title: DJ-1 Protects Pancreatic Beta Cells from Cytokine- and Streptozotocin-Mediated Cell Death.
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.
authors.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.
authors.forename: Deepak
authors.initials: D
authors.lastname: Jain
authors.affiliation: Institute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Gesine
authors.initials: G
authors.lastname: Weber
authors.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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Eberhard
authors.affiliation: Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Freiburg, Germany; Department of Zoology, Faculty of Science, Suez Canal University, Ismailia, Egypt.
authors.forename: Amir E
authors.initials: AE
authors.lastname: Mehana
authors.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.
authors.forename: Jan
authors.initials: J
authors.lastname: Eglinger
authors.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; Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Alena
authors.initials: A
authors.lastname: Welters
authors.affiliation: Institute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bartosinska
authors.affiliation: Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Jeruschke
authors.affiliation: Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weiss
authors.affiliation: Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Freiburg, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Päth
authors.affiliation: Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku, N12 W6, Sapporo, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Ariga
authors.affiliation: Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Freiburg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Seufert
authors.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.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Lammert
mesh_terms: D000818:Animals; D016923:Cell Death; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism*; D000071617:Protein Deglycase DJ-1; D022142:Secretory Vesicles / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D007328:Insulin; D015513:Oncogene Proteins; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1