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DJ-1 Protects Pancreatic Beta Cells from Cytokine- and Streptozotocin-Mediated Cell Death.

Jain D, Weber G, Eberhard D, Mehana AE, Eglinger J, Welters A, Bartosinska B, Jeruschke K, Weiss J, Päth G, Ariga H, Seufert J, Lammert E - PLoS ONE (2015)

Bottom Line: Insulin concentrations were substantially reduced, and fasting blood glucose concentrations were significantly higher in MLDS-treated DJ-1 KO mice compared to equally treated wild type mice.Rates of beta cell apoptosis upon MLDS treatment were twofold higher in DJ-1 KO mice compared to wild type mice, and in vitro inflammatory cytokines led to twice as much beta cell death in pancreatic islets from DJ-1 KO mice versus those of wild type mice.In conclusion, this study identified the anti-oxidant protein DJ-1 as being capable of protecting pancreatic islet cells from cell death induced by an inflammatory and cytotoxic setting.

View Article: PubMed Central - PubMed

Affiliation: Institute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, Germany; Institute for Beta Cell Biology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Düsseldorf Partner Institute, Düsseldorf, Germany.

ABSTRACT
A hallmark feature of type 1 and type 2 diabetes mellitus is the progressive dysfunction and loss of insulin-producing pancreatic beta cells, and inflammatory cytokines are known to trigger beta cell death. Here we asked whether the anti-oxidant protein DJ-1 encoded by the Parkinson's disease gene PARK7 protects islet cells from cytokine- and streptozotocin-mediated cell death. Wild type and DJ-1 knockout mice (KO) were treated with multiple low doses of streptozotocin (MLDS) to induce inflammatory beta cell stress and cell death. Subsequently, glucose tolerance tests were performed, and plasma insulin as well as fasting and random blood glucose concentrations were monitored. Mitochondrial morphology and number of insulin granules were quantified in beta cells. Moreover, islet cell damage was determined in vitro after streptozotocin and cytokine treatment of isolated wild type and DJ-1 KO islets using calcein AM/ethidium homodimer-1 staining and TUNEL staining. Compared to wild type mice, DJ-1 KO mice became diabetic following MLDS treatment. Insulin concentrations were substantially reduced, and fasting blood glucose concentrations were significantly higher in MLDS-treated DJ-1 KO mice compared to equally treated wild type mice. Rates of beta cell apoptosis upon MLDS treatment were twofold higher in DJ-1 KO mice compared to wild type mice, and in vitro inflammatory cytokines led to twice as much beta cell death in pancreatic islets from DJ-1 KO mice versus those of wild type mice. In conclusion, this study identified the anti-oxidant protein DJ-1 as being capable of protecting pancreatic islet cells from cell death induced by an inflammatory and cytotoxic setting.

No MeSH data available.


Related in: MedlinePlus

DJ-1 is required for maintaining mitochondrial morphology and number of insulin secretory granules after MLDS treatment.(a,b) Electron micrographs of islets from male control (a) and DJ-1 KO mice (b) after 4 weeks of MLDS treatment. (c,d) Image segmentation into mitochondria (red) and insulin secretory granules (green) using the trainable Weka Segmentation plugin for Fiji/ImageJ. Scale bar, 2 μm. (e,f) Quantification of total number of secretory granules (e) and mitochondrial area per section (f) in control and DJ-1 KO mice. n > 30 images per condition from n = 2 control and n = 3 DJ KO mice. Data are expressed as means ± SD.
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pone.0138535.g004: DJ-1 is required for maintaining mitochondrial morphology and number of insulin secretory granules after MLDS treatment.(a,b) Electron micrographs of islets from male control (a) and DJ-1 KO mice (b) after 4 weeks of MLDS treatment. (c,d) Image segmentation into mitochondria (red) and insulin secretory granules (green) using the trainable Weka Segmentation plugin for Fiji/ImageJ. Scale bar, 2 μm. (e,f) Quantification of total number of secretory granules (e) and mitochondrial area per section (f) in control and DJ-1 KO mice. n > 30 images per condition from n = 2 control and n = 3 DJ KO mice. Data are expressed as means ± SD.

Mentions: In order to gain insight into the effect of MLDS treatment on different organelles of the beta cell, electron microscopy was performed on islets isolated from MLDS-treated DJ-1 KO and MLDS-treated wild type mice (Fig 4). Distinct ultrastructural abnormalities were observed in DJ-1 KO islets. More specifically, compared to islets isolated from wild type mice, the total number of insulin secretory granules and the size of the mitochondrial network were reduced (Fig 4). In sum, these data suggest that DJ-1 preserves beta cell integrity upon MLDS treatment.


DJ-1 Protects Pancreatic Beta Cells from Cytokine- and Streptozotocin-Mediated Cell Death.

Jain D, Weber G, Eberhard D, Mehana AE, Eglinger J, Welters A, Bartosinska B, Jeruschke K, Weiss J, Päth G, Ariga H, Seufert J, Lammert E - PLoS ONE (2015)

DJ-1 is required for maintaining mitochondrial morphology and number of insulin secretory granules after MLDS treatment.(a,b) Electron micrographs of islets from male control (a) and DJ-1 KO mice (b) after 4 weeks of MLDS treatment. (c,d) Image segmentation into mitochondria (red) and insulin secretory granules (green) using the trainable Weka Segmentation plugin for Fiji/ImageJ. Scale bar, 2 μm. (e,f) Quantification of total number of secretory granules (e) and mitochondrial area per section (f) in control and DJ-1 KO mice. n > 30 images per condition from n = 2 control and n = 3 DJ KO mice. Data are expressed as means ± SD.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4589499&req=5

pone.0138535.g004: DJ-1 is required for maintaining mitochondrial morphology and number of insulin secretory granules after MLDS treatment.(a,b) Electron micrographs of islets from male control (a) and DJ-1 KO mice (b) after 4 weeks of MLDS treatment. (c,d) Image segmentation into mitochondria (red) and insulin secretory granules (green) using the trainable Weka Segmentation plugin for Fiji/ImageJ. Scale bar, 2 μm. (e,f) Quantification of total number of secretory granules (e) and mitochondrial area per section (f) in control and DJ-1 KO mice. n > 30 images per condition from n = 2 control and n = 3 DJ KO mice. Data are expressed as means ± SD.
Mentions: In order to gain insight into the effect of MLDS treatment on different organelles of the beta cell, electron microscopy was performed on islets isolated from MLDS-treated DJ-1 KO and MLDS-treated wild type mice (Fig 4). Distinct ultrastructural abnormalities were observed in DJ-1 KO islets. More specifically, compared to islets isolated from wild type mice, the total number of insulin secretory granules and the size of the mitochondrial network were reduced (Fig 4). In sum, these data suggest that DJ-1 preserves beta cell integrity upon MLDS treatment.

Bottom Line: Insulin concentrations were substantially reduced, and fasting blood glucose concentrations were significantly higher in MLDS-treated DJ-1 KO mice compared to equally treated wild type mice.Rates of beta cell apoptosis upon MLDS treatment were twofold higher in DJ-1 KO mice compared to wild type mice, and in vitro inflammatory cytokines led to twice as much beta cell death in pancreatic islets from DJ-1 KO mice versus those of wild type mice.In conclusion, this study identified the anti-oxidant protein DJ-1 as being capable of protecting pancreatic islet cells from cell death induced by an inflammatory and cytotoxic setting.

View Article: PubMed Central - PubMed

Affiliation: Institute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, Germany; Institute for Beta Cell Biology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Düsseldorf Partner Institute, Düsseldorf, Germany.

ABSTRACT
A hallmark feature of type 1 and type 2 diabetes mellitus is the progressive dysfunction and loss of insulin-producing pancreatic beta cells, and inflammatory cytokines are known to trigger beta cell death. Here we asked whether the anti-oxidant protein DJ-1 encoded by the Parkinson's disease gene PARK7 protects islet cells from cytokine- and streptozotocin-mediated cell death. Wild type and DJ-1 knockout mice (KO) were treated with multiple low doses of streptozotocin (MLDS) to induce inflammatory beta cell stress and cell death. Subsequently, glucose tolerance tests were performed, and plasma insulin as well as fasting and random blood glucose concentrations were monitored. Mitochondrial morphology and number of insulin granules were quantified in beta cells. Moreover, islet cell damage was determined in vitro after streptozotocin and cytokine treatment of isolated wild type and DJ-1 KO islets using calcein AM/ethidium homodimer-1 staining and TUNEL staining. Compared to wild type mice, DJ-1 KO mice became diabetic following MLDS treatment. Insulin concentrations were substantially reduced, and fasting blood glucose concentrations were significantly higher in MLDS-treated DJ-1 KO mice compared to equally treated wild type mice. Rates of beta cell apoptosis upon MLDS treatment were twofold higher in DJ-1 KO mice compared to wild type mice, and in vitro inflammatory cytokines led to twice as much beta cell death in pancreatic islets from DJ-1 KO mice versus those of wild type mice. In conclusion, this study identified the anti-oxidant protein DJ-1 as being capable of protecting pancreatic islet cells from cell death induced by an inflammatory and cytotoxic setting.

No MeSH data available.


Related in: MedlinePlus