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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

MLDS treatment induces a diabetic phenotype in the absence of DJ-1.Male control and DJ-1 KO mice at 12–13 weeks of age were treated with 40 mg STZ/kg body weight on five consecutive days. Blood glucose concentrations, glucose tolerance, and plasma insulin concentrations were determined. (a,c) Random (a) and fasting (c) blood glucose concentrations in control (black squares) and DJ-1 KO mice (grey squares). n = 6–8 mice per experimental group. (b,d) Corresponding areas under the curve (AUC) to (a,c) are shown for control (black columns) and DJ-1 KO (grey columns) mice each. (e,f) Glucose tolerance test (e) and its corresponding AUC (f) in 14–16 weeks-old control (black squares and black column) and DJ-1 KO mice (grey squares and grey column). The glucose tolerance test was performed after intraperitoneal administration of glucose (1 g/kg body weight). n = 8 mice per experimental group. (g,h) Relative fasting (g) and non-fasting (h) plasma insulin concentrations in 14–16 weeks-old control (black columns) and DJ-1 KO mice (grey columns) normalised to controls. n = 8 mice per experimental group in (g) and n = 5 in (h). *p<0.05 (Student’s t-test in b, d, f-h. Student’s t-test with Holm-Bonferroni correction in a, c, e). All values are means ± SD.
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pone.0138535.g001: MLDS treatment induces a diabetic phenotype in the absence of DJ-1.Male control and DJ-1 KO mice at 12–13 weeks of age were treated with 40 mg STZ/kg body weight on five consecutive days. Blood glucose concentrations, glucose tolerance, and plasma insulin concentrations were determined. (a,c) Random (a) and fasting (c) blood glucose concentrations in control (black squares) and DJ-1 KO mice (grey squares). n = 6–8 mice per experimental group. (b,d) Corresponding areas under the curve (AUC) to (a,c) are shown for control (black columns) and DJ-1 KO (grey columns) mice each. (e,f) Glucose tolerance test (e) and its corresponding AUC (f) in 14–16 weeks-old control (black squares and black column) and DJ-1 KO mice (grey squares and grey column). The glucose tolerance test was performed after intraperitoneal administration of glucose (1 g/kg body weight). n = 8 mice per experimental group. (g,h) Relative fasting (g) and non-fasting (h) plasma insulin concentrations in 14–16 weeks-old control (black columns) and DJ-1 KO mice (grey columns) normalised to controls. n = 8 mice per experimental group in (g) and n = 5 in (h). *p<0.05 (Student’s t-test in b, d, f-h. Student’s t-test with Holm-Bonferroni correction in a, c, e). All values are means ± SD.

Mentions: DJ-1 KO and wild type mice received 40 mg STZ/kg body weight on five consecutive days. The body weight, random and fasting blood glucose concentrations as well as glucose tolerance were monitored. In both groups (wild type and DJ-1 KO mice), MLDS treatment increased random blood glucose concentrations over the course of 28 days (Fig 1a). However, the effect was significantly more pronounced in mice lacking DJ-1 (Fig 1a and 1b). In addition, compared to MLDS-treated wild type mice, DJ-1 KO led to higher fasting blood glucose concentrations (Fig 1c and 1d), and glucose tolerance was impaired in DJ-1 KO mice (Fig 1e and 1f). DJ-1 KO mice also lost weight in the weeks following the STZ injections, whereas the body weight of MLDS-treated wild type mice remained unchanged (S2 Fig). Since both the fasting and random plasma insulin concentrations were significantly lower in DJ-1 KO mice compared to MLDS-treated wild type mice (Fig 1g and 1h), the data suggest that DJ-1 helps to protect pancreatic islets from cell death induced by the 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)

MLDS treatment induces a diabetic phenotype in the absence of DJ-1.Male control and DJ-1 KO mice at 12–13 weeks of age were treated with 40 mg STZ/kg body weight on five consecutive days. Blood glucose concentrations, glucose tolerance, and plasma insulin concentrations were determined. (a,c) Random (a) and fasting (c) blood glucose concentrations in control (black squares) and DJ-1 KO mice (grey squares). n = 6–8 mice per experimental group. (b,d) Corresponding areas under the curve (AUC) to (a,c) are shown for control (black columns) and DJ-1 KO (grey columns) mice each. (e,f) Glucose tolerance test (e) and its corresponding AUC (f) in 14–16 weeks-old control (black squares and black column) and DJ-1 KO mice (grey squares and grey column). The glucose tolerance test was performed after intraperitoneal administration of glucose (1 g/kg body weight). n = 8 mice per experimental group. (g,h) Relative fasting (g) and non-fasting (h) plasma insulin concentrations in 14–16 weeks-old control (black columns) and DJ-1 KO mice (grey columns) normalised to controls. n = 8 mice per experimental group in (g) and n = 5 in (h). *p<0.05 (Student’s t-test in b, d, f-h. Student’s t-test with Holm-Bonferroni correction in a, c, e). All values are means ± SD.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4589499&req=5

pone.0138535.g001: MLDS treatment induces a diabetic phenotype in the absence of DJ-1.Male control and DJ-1 KO mice at 12–13 weeks of age were treated with 40 mg STZ/kg body weight on five consecutive days. Blood glucose concentrations, glucose tolerance, and plasma insulin concentrations were determined. (a,c) Random (a) and fasting (c) blood glucose concentrations in control (black squares) and DJ-1 KO mice (grey squares). n = 6–8 mice per experimental group. (b,d) Corresponding areas under the curve (AUC) to (a,c) are shown for control (black columns) and DJ-1 KO (grey columns) mice each. (e,f) Glucose tolerance test (e) and its corresponding AUC (f) in 14–16 weeks-old control (black squares and black column) and DJ-1 KO mice (grey squares and grey column). The glucose tolerance test was performed after intraperitoneal administration of glucose (1 g/kg body weight). n = 8 mice per experimental group. (g,h) Relative fasting (g) and non-fasting (h) plasma insulin concentrations in 14–16 weeks-old control (black columns) and DJ-1 KO mice (grey columns) normalised to controls. n = 8 mice per experimental group in (g) and n = 5 in (h). *p<0.05 (Student’s t-test in b, d, f-h. Student’s t-test with Holm-Bonferroni correction in a, c, e). All values are means ± SD.
Mentions: DJ-1 KO and wild type mice received 40 mg STZ/kg body weight on five consecutive days. The body weight, random and fasting blood glucose concentrations as well as glucose tolerance were monitored. In both groups (wild type and DJ-1 KO mice), MLDS treatment increased random blood glucose concentrations over the course of 28 days (Fig 1a). However, the effect was significantly more pronounced in mice lacking DJ-1 (Fig 1a and 1b). In addition, compared to MLDS-treated wild type mice, DJ-1 KO led to higher fasting blood glucose concentrations (Fig 1c and 1d), and glucose tolerance was impaired in DJ-1 KO mice (Fig 1e and 1f). DJ-1 KO mice also lost weight in the weeks following the STZ injections, whereas the body weight of MLDS-treated wild type mice remained unchanged (S2 Fig). Since both the fasting and random plasma insulin concentrations were significantly lower in DJ-1 KO mice compared to MLDS-treated wild type mice (Fig 1g and 1h), the data suggest that DJ-1 helps to protect pancreatic islets from cell death induced by the 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