Insulin increases H2O2-induced pancreatic beta cell death (original) (raw)

Abstract

Insulin resistance results, in part, from impaired insulin signaling in insulin target tissues. Consequently, increased levels of insulin are necessary to control plasma glucose levels. The effects of elevated insulin levels on pancreatic beta (b) cell function, however, are unclear. In this study, we investigated the possibility that insulin may influence survival of pancreatic b cells. Studies were conducted on RINm, RINm5F and Min-6 pancreatic bcells. Cell death was induced by treatment with H 2 O 2 , and was estimated by measurements of LDH levels, viability assay (Cell-Titer Blue), propidium iodide staining and FACS analysis, and mitochondrial membrane potential (JC-1). In addition, levels of cleaved caspase-3 and caspase activity were determined. Treatment with H 2 O 2 increased cell death; this effect was increased by simultaneous treatment of cells with insulin. Insulin treatment alone caused a slight increase in cell death. Inhibition of caspase-3 reduced the effect of insulin to increase H 2 O 2-induced cell death. Insulin increased ROS production by pancreatic b cells and increased the effect of H 2 O 2. These effects were increased by inhibition of IR signaling, indicative of an effect independent of the IR cascade. We conclude that elevated levels of insulin may act to exacerbate cell death induced by H 2 O 2 and, perhaps, other inducers of apoptosis. Keywords Apoptosis Á ROS Á IR signaling Á Beta cell death Á Oxidative stress Abbreviations ROS Reactive oxygen species T1DM Type 1 diabetes mellitus T2DM Type 2 diabetes mellitus

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References (48)

  1. Nakamura U, Iwase M, Uchizono Y, Sonoki K, Sasaki N, Imoto H, Goto D, Iida M (2006) Rapid intracellular acidification and cell death by H 2 O 2 and alloxan in pancreatic beta cells. Free Radic Biol Med 40:2047-2055
  2. Pipeleers D, Hoorens A, Marichal-Pipeleers M, Van de CM, Bouwens L, Ling Z (2001) Role of pancreatic beta-cells in the process of beta-cell death. Diabetes 50(Suppl 1):S52-S57
  3. Tang C, Han P, Oprescu AI, Lee SC, Gyulkhandanyan AV, Chan GN, Wheeler MB, Giacca A (2007) Evidence for a role of superoxide generation in glucose-induced beta-cell dysfunction in vivo. Diabetes 56:2722-2731
  4. Hou N, Torii S, Saito N, Hosaka M, Takeuchi T (2008) Reactive oxygen species-mediated pancreatic beta-cell death is regulated by interactions between stress-activated protein kinases, p38 and c-Jun N-terminal kinase, and mitogen-activated protein kinase phosphatases. Endocrinology 149:1654-1665
  5. Tiedge M, Lortz S, Drinkgern J, Lenzen S (1997) Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. Diabetes 46:1733-1742
  6. Tiedge M, Lortz S, Munday R, Lenzen S (1998) Complementary action of antioxidant enzymes in the protection of bioengineered insulin-producing RINm5F cells against the toxicity of reactive oxygen species. Diabetes 47:1578-1585
  7. Kajimoto Y, Kaneto H 2004 Role of oxidative stress in pancreatic beta-cell dysfunction. Ann N Y Acad Sci 1011:168-176
  8. Lenzen S, Drinkgern J, Tiedge M (1996) Low antioxidant enzyme gene expression in pancreatic islets compared with var- ious other mouse tissues. Free Radic Biol Med 20:463-466
  9. Robertson RP (2004) Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem 279:42351-42354
  10. Robertson RP, Harmon JS (2006) Diabetes, glucose toxicity, and oxidative stress: a case of double jeopardy for the pancreatic islet beta cell. Free Radic Biol Med 41:177-184
  11. Kaneto H, Kajimoto Y, Miyagawa J, Matsuoka T, Fujitani Y, Umayahara Y, Hanafusa T, Matsuzawa Y, Yamasaki Y, Hori M (1999) Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity. Diabetes 48:2398-2406
  12. Navarro-Tableros V, Sanchez-Soto MC, Garcia S, Hiriart M (2004) Autocrine regulation of single pancreatic beta-cell sur- vival. Diabetes 53:2018-2023
  13. Aston-Mourney K, Proietto J, Morahan G, Andrikopoulos S (2008) Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin. Diabetologia 51:540-545
  14. Del PA (2008) Insulin may have a role to play in protecting beta cells from deterioration in diabetes. Diabetologia 51:1340-1342
  15. Guillen C, Bartolome A, Nevado C, Benito M (2008) Biphasic effect of insulin on beta cell apoptosis depending on glucose deprivation. FEBS Lett 582:3855-3860
  16. Bashan N, Kovsan J, Kachko I, Ovadia H, Rudich A (2009) Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species. Physiol Rev 89:27-71
  17. Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C (1991) A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 139:271-279
  18. Riccardi C, Nicoletti I (2006) Analysis of apoptosis by propidium iodide staining and flow cytometry. Nat Protoc 1:1458-1461
  19. Numazawa S, Sakaguchi H, Aoki R, Taira T, Yoshida T (2008) Regulation of the susceptibility to oxidative stress by cysteine availability in pancreatic beta cells. Am J Physiol Cell Physiol 295:C468-C474
  20. Rasilainen S, Nieminen JM, Levonen AL, Otonkoski T, Lapatto R (2002) Dose-dependent cysteine-mediated protection of insu- lin-producing cells from damage by hydrogen peroxide. Biochem Pharmacol 63:1297-1304
  21. Verga FC, Panacchia L, Bucci B, Stigliano A, Cavallo MG, Brunetti E, Toscano V, Misiti S (2006) 3,5,3 0 -triiodothyronine (T3) is a survival factor for pancreatic beta-cells undergoing apoptosis. J Cell Physiol 206:309-321
  22. Hayes GR, Lockwood DH (1987) Role of insulin receptor phosphorylation in the insulinomimetic effects of hydrogen per- oxide. Proc Natl Acad Sci USA 84:8115-8119
  23. Ge X, Yu Q, Qi W, Shi X, Zhai Q (2008) Chronic insulin treatment causes insulin resistance in 3T3-L1 adipocytes through oxidative stress. Free Radic Res 42:582-591
  24. Goldstein BJ, Mahadev K, Wu X (2005) Redox paradox: insulin action is facilitated by insulin-stimulated reactive oxygen species with multiple potential signaling targets. Diabetes 54:311-321
  25. Krieger-Brauer HI, Kather H (1992) Human fat cells possess a plasma membrane-bound H 2 O 2 -generating system that is acti- vated by insulin via a mechanism bypassing the receptor kinase. J Clin Invest 89:1006-1013
  26. Goldstein BJ, Bittner-Kowalczyk A, White MF, Harbeck M (2000) Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein. J Biol Chem 275:4283-4289
  27. Mehdi MZ, Pandey NR, Pandey SK, Srivastava AK (2005) H 2 O 2 - induced phosphorylation of ERK1/2 and PKB requires tyrosine kinase activity of insulin receptor and c-Src. Antioxid Redox Signal 7:1014-1020
  28. Mandrup-Poulsen T (2003) Apoptotic signal transduction path- ways in diabetes. Biochem Pharmacol 66:1433-1440
  29. Bertrand F, Atfi A, Cadoret A, L'Allemain G, Robin H, Lascols O, Capeau J, Cherqui G (1998) A role for nuclear factor kappaB in the antiapoptotic function of insulin. J Biol Chem 273:2931-2938
  30. Bertrand F, Desbois-Mouthon C, Cadoret A, Prunier C, Robin H, Capeau J, Atfi A, Cherqui G (1999) Insulin antiapoptotic signaling involves insulin activation of the nuclear factor kappaB-dependent survival genes encoding tumor necrosis factor receptor-associated factor 2 and manganese-superoxide dismutase. J Biol Chem 274:30596-30602
  31. Kang S, Song J, Kang H, Kim S, Lee Y, Park D (2003) Insulin can block apoptosis by decreasing oxidative stress via phospha- tidylinositol 3-kinase-and extracellular signal-regulated protein kinase-dependent signaling pathways in HepG2 cells. Eur J Endocrinol 148:147-155
  32. Rakatzi I, Seipke G, Eckel J (2003) [LysB3, GluB29] insulin: a novel insulin analog with enhanced beta-cell protective action. Biochem Biophys Res Commun 310:852-859
  33. Valverde AM, Mur C, Brownlee M, Benito M (2004) Suscepti- bility to apoptosis in insulin-like growth factor-I receptor-defi- cient brown adipocytes. Mol Biol Cell 15:5101-5117
  34. Chaoui D, Faussat AM, Majdak P, Tang R, Perrot JY, Pasco S, Klein C, Marie JP, Legrand O (2006) JC-1, a sensitive probe for a simultaneous detection of P-glycoprotein activity and apoptosis in leukemic cells. Cytometry B Clin Cytom 70:189-196
  35. Dogliotti G, Galliera E, Dozio E, Vianello E, Villa RE, Licastro F, Barajon I, Corsi MM (2010) Okadaic acid induces apoptosis in Down syndrome fibroblasts. Toxicol In Vitro 24:815-821
  36. Kothakota S, Azuma T, Reinhard C, Klippel A, Tang J, Chu K, McGarry TJ, Kirschner MW, Koths K, Kwiatkowski DJ, Williams LT (1997) Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis. Science 278: 294-298
  37. Porras A, Zuluaga S, Valladares A, Alvarez AM, Herrera B, Fabregat I, Benito M (2003) Long-term treatment with insulin induces apoptosis in brown adipocytes: role of oxidative stress. Endocrinology 144:5390-5401
  38. May JM, de HC (1979) Insulin-stimulated intracellular hydrogen peroxide production in rat epididymal fat cells. J Biol Chem 254:2214-2220
  39. Mahadev K, Wu X, Zilbering A, Zhu L, Lawrence JT, Goldstein BJ (2001) Hydrogen peroxide generated during cellular insulin stimulation is integral to activation of the distal insulin signaling cascade in 3T3-L1 adipocytes. J Biol Chem 276:48662-48669
  40. Espinosa A, Garcia A, Hartel S, Hidalgo C, Jaimovich E (2009) NADPH oxidase and hydrogen peroxide mediate insulin-induced calcium increase in skeletal muscle cells. J Biol Chem 284:2568- 2575
  41. Schmid E, Hotz-Wagenblatt A, Hacj V, Droge W (1999) Phos- phorylation of the insulin receptor kinase by phosphocreatine in combination with hydrogen peroxide: the structural basis of redox priming. FASEB J 13:1491-1500
  42. Biswas S, Gupta MK, Chattopadhyay D, Mukhopadhyay CK (2007) Insulin-induced activation of hypoxia-inducible factor-1 requires generation of reactive oxygen species by NADPH oxidase. Am J Physiol Heart Circ Physiol 292:H758-H766
  43. Guichard C, Pedruzzi E, Fay M, Ben MS, Coant N, Daniel F, Ogier-Denis E (2006) The Nox/Duox family of ROS-generating NADPH oxidases. Med Sci (Paris) 22:953-959
  44. Guichard C, Moreau R, Pessayre D, Epperson TK, Krause KH (2008) NOX family NADPH oxidases in liver and in pancreatic islets: a role in the metabolic syndrome and diabetes? Biochem Soc Trans 36:920-929
  45. Srinivasan S, Ohsugi M, Liu Z, Fatrai S, Bernal-Mizrachi E, Permutt MA (2005) Endoplasmic reticulum stress-induced apop- tosis is partly mediated by reduced insulin signaling through phosphatidylinositol 3-kinase/Akt and increased glycogen synthase kinase-3beta in mouse insulinoma cells. Diabetes 54:968-975
  46. Johnson JD, Bernal-Mizrachi E, Alejandro EU, Han Z, Kalynyak TB, Li H, Beith JL, Gross J, Warnock GL, Townsend RR, Per- mutt MA, Polonsky KS (2006) Insulin protects islets from apoptosis via Pdx1 and specific changes in the human islet pro- teome. Proc Natl Acad Sci USA 103:19575-19580
  47. Aikin R, Hanley S, Maysinger D, Lipsett M, Castellarin M, Paraskevas S, Rosenberg L (2006) Autocrine insulin action activates Akt and increases survival of isolated human islets. Diabetologia 49:2900-2909
  48. Muller D, Jones PM, Persaud SJ (2006) Autocrine anti-apoptotic and proliferative effects of insulin in pancreatic beta-cells. FEBS Lett 580:6977-6980