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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 to reduce loss of beta cell mass following treatment with MLDS.(a,d) Representative fluorescence microscopy images of pancreatic sections from 16 weeks-old male control and DJ-1 KO mice following MLDS treatment, stained for cell nuclei (DAPI) and beta cells (insulin). Scale bars, 0.5 mm. (b,c,e,f) LSM images of pancreatic islets in sections of pancreata from male control (b,c) and DJ-1 KO mice (e-f) after MLDS treatment, stained for cell nuclei (DAPI) and beta cells (insulin) (b,e). Merged images (c,f) are also shown. Scale bars, 50 μm. (g) Morphometric analyses of relative beta cell area from DJ-1 KO and control mice calculated as insulin-positive area per total nuclei area of evenly spaced pancreatic sections. n = 3 mouse pancreata per experimental group. Beta cell area was quantified after four weeks of STZ treatment. For comparison, untreated control/wild type mice without STZ treatment were included. *p<0.05 (One-way ANOVA followed by Tukey´s multiple comparison test). Data are expressed as means ± S.D.
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pone.0138535.g003: DJ-1 is required to reduce loss of beta cell mass following treatment with MLDS.(a,d) Representative fluorescence microscopy images of pancreatic sections from 16 weeks-old male control and DJ-1 KO mice following MLDS treatment, stained for cell nuclei (DAPI) and beta cells (insulin). Scale bars, 0.5 mm. (b,c,e,f) LSM images of pancreatic islets in sections of pancreata from male control (b,c) and DJ-1 KO mice (e-f) after MLDS treatment, stained for cell nuclei (DAPI) and beta cells (insulin) (b,e). Merged images (c,f) are also shown. Scale bars, 50 μm. (g) Morphometric analyses of relative beta cell area from DJ-1 KO and control mice calculated as insulin-positive area per total nuclei area of evenly spaced pancreatic sections. n = 3 mouse pancreata per experimental group. Beta cell area was quantified after four weeks of STZ treatment. For comparison, untreated control/wild type mice without STZ treatment were included. *p<0.05 (One-way ANOVA followed by Tukey´s multiple comparison test). Data are expressed as means ± S.D.

Mentions: MLDS treatment was shown to induce beta cell death, primarily apoptosis. Therefore, the extent of beta cell apoptosis was determined using pancreatic sections obtained from DJ-1 KO and wild type mice treated with MLDS. In DJ-1 KO mice, significantly more apoptotic pancreatic beta cells were found compared to equally treated wild type mice, suggesting that DJ-1 is required to reduce the extent of beta cell apoptosis following treatment with MLDS (Fig 2). Consistent with this notion, MLDS-treated DJ-1 KO mice had a stronger reduction in the beta cell area compared to MLDS-treated wild type mice (Fig 3), indicating that DJ-1 helps to preserve the beta cell mass 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 to reduce loss of beta cell mass following treatment with MLDS.(a,d) Representative fluorescence microscopy images of pancreatic sections from 16 weeks-old male control and DJ-1 KO mice following MLDS treatment, stained for cell nuclei (DAPI) and beta cells (insulin). Scale bars, 0.5 mm. (b,c,e,f) LSM images of pancreatic islets in sections of pancreata from male control (b,c) and DJ-1 KO mice (e-f) after MLDS treatment, stained for cell nuclei (DAPI) and beta cells (insulin) (b,e). Merged images (c,f) are also shown. Scale bars, 50 μm. (g) Morphometric analyses of relative beta cell area from DJ-1 KO and control mice calculated as insulin-positive area per total nuclei area of evenly spaced pancreatic sections. n = 3 mouse pancreata per experimental group. Beta cell area was quantified after four weeks of STZ treatment. For comparison, untreated control/wild type mice without STZ treatment were included. *p<0.05 (One-way ANOVA followed by Tukey´s multiple comparison test). Data are expressed as means ± S.D.
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Related In: Results  -  Collection

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pone.0138535.g003: DJ-1 is required to reduce loss of beta cell mass following treatment with MLDS.(a,d) Representative fluorescence microscopy images of pancreatic sections from 16 weeks-old male control and DJ-1 KO mice following MLDS treatment, stained for cell nuclei (DAPI) and beta cells (insulin). Scale bars, 0.5 mm. (b,c,e,f) LSM images of pancreatic islets in sections of pancreata from male control (b,c) and DJ-1 KO mice (e-f) after MLDS treatment, stained for cell nuclei (DAPI) and beta cells (insulin) (b,e). Merged images (c,f) are also shown. Scale bars, 50 μm. (g) Morphometric analyses of relative beta cell area from DJ-1 KO and control mice calculated as insulin-positive area per total nuclei area of evenly spaced pancreatic sections. n = 3 mouse pancreata per experimental group. Beta cell area was quantified after four weeks of STZ treatment. For comparison, untreated control/wild type mice without STZ treatment were included. *p<0.05 (One-way ANOVA followed by Tukey´s multiple comparison test). Data are expressed as means ± S.D.
Mentions: MLDS treatment was shown to induce beta cell death, primarily apoptosis. Therefore, the extent of beta cell apoptosis was determined using pancreatic sections obtained from DJ-1 KO and wild type mice treated with MLDS. In DJ-1 KO mice, significantly more apoptotic pancreatic beta cells were found compared to equally treated wild type mice, suggesting that DJ-1 is required to reduce the extent of beta cell apoptosis following treatment with MLDS (Fig 2). Consistent with this notion, MLDS-treated DJ-1 KO mice had a stronger reduction in the beta cell area compared to MLDS-treated wild type mice (Fig 3), indicating that DJ-1 helps to preserve the beta cell mass 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