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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 reduced cell apoptosis in PA-impaired islets.(A) Cultured islets were treated with PA in the presence/absence of different compounds for 48 h, then TUNEL staining was performed. Red fluorescence nuclei indicate apoptotic cells. Blue fluorescence showed all nuclei. Scale bar = 100 μm and referred to all panels. (B) Apoptotic rate was calculated as TUNEL-positive cell number modified by islet area. 10 islets were analyzed from six duplicated wells. * p<0.05; ** p<0.01 denote significant difference versus the PA-treated alone group, n = 6.
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pone.0132411.g007: Nifedipine and diazoxide reduced cell apoptosis in PA-impaired islets.(A) Cultured islets were treated with PA in the presence/absence of different compounds for 48 h, then TUNEL staining was performed. Red fluorescence nuclei indicate apoptotic cells. Blue fluorescence showed all nuclei. Scale bar = 100 μm and referred to all panels. (B) Apoptotic rate was calculated as TUNEL-positive cell number modified by islet area. 10 islets were analyzed from six duplicated wells. * p<0.05; ** p<0.01 denote significant difference versus the PA-treated alone group, n = 6.

Mentions: To further evaluate whether the two Ca2+ influx inhibitors, nifedipine and diazoxide, could reduce PA-induced apoptosis in primary cultured islets, TUNEL staining was used to indicate apoptosis by detecting DNA fragmentation. After the islets were treated with 0.5 mM PA for 48 h, the number of TUNEL-positive cells increased significantly compared to untreated islets (Fig 7A and 7B). As the experiments performed in MIN6 cells, nifedipine and diazoxide reduced PA-induced apoptosis in islets significantly (Fig 7A and 7B).


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 reduced cell apoptosis in PA-impaired islets.(A) Cultured islets were treated with PA in the presence/absence of different compounds for 48 h, then TUNEL staining was performed. Red fluorescence nuclei indicate apoptotic cells. Blue fluorescence showed all nuclei. Scale bar = 100 μm and referred to all panels. (B) Apoptotic rate was calculated as TUNEL-positive cell number modified by islet area. 10 islets were analyzed from six duplicated wells. * p<0.05; ** p<0.01 denote significant difference versus the PA-treated alone group, n = 6.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0132411.g007: Nifedipine and diazoxide reduced cell apoptosis in PA-impaired islets.(A) Cultured islets were treated with PA in the presence/absence of different compounds for 48 h, then TUNEL staining was performed. Red fluorescence nuclei indicate apoptotic cells. Blue fluorescence showed all nuclei. Scale bar = 100 μm and referred to all panels. (B) Apoptotic rate was calculated as TUNEL-positive cell number modified by islet area. 10 islets were analyzed from six duplicated wells. * p<0.05; ** p<0.01 denote significant difference versus the PA-treated alone group, n = 6.
Mentions: To further evaluate whether the two Ca2+ influx inhibitors, nifedipine and diazoxide, could reduce PA-induced apoptosis in primary cultured islets, TUNEL staining was used to indicate apoptosis by detecting DNA fragmentation. After the islets were treated with 0.5 mM PA for 48 h, the number of TUNEL-positive cells increased significantly compared to untreated islets (Fig 7A and 7B). As the experiments performed in MIN6 cells, nifedipine and diazoxide reduced PA-induced apoptosis in islets significantly (Fig 7A and 7B).

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