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.
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 (Ca(2+)) store leading to cytosolic Ca(2+) 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 glutathione (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.
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan ; Department of Physical Medicine and Rehabilitation, Chia-Yi Chang Gung Memorial Hospital, Chia-Yi, Taiwan ; Department of Nursing, Chang-Gung University of Science and Technology, Chia-Yi, Taiwan.
Hung-Chih
HC
Hsu
Jeng-Fong
JF
Chiou
Yu-Huei
YH
Wang
Chia-Hui
CH
Chen
Shin-Yi
SY
Mau
Chun-Te
CT
Ho
Pey-Jium
PJ
Chang
Tsan-Zon
TZ
Liu
Ching-Hsein
CH
Chen
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D061252:Feeder Cells; D005494:Folic Acid Deficiency / Q000378:metabolism* / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000096:biosynthesis* / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000502:physiology; D053078:Membrane Potential, Mitochondrial; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D007328:Insulin; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D005978:Glutathione; D002118:Calcium