Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes.

The progression from insulin resistance to type 2 diabetes is caused by the failure of pancreatic beta cells to produce sufficient levels of insulin to meet the metabolic demand. Recent studies indicate that nutrient fluctuations and insulin resistance increase proinsulin synthesis in beta cells beyond the capacity for folding of nascent polypeptides within the endoplasmic reticulum (ER) lumen, thereby disrupting ER homeostasis and triggering the unfolded protein response (UPR). Chronic ER stress promotes apoptosis, at least in part through the UPR-induced transcription factor C/EBP homologous protein (CHOP). We assessed the effect of Chop deletion in multiple mouse models of type 2 diabetes and found that Chop-/- mice had improved glycemic control and expanded beta cell mass in all conditions analyzed. In both genetic and diet-induced models of insulin resistance, CHOP deficiency improved beta cell ultrastructure and promoted cell survival. In addition, we found that isolated islets from Chop-/- mice displayed increased expression of UPR and oxidative stress response genes and reduced levels of oxidative damage. These findings suggest that CHOP is a fundamental factor that links protein misfolding in the ER to oxidative stress and apoptosis in beta cells under conditions of increased insulin demand.

[1]  D. R. Laybutt,et al.  Cytokine-Induced β-Cell Death Is Independent of Endoplasmic Reticulum Stress Signaling , 2008, Diabetes.

[2]  Tsonwin Hai,et al.  Initiation and execution of lipotoxic ER stress in pancreatic β-cells , 2008, Journal of Cell Science.

[3]  L. Glimcher,et al.  Regulation of Hepatic Lipogenesis by the Transcription Factor XBP1 , 2008, Science.

[4]  D. Ron,et al.  Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance and attenuates hepatosteatosis in mice. , 2008, Cell metabolism.

[5]  T. Hansen,et al.  Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. , 2008, The Journal of clinical investigation.

[6]  D. Scheuner,et al.  The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes. , 2008, Endocrine reviews.

[7]  F. Urano,et al.  The Role of Nitric Oxide and the Unfolded Protein Response in Cytokine-Induced β-Cell Death , 2008, Diabetes.

[8]  J. Miyazaki,et al.  Transgenic expression of antioxidant protein thioredoxin in pancreatic beta cells prevents progression of type 2 diabetes mellitus. , 2008, Antioxidants & redox signaling.

[9]  F. Urano,et al.  The role of nitric oxide and the unfolded protein response in cytokine-induced beta-cell death. , 2008, Diabetes.

[10]  R. Kaufman,et al.  Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? , 2007, Antioxidants & redox signaling.

[11]  P. Arvan,et al.  Proinsulin maturation, misfolding, and proteotoxicity , 2007, Proceedings of the National Academy of Sciences.

[12]  A. Hattersley,et al.  Insulin gene mutations as a cause of permanent neonatal diabetes , 2007, Proceedings of the National Academy of Sciences.

[13]  R. Kaufman,et al.  ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. , 2007, Developmental cell.

[14]  Haowei Song,et al.  The group VIA calcium-independent phospholipase A2 participates in ER stress-induced INS-1 insulinoma cell apoptosis by promoting ceramide generation via hydrolysis of sphingomyelins by neutral sphingomyelinase. , 2007, Biochemistry.

[15]  Hiderou Yoshida,et al.  Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. , 2007, Developmental cell.

[16]  R. Rizza,et al.  High Expression Rates of Human Islet Amyloid Polypeptide Induce Endoplasmic Reticulum Stress–Mediated β-Cell Apoptosis, a Characteristic of Humans With Type 2 but Not Type 1 Diabetes , 2007, Diabetes.

[17]  Nathan H. Lents,et al.  XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. , 2007, Molecular cell.

[18]  S. Okada,et al.  Chop‐deficient Mice Showed Increased Adiposity But No Glucose Intolerance , 2007, Obesity.

[19]  P. Walter,et al.  Signal integration in the endoplasmic reticulum unfolded protein response , 2007, Nature Reviews Molecular Cell Biology.

[20]  P. Leung,et al.  Angiotensin II Type 1 Receptor Antagonism Mediates Uncoupling Protein 2-Driven Oxidative Stress and Ameliorates Pancreatic Islet β-Cell Function in Young Type 2 Diabetic Mice , 2007 .

[21]  F. Schuit,et al.  Acute nutrient regulation of the unfolded protein response and integrated stress response in cultured rat pancreatic islets , 2007, Diabetologia.

[22]  E. Wolf,et al.  Dominant-Negative Effects of a Novel Mutated Ins2 Allele Causes Early-Onset Diabetes and Severe β-Cell Loss in Munich Ins2C95S Mutant Mice , 2007, Diabetes.

[23]  R. Robertson,et al.  Chronic oxidative stress as a mechanism for glucose toxicity of the beta cell in Type 2 diabetes , 2007, Cell Biochemistry and Biophysics.

[24]  Deborah Fass,et al.  Modulation of Cellular Disulfide-Bond Formation and the ER Redox Environment by Feedback Regulation of Ero1 , 2007, Cell.

[25]  B. Wajchenberg.  beta-cell failure in diabetes and preservation by clinical treatment. , 2007, Endocrine reviews.

[26]  M. Bollen,et al.  Glucose activates a protein phosphatase-1-mediated signaling pathway to enhance overall translation in pancreatic beta-cells. , 2007, Endocrinology.

[27]  H. Kaneto,et al.  Involvement of oxidative stress in the pathogenesis of diabetes. , 2006, Antioxidants & redox signaling.

[28]  P. Leung,et al.  Angiotensin II Type 1 receptor antagonism mediates uncoupling protein 2-driven oxidative stress and ameliorates pancreatic islet beta-cell function in young Type 2 diabetic mice. , 2007, Antioxidants & redox signaling.

[29]  J. Kench,et al.  Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes , 2007, Diabetologia.

[30]  Barbara C. McGrath,et al.  PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis. , 2006, Cell metabolism.

[31]  B. Yusta,et al.  GLP-1 receptor activation improves β cell function and survival following induction of endoplasmic reticulum stress , 2006 .

[32]  R. Kaufman,et al.  Adaptation to ER Stress Is Mediated by Differential Stabilities of Pro-Survival and Pro-Apoptotic mRNAs and Proteins , 2006, PLoS biology.

[33]  Afshin Samali,et al.  Mediators of endoplasmic reticulum stress‐induced apoptosis , 2006, EMBO reports.

[34]  Kathryn L. Lipson,et al.  Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. , 2006, Cell metabolism.

[35]  E. Yilmaz,et al.  Chemical Chaperones Reduce ER Stress and Restore Glucose Homeostasis in a Mouse Model of Type 2 Diabetes , 2006, Science.

[36]  M. Katze,et al.  Cotranslocational Degradation Protects the Stressed Endoplasmic Reticulum from Protein Overload , 2006, Cell.

[37]  M. Prentki,et al.  Islet beta cell failure in type 2 diabetes. , 2006, The Journal of clinical investigation.

[38]  Yue Feng,et al.  Chronic Inhibition of Dipeptidyl Peptidase-4 With a Sitagliptin Analog Preserves Pancreatic β-Cell Mass and Function in a Rodent Model of Type 2 Diabetes , 2006, Diabetes.

[39]  D. Eizirik,et al.  Interferon-γ potentiates endoplasmic reticulum stress-induced death by reducing pancreatic beta cell defence mechanisms , 2006, Diabetologia.

[40]  B. Yusta,et al.  GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. , 2006, Cell metabolism.

[41]  J. Kushner,et al.  Very Slow Turnover of β-Cells in Aged Adult Mice , 2005 .

[42]  Colin Mathers,et al.  The burden of mortality attributable to diabetes: realistic estimates for the year 2000. , 2005, Diabetes care.

[43]  D. Scheuner,et al.  Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis , 2005, Nature Medicine.

[44]  Michael Brownlee,et al.  The pathobiology of diabetic complications: a unifying mechanism. , 2005, Diabetes.

[45]  M. Katze,et al.  Pancreatic (cid:1) -Cell Failure and Diabetes in Mice With a Deletion Mutation of the Endoplasmic Reticulum Molecular Chaperone Gene P58 IPK , 2022 .

[46]  F. Ortis,et al.  Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic beta-cells. , 2005, Diabetes.

[47]  B. Lowell,et al.  Mitochondrial Dysfunction and Type 2 Diabetes , 2005, Science.

[48]  J. Kushner,et al.  Very slow turnover of beta-cells in aged adult mice. , 2005, Diabetes.

[49]  D. Ron,et al.  CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. , 2004, Genes & development.

[50]  M. Cnop,et al.  Free Fatty Acids and Cytokines Induce Pancreatic β-Cell Apoptosis by Different Mechanisms: Role of Nuclear Factor-κB and Endoplasmic Reticulum Stress , 2004 .

[51]  L. Glimcher,et al.  Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes , 2004, Science.

[52]  A. Cooper,et al.  Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. , 2004, Molecular cell.

[53]  Toshiaki Tanaka,et al.  Pioglitazone improves insulin secretory capacity and prevents the loss of beta-cell mass in obese diabetic db/db mice: Possible protection of beta cells from oxidative stress. , 2004, Metabolism: clinical and experimental.

[54]  J. Cunningham,et al.  Antioxidant enzyme activity and mRNA expression in the islets of Langerhans from the BB/S rat model of type 1 diabetes and an insulin-producing cell line , 2004, Journal of Molecular Medicine.

[55]  Haowei Song,et al.  Apoptosis of insulin-secreting cells induced by endoplasmic reticulum stress is amplified by overexpression of group VIA calcium-independent phospholipase A2 (iPLA2 beta) and suppressed by inhibition of iPLA2 beta. , 2004, Biochemistry.

[56]  D. Eizirik,et al.  Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. , 2004, Endocrinology.

[57]  Jonathan S. Weissman,et al.  Oxidative protein folding in eukaryotes: mechanisms and consequences , 2004 .

[58]  L. Scorrano,et al.  Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction. , 2003, The Journal of clinical investigation.

[59]  R. Paules,et al.  An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. , 2003, Molecular cell.

[60]  Xi Chen,et al.  ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. , 2002, Developmental cell.

[61]  H. Kaneto,et al.  Probucol preserves pancreatic beta-cell function through reduction of oxidative stress in type 2 diabetes. , 2002, Diabetes research and clinical practice.

[62]  L. Hendershot,et al.  Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. , 2002, Journal of molecular biology.

[63]  Masataka Mori,et al.  Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. , 2002, The Journal of clinical investigation.

[64]  K. Mori,et al.  XBP1 mRNA Is Induced by ATF6 and Spliced by IRE1 in Response to ER Stress to Produce a Highly Active Transcription Factor , 2001, Cell.

[65]  S. Shenolikar,et al.  Growth Arrest and DNA Damage-Inducible Protein GADD34 Assembles a Novel Signaling Complex Containing Protein Phosphatase 1 and Inhibitor 1 , 2001, Molecular and Cellular Biology.

[66]  Masataka Mori,et al.  Nitric oxide-induced apoptosis in pancreatic β cells is mediated by the endoplasmic reticulum stress pathway , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[67]  E McEwen,et al.  Translational control is required for the unfolded protein response and in vivo glucose homeostasis. , 2001, Molecular cell.

[68]  D. Ron,et al.  Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. , 2001, Molecular cell.

[69]  M. Lane,et al.  Role of C/EBP homologous protein (CHOP-10) in the programmed activation of CCAAT/enhancer-binding protein-beta during adipogenesis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[70]  G. Reaven,et al.  A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. , 2000, Metabolism: clinical and experimental.

[71]  M. Schapira,et al.  Regulated translation initiation controls stress-induced gene expression in mammalian cells. , 2000, Molecular cell.

[72]  G. Lathrop,et al.  EIF2AK3, encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott-Rallison syndrome , 2000, Nature Genetics.

[73]  Y. Matsuzawa,et al.  Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity. , 1999, Diabetes.

[74]  K. Mori,et al.  Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. , 1999, Molecular biology of the cell.

[75]  J. Heinecke,et al.  Nitrogen dioxide radical generated by the myeloperoxidase‐hydrogen peroxide‐nitrite system promotes lipid peroxidation of low density lipoprotein , 1999, FEBS letters.

[76]  T. W. Fawcett,et al.  Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. , 1999, The Biochemical journal.

[77]  Danhong Lu,et al.  A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse. , 1999, The Journal of clinical investigation.

[78]  G. Reaven,et al.  Nongenetic mouse models of non-insulin-dependent diabetes mellitus. , 1998, Metabolism: clinical and experimental.

[79]  Xiaozhong Wang,et al.  CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. , 1998, Genes & development.

[80]  S. Lenzen,et al.  Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. , 1996, Free radical biology & medicine.

[81]  X. Wang,et al.  Inhibition of adipogenesis by the stress‐induced protein CHOP (Gadd153). , 1995, The EMBO journal.

[82]  J. Heinecke,et al.  Tyrosyl radical generated by myeloperoxidase is a physiological catalyst for the initiation of lipid peroxidation in low density lipoprotein. , 1994, The Journal of biological chemistry.

[83]  P. Lacy,et al.  The use of ficoll in the preparation of viable islets of langerhans from the rat pancreas. , 1973, Transplantation.

[84]  P. Lacy,et al.  Method for the Isolation of Intact Islets of Langerhans from the Rat Pancreas , 1967, Diabetes.