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Inhibition of Calcium Influx Reduces Dysfunction and Apoptosis in Lipotoxic Pancreatic β-Cells via Regulation of Endoplasmic Reticulum Stress.

Zhou Y, Sun P, Wang T, Chen K, Zhu W, Wang H - PLoS ONE (2015)

Bottom Line: And whether the compounds could reduce palmitic acid-induced β-cell failure and the underlying mechanism were also investigated.It was found that both nifedipine and diazoxide protected MIN6 pancreatic β-cells and primary cultured murine islets from palmitic acid-induced apoptosis.Our results verified that nifedipine and diazoxide could reduce palmitic acid-induced endoplasmic reticulum stress to generate protective effects on pancreatic β-cells.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.

ABSTRACT
Lipotoxicity plays an important role in pancreatic β-cell failure during the development of type 2 diabetes. Prolonged exposure of β-cells to elevated free fatty acids level could cause deterioration of β-cell function and induce cell apoptosis. Therefore, inhibition of fatty acids-induced β-cell dysfunction and apoptosis might provide benefit for the therapy of type 2 diabetes. The present study examined whether regulation of fatty acids-triggered calcium influx could protect pancreatic β-cells from lipotoxicity. Two small molecule compounds, L-type calcium channel blocker nifedipine and potassium channel activator diazoxide were used to inhibit palmitic acid-induced calcium influx. And whether the compounds could reduce palmitic acid-induced β-cell failure and the underlying mechanism were also investigated. It was found that both nifedipine and diazoxide protected MIN6 pancreatic β-cells and primary cultured murine islets from palmitic acid-induced apoptosis. Meanwhile, the impaired insulin secretion was also recovered to varying degrees by these two compounds. Our results verified that nifedipine and diazoxide could reduce palmitic acid-induced endoplasmic reticulum stress to generate protective effects on pancreatic β-cells. More importantly, it suggested that regulation of calcium influx by small molecule compounds might provide benefits for the prevention and therapy of type 2 diabetes.

No MeSH data available.


Related in: MedlinePlus

Nifedipine and diazoxide suppressed PA-induced phosphorylation of JNK.(A) After MIN6 cells were treated in 0.5 mM PA with/without different concentration of nifedipine for 48 h, the phosphorylation of JNK was detected by western blot. (B) The phosphorylation rate of JNK was calculated as optical density of phosphorylated-JNK (p-JNK) divide by total JNK (t-JNK). * p<0.05; *** p<0.001 denote significant difference versus the PA-treated alone group, n = 3. (C) After the cells were treated in 0.5 mM PA with/without different concentration of diazoxide, the phosphorylation of JNK was detected by western blot. (D) The phosphorylation rate of JNK was calculated. *** p<0.001 denote significant difference versus the PA-treated alone group, n = 3.
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pone.0132411.g005: Nifedipine and diazoxide suppressed PA-induced phosphorylation of JNK.(A) After MIN6 cells were treated in 0.5 mM PA with/without different concentration of nifedipine for 48 h, the phosphorylation of JNK was detected by western blot. (B) The phosphorylation rate of JNK was calculated as optical density of phosphorylated-JNK (p-JNK) divide by total JNK (t-JNK). * p<0.05; *** p<0.001 denote significant difference versus the PA-treated alone group, n = 3. (C) After the cells were treated in 0.5 mM PA with/without different concentration of diazoxide, the phosphorylation of JNK was detected by western blot. (D) The phosphorylation rate of JNK was calculated. *** p<0.001 denote significant difference versus the PA-treated alone group, n = 3.

Mentions: To further explore the signal pathway between calcium signal and apoptosis, the mitogen-activated protein kinase (MAPK) signal was examined. It was found that PA-activated JNK phosphorylation was significantly suppressed in MIN6 cell by nifedipine or diazoxide (Fig 5A–5C). However, no alteration was found in PA-activated extracellular signal-regulated kinase (ERK) and p38 MAPK (Data not shown), suggested that inhibition of JNK phosphorylation but not ERK or p38 MAPK might be involved in the cytoprotective effect of nifedipine and diazoxide on PA-impaired β-cells.


Inhibition of Calcium Influx Reduces Dysfunction and Apoptosis in Lipotoxic Pancreatic β-Cells via Regulation of Endoplasmic Reticulum Stress.

Zhou Y, Sun P, Wang T, Chen K, Zhu W, Wang H - PLoS ONE (2015)

Nifedipine and diazoxide suppressed PA-induced phosphorylation of JNK.(A) After MIN6 cells were treated in 0.5 mM PA with/without different concentration of nifedipine for 48 h, the phosphorylation of JNK was detected by western blot. (B) The phosphorylation rate of JNK was calculated as optical density of phosphorylated-JNK (p-JNK) divide by total JNK (t-JNK). * p<0.05; *** p<0.001 denote significant difference versus the PA-treated alone group, n = 3. (C) After the cells were treated in 0.5 mM PA with/without different concentration of diazoxide, the phosphorylation of JNK was detected by western blot. (D) The phosphorylation rate of JNK was calculated. *** p<0.001 denote significant difference versus the PA-treated alone group, n = 3.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4492560&req=5

pone.0132411.g005: Nifedipine and diazoxide suppressed PA-induced phosphorylation of JNK.(A) After MIN6 cells were treated in 0.5 mM PA with/without different concentration of nifedipine for 48 h, the phosphorylation of JNK was detected by western blot. (B) The phosphorylation rate of JNK was calculated as optical density of phosphorylated-JNK (p-JNK) divide by total JNK (t-JNK). * p<0.05; *** p<0.001 denote significant difference versus the PA-treated alone group, n = 3. (C) After the cells were treated in 0.5 mM PA with/without different concentration of diazoxide, the phosphorylation of JNK was detected by western blot. (D) The phosphorylation rate of JNK was calculated. *** p<0.001 denote significant difference versus the PA-treated alone group, n = 3.
Mentions: To further explore the signal pathway between calcium signal and apoptosis, the mitogen-activated protein kinase (MAPK) signal was examined. It was found that PA-activated JNK phosphorylation was significantly suppressed in MIN6 cell by nifedipine or diazoxide (Fig 5A–5C). However, no alteration was found in PA-activated extracellular signal-regulated kinase (ERK) and p38 MAPK (Data not shown), suggested that inhibition of JNK phosphorylation but not ERK or p38 MAPK might be involved in the cytoprotective effect of nifedipine and diazoxide on PA-impaired β-cells.

Bottom Line: And whether the compounds could reduce palmitic acid-induced β-cell failure and the underlying mechanism were also investigated.It was found that both nifedipine and diazoxide protected MIN6 pancreatic β-cells and primary cultured murine islets from palmitic acid-induced apoptosis.Our results verified that nifedipine and diazoxide could reduce palmitic acid-induced endoplasmic reticulum stress to generate protective effects on pancreatic β-cells.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.

ABSTRACT
Lipotoxicity plays an important role in pancreatic β-cell failure during the development of type 2 diabetes. Prolonged exposure of β-cells to elevated free fatty acids level could cause deterioration of β-cell function and induce cell apoptosis. Therefore, inhibition of fatty acids-induced β-cell dysfunction and apoptosis might provide benefit for the therapy of type 2 diabetes. The present study examined whether regulation of fatty acids-triggered calcium influx could protect pancreatic β-cells from lipotoxicity. Two small molecule compounds, L-type calcium channel blocker nifedipine and potassium channel activator diazoxide were used to inhibit palmitic acid-induced calcium influx. And whether the compounds could reduce palmitic acid-induced β-cell failure and the underlying mechanism were also investigated. It was found that both nifedipine and diazoxide protected MIN6 pancreatic β-cells and primary cultured murine islets from palmitic acid-induced apoptosis. Meanwhile, the impaired insulin secretion was also recovered to varying degrees by these two compounds. Our results verified that nifedipine and diazoxide could reduce palmitic acid-induced endoplasmic reticulum stress to generate protective effects on pancreatic β-cells. More importantly, it suggested that regulation of calcium influx by small molecule compounds might provide benefits for the prevention and therapy of type 2 diabetes.

No MeSH data available.


Related in: MedlinePlus