan Zon; Chen, Ching Hsein.

In: PLoS One, Vol. 8, No. 11, e77931, 04.11.2013.

Research output: Contribution to journalArticle

Hsu, Hung Chih ; Chiou, Jeng Fong ; Wang, Yu Huei ; Chen, Chia Hui ; Mau, Shin Yi ; Ho, Chun Te ; Chang, Pey Jium ; Liu, Tsan Zon ; Chen, Ching Hsein. / Folate deficiency triggers an oxidative-nitrosative stress-mediated apoptotic cell death and impedes insulin biosynthesis in RINm5F pancreatic islet β-cells : Relevant to the pathogenesis of diabetes. In: PLoS One. 2013 ; Vol. 8, No. 11.
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