Pflügers Archiv - European Journal of Physiology

, Volume 460, Issue 4, pp 703–718 | Cite as

Oxidative stress and beta-cell dysfunction

  • Gisela Drews
  • Peter Krippeit-Drews
  • Martina Düfer
Invited Review


Diabetes mellitus type 1 and 2 (T1DM and T2DM) are complex multifactorial diseases. Loss of beta-cell function caused by reduced secretory capacity and enhanced apoptosis is a key event in the pathogenesis of both diabetes types. Oxidative stress induced by reactive oxygen and nitrogen species is critically involved in the impairment of beta-cell function during the development of diabetes. Because of their low antioxidant capacity, beta-cells are extremely sensitive towards oxidative stress. In beta-cells, important targets for an oxidant insult are cell metabolism and KATP channels. The oxidant-evoked alterations of KATP channel activity seem to be critical for oxidant-induced dysfunction because genetic ablation of KATP channels attenuates the effects of oxidative stress on beta-cell function. Besides the effects on metabolism, interference of oxidants with mitochondria induces key events in apoptosis. Consequently, increasing antioxidant defence is a promising strategy to delay beta cell failure in (pre)-diabetic patients or during islet transplantation. Knock-out of KATP channels has beneficial effects on oxidant-induced inhibition of insulin secretion and cell death. Interestingly, these effects can be mimicked by sulfonylureas that have been used in the treatment of T2DM for many years. Loss of functional KATP channels leads to up-regulation of antioxidant enzymes, a process that depends on cytosolic Ca2+. These observations are of great importance for clinical intervention because they show a possibility to protect beta-cells at an early stage before dramatic changes of the secretory capacity and loss of cell mass become manifest and lead to glucose intolerance or even overt diabetes.


Sulphonylurea Mitochondria Diabetes mellitus Oxidative stress Apoptosis ATP-dependent potassium channel SUR1 Hydrogen peroxide Transplantation Pancreatic beta-cell 


  1. 1.
    Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335–344PubMedCrossRefGoogle Scholar
  2. 2.
    Lenaz G (2001) The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology. IUBMB Life 52:159–164PubMedCrossRefGoogle Scholar
  3. 3.
    Newsholme P, Haber EP, Hirabara SM, Rebelato EL, Procopio J, Morgan D, Oliveira-Emilio HC, Carpinelli AR, Curi R (2007) Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mitochondrial ROS production and activity. J Physiol 583:9–24PubMedCrossRefGoogle Scholar
  4. 4.
    Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790PubMedCrossRefGoogle Scholar
  5. 5.
    Bindokas VP, Kuznetsov A, Sreenan S, Polonsky KS, Roe MW, Philipson LH (2003) Visualizing superoxide production in normal and diabetic rat islets of Langerhans. J Biol Chem 278:9796–9801PubMedCrossRefGoogle Scholar
  6. 6.
    Newsholme P, Morgan D, Rebelato E, Oliveira-Emilio HC, Procopio J, Curi R, Carpinelli A (2009) Insights into the critical role of NADPH oxidase(s) in the normal and dysregulated pancreatic beta cell. Diabetologia 52(12):2489–2498PubMedCrossRefGoogle Scholar
  7. 7.
    Uchizono Y, Takeya R, Iwase M, Sasaki N, Oku M, Imoto H, Iida M, Sumimoto H (2006) Expression of isoforms of NADPH oxidase components in rat pancreatic islets. Life Sci 80:133–139PubMedCrossRefGoogle Scholar
  8. 8.
    Block K, Gorin Y, Abboud HE (2009) Subcellular localization of Nox4 and regulation in diabetes. Proc Natl Acad Sci USA 106:14385–14390PubMedCrossRefGoogle Scholar
  9. 9.
    Henningsson R, Salehi A, Lundquist I (2002) Role of nitric oxide synthase isoforms in glucose-stimulated insulin release. Am J Physiol Cell Physiol 283:C296–C304PubMedGoogle Scholar
  10. 10.
    Nakada S, Ishikawa T, Yamamoto Y, Kaneko Y, Nakayama K (2003) Constitutive nitric oxide synthases in rat pancreatic islets: direct imaging of glucose-induced nitric oxide production in beta-cells. Pflugers Arch 447:305–311PubMedCrossRefGoogle Scholar
  11. 11.
    Darville MI, Eizirik DL (1998) Regulation by cytokines of the inducible nitric oxide synthase promoter in insulin-producing cells. Diabetologia 41:1101–1108PubMedCrossRefGoogle Scholar
  12. 12.
    Kutlu B, Cardozo AK, Darville MI, Kruhoffer M, Magnusson N, Orntoft T, Eizirik DL (2003) Discovery of gene networks regulating cytokine-induced dysfunction and apoptosis in insulin-producing INS-1 cells. Diabetes 52:2701–2719PubMedCrossRefGoogle Scholar
  13. 13.
    Kaneto H, Fujii J, Seo HG, Suzuki K, Matsuoka T, Nakamura M, Tatsumi H, Yamasaki Y, Kamada T, Taniguchi N (1995) Apoptotic cell death triggered by nitric oxide in pancreatic beta-cells. Diabetes 44:733–738PubMedCrossRefGoogle Scholar
  14. 14.
    Eizirik DL, Colli ML, Ortis F (2009) The role of inflammation in insulitis and beta-cell loss in type 1 diabetes. Nat Rev Endocrinol 5:219–226PubMedCrossRefGoogle Scholar
  15. 15.
    Lortz S, Tiedge M, Nachtwey T, Karlsen AE, Nerup J, Lenzen S (2000) Protection of insulin-producing RINm5F cells against cytokine-mediated toxicity through overexpression of antioxidant enzymes. Diabetes 49:1123–1130PubMedCrossRefGoogle Scholar
  16. 16.
    Suarez-Pinzon WL, Strynadka K, Rabinovitch A (1996) Destruction of rat pancreatic islet beta-cells by cytokines involves the production of cytotoxic aldehydes. Endocrinology 137:5290–5296PubMedCrossRefGoogle Scholar
  17. 17.
    Suarez-Pinzon WL, Szabo C, Rabinovitch A (1997) Development of autoimmune diabetes in NOD mice is associated with the formation of peroxynitrite in pancreatic islet beta-cells. Diabetes 46:907–911PubMedCrossRefGoogle Scholar
  18. 18.
    Donath MY, Storling J, Maedler K, Mandrup-Poulsen T (2003) Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes. J Mol Med 81:455–470PubMedCrossRefGoogle Scholar
  19. 19.
    Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S, Mathis D (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15:930–939PubMedCrossRefGoogle Scholar
  20. 20.
    Sakuraba H, Mizukami H, Yagihashi N, Wada R, Hanyu C, Yagihashi S (2002) Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients. Diabetologia 45:85–96PubMedCrossRefGoogle Scholar
  21. 21.
    Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110PubMedCrossRefGoogle Scholar
  22. 22.
    Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M, Aoki T, Etoh T, Hashimoto T, Naruse M, Sano H, Utsumi H, Nawata H (2000) High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C–dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 49:1939–1945PubMedCrossRefGoogle Scholar
  23. 23.
    Li N, Frigerio F, Maechler P (2008) The sensitivity of pancreatic beta-cells to mitochondrial injuries triggered by lipotoxicity and oxidative stress. Biochem Soc Trans 36:930–934PubMedCrossRefGoogle Scholar
  24. 24.
    Tanaka Y, Tran PO, Harmon J, Robertson RP (2002) A role for glutathione peroxidase in protecting pancreatic beta cells against oxidative stress in a model of glucose toxicity. Proc Natl Acad Sci USA 99:12363–12368PubMedCrossRefGoogle Scholar
  25. 25.
    Sakai K, Matsumoto K, Nishikawa T, Suefuji M, Nakamaru K, Hirashima Y, Kawashima J, Shirotani T, Ichinose K, Brownlee M, Araki E (2003) Mitochondrial reactive oxygen species reduce insulin secretion by pancreatic beta-cells. Biochem Biophys Res Commun 300:216–222PubMedCrossRefGoogle Scholar
  26. 26.
    Morgan D, Oliveira-Emilio HR, Keane D, Hirata AE, Santos da Rocha M, Bordin S, Curi R, Newsholme P, Carpinelli AR (2007) Glucose, palmitate and pro-inflammatory cytokines modulate production and activity of a phagocyte-like NADPH oxidase in rat pancreatic islets and a clonal beta cell line. Diabetologia 50:359–369PubMedCrossRefGoogle Scholar
  27. 27.
    Pi J, Bai Y, Zhang Q, Wong V, Floering LM, Daniel K, Reece JM, Deeney JT, Andersen ME, Corkey BE, Collins S (2007) Reactive oxygen species as a signal in glucose-stimulated insulin secretion. Diabetes 56:1783–1791PubMedCrossRefGoogle Scholar
  28. 28.
    Fridlyand LE, Philipson LH (2004) Does the glucose-dependent insulin secretion mechanism itself cause oxidative stress in pancreatic beta-cells? Diabetes 53:1942–1948PubMedCrossRefGoogle Scholar
  29. 29.
    Starkov AA, Polster BM, Fiskum G (2002) Regulation of hydrogen peroxide production by brain mitochondria by calcium and Bax. J Neurochem 83:220–228PubMedCrossRefGoogle Scholar
  30. 30.
    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 149:1654–1665PubMedCrossRefGoogle Scholar
  31. 31.
    Martens GA, Cai Y, Hinke S, Stange G, Van de Casteele M, Pipeleers D (2005) Glucose suppresses superoxide generation in metabolically responsive pancreatic beta cells. J Biol Chem 280:20389–20396PubMedCrossRefGoogle Scholar
  32. 32.
    Schmidt HH, Warner TD, Ishii K, Sheng H, Murad F (1992) Insulin secretion from pancreatic B cells caused by L-arginine-derived nitrogen oxides. Science 255:721–723PubMedCrossRefGoogle Scholar
  33. 33.
    Meidute Abaraviciene S, Lundquist I, Galvanovskis J, Flodgren E, Olde B, Salehi A (2008) Palmitate-induced beta-cell dysfunction is associated with excessive NO production and is reversed by thiazolidinedione-mediated inhibition of GPR40 transduction mechanisms. PLoS ONE 3:e2182PubMedCrossRefGoogle Scholar
  34. 34.
    Rhee SG (2006) Cell signaling. H2O2, a necessary evil for cell signaling. Science 312:1882–1883PubMedCrossRefGoogle Scholar
  35. 35.
    Dröge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95PubMedGoogle Scholar
  36. 36.
    Leloup C, Tourrel-Cuzin C, Magnan C, Karaca M, Castel J, Carneiro L, Colombani AL, Ktorza A, Casteilla L, Penicaud L (2009) Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion. Diabetes 58:673–681PubMedCrossRefGoogle Scholar
  37. 37.
    Robertson RP, Harmon J, Tran PO, Tanaka Y, Takahashi H (2003) Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 52:581–587PubMedCrossRefGoogle Scholar
  38. 38.
    Kaneko Y, Ishikawa T, Amano S, Nakayama K (2003) Dual effect of nitric oxide on cytosolic Ca2+ concentration and insulin secretion in rat pancreatic beta-cells. Am J Physiol Cell Physiol 284:C1215–C1222PubMedGoogle Scholar
  39. 39.
    Drews G, Krämer C, Krippeit-Drews P (2000) Dual effect of NO on KATP+ current of mouse pancreatic B-cells: stimulation by deenergizing mitochondria and inhibition by direct interaction with the channel. Biochim Biophys Acta 1464:62–68PubMedCrossRefGoogle Scholar
  40. 40.
    Lenzen S, Drinkgern J, Tiedge M (1996) Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radic Biol Med 20:463–466PubMedCrossRefGoogle Scholar
  41. 41.
    Tiedge M, Lortz S, Drinkgern J, Lenzen S (1997) Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. Diabetes 46:1733–1742PubMedCrossRefGoogle Scholar
  42. 42.
    Grankvist K, Marklund SL, Taljedal IB (1981) CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse. Biochem J 199:393–398PubMedGoogle Scholar
  43. 43.
    Eizirik DL (1996) Beta-cell defence and repair mechanisms in human pancreatic islets. Horm Metab Res 28:302–305PubMedCrossRefGoogle Scholar
  44. 44.
    Welsh N, Margulis B, Borg LA, Wiklund HJ, Saldeen J, Flodstrom M, Mello MA, Andersson A, Pipeleers DG, Hellerstrom C et al (1995) Differences in the expression of heat-shock proteins and antioxidant enzymes between human and rodent pancreatic islets: implications for the pathogenesis of insulin-dependent diabetes mellitus. Mol Med 1:806–820PubMedGoogle Scholar
  45. 45.
    Eizirik DL, Pipeleers DG, Ling Z, Welsh N, Hellerstrom C, Andersson A (1994) Major species differences between humans and rodents in the susceptibility to pancreatic beta-cell injury. Proc Natl Acad Sci USA 91:9253–9256PubMedCrossRefGoogle Scholar
  46. 46.
    Robertson RP, Harmon JS (2007) Pancreatic islet beta-cell and oxidative stress: the importance of glutathione peroxidase. FEBS Lett 581:3743–3748PubMedCrossRefGoogle Scholar
  47. 47.
    Tonooka N, Oseid E, Zhou H, Harmon JS, Robertson RP (2007) Glutathione peroxidase protein expression and activity in human islets isolated for transplantation. Clin Transplant 21:767–772PubMedGoogle Scholar
  48. 48.
    Rashidi A, Kirkwood TB, Shanley DP (2009) Metabolic evolution suggests an explanation for the weakness of antioxidant defences in beta-cells. Mech Ageing Dev 130:216–221PubMedCrossRefGoogle Scholar
  49. 49.
    Reinbothe TM, Ivarsson R, Li DQ, Niazi O, Jing X, Zhang E, Stenson L, Bryborn U, Renstrom E (2009) Glutaredoxin-1 mediates NADPH-dependent stimulation of calcium-dependent insulin secretion. Mol Endocrinol 23:893–900PubMedCrossRefGoogle Scholar
  50. 50.
    Chen J, Saxena G, Mungrue IN, Lusis AJ, Shalev A (2008) Thioredoxin-interacting protein: a critical link between glucose toxicity and beta-cell apoptosis. Diabetes 57:938–944PubMedCrossRefGoogle Scholar
  51. 51.
    Corbett JA (2008) Thioredoxin-interacting protein is killing my beta-cells! Diabetes 57:797–798PubMedCrossRefGoogle Scholar
  52. 52.
    Chen J, Gusdon AM, Thayer TC, Mathews CE (2008) Role of increased ROS dissipation in prevention of T1D. Ann NY Acad Sci 1150:157–166PubMedCrossRefGoogle Scholar
  53. 53.
    Nerup J, Mandrup-Poulsen T, Molvig J, Helqvist S, Wogensen L, Egeberg J (1988) Mechanisms of pancreatic beta-cell destruction in type I diabetes. Diab Care 11 Suppl 1:16–23Google Scholar
  54. 54.
    Horio F, Fukuda M, Katoh H, Petruzzelli M, Yano N, Rittershaus C, Bonner-Weir S, Hattori M (1994) Reactive oxygen intermediates in autoimmune islet cell destruction of the NOD mouse induced by peritoneal exudate cells (rich in macrophages) but not T cells. Diabetologia 37:22–31PubMedCrossRefGoogle Scholar
  55. 55.
    Rabinovitch A, Suarez-Pinzon WL (1998) Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus. Biochem Pharmacol 55:1139–1149PubMedCrossRefGoogle Scholar
  56. 56.
    Evans JL, Goldfine ID, Maddux BA, Grodsky GM (2002) Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev 23:599–622PubMedCrossRefGoogle Scholar
  57. 57.
    Poitout V, Robertson RP (2008) Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr Rev 29:351–366PubMedCrossRefGoogle Scholar
  58. 58.
    Montana E, Bonner-Weir S, Weir GC (1993) Beta cell mass and growth after syngeneic islet cell transplantation in normal and streptozocin diabetic C57BL/6 mice. J Clin Invest 91:780–787PubMedCrossRefGoogle Scholar
  59. 59.
    Kaneto H, Fujii J, Myint T, Miyazawa N, Islam KN, Kawasaki Y, Suzuki K, Nakamura M, Tatsumi H, Yamasaki Y, Taniguchi N (1996) Reducing sugars trigger oxidative modification and apoptosis in pancreatic beta-cells by provoking oxidative stress through the glycation reaction. Biochem J 320 Pt 3:855–863PubMedGoogle Scholar
  60. 60.
    Tajiri Y, Moller C, Grill V (1997) Long-term effects of aminoguanidine on insulin release and biosynthesis: evidence that the formation of advanced glycosylation end products inhibits B cell function. Endocrinology 138:273–280PubMedCrossRefGoogle Scholar
  61. 61.
    Shimabukuro M, Zhou YT, Levi M, Unger RH (1998) Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci USA 95:2498–2502PubMedCrossRefGoogle Scholar
  62. 62.
    Nakayama M, Inoguchi T, Sonta T, Maeda Y, Sasaki S, Sawada F, Tsubouchi H, Sonoda N, Kobayashi K, Sumimoto H, Nawata H (2005) Increased expression of NAD(P)H oxidase in islets of animal models of type 2 diabetes and its improvement by an AT1 receptor antagonist. Biochem Biophys Res Commun 332:927–933PubMedCrossRefGoogle Scholar
  63. 63.
    Lu H, Koshkin V, Allister EM, Gyulkhandanyan AV, Wheeler MB (2010) Molecular and metabolic evidence for mitochondrial defects associated with beta-cell dysfunction in a mouse model of type 2 diabetes. Diabetes 59:448–459PubMedCrossRefGoogle Scholar
  64. 64.
    Nourooz-Zadeh J, Tajaddini-Sarmadi J, McCarthy S, Betteridge DJ, Wolff SP (1995) Elevated levels of authentic plasma hydroperoxides in NIDDM. Diabetes 44:1054–1058PubMedCrossRefGoogle Scholar
  65. 65.
    Shin CS, Moon BS, Park KS, Kim SY, Park SJ, Chung MH, Lee HK (2001) Serum 8-hydroxy-guanine levels are increased in diabetic patients. Diab Care 24:733–737CrossRefGoogle Scholar
  66. 66.
    Murakami K, Kondo T, Ohtsuka Y, Fujiwara Y, Shimada M, Kawakami Y (1989) Impairment of glutathione metabolism in erythrocytes from patients with diabetes mellitus. Metabolism 38:753–758PubMedCrossRefGoogle Scholar
  67. 67.
    Sharma A, Kharb S, Chugh SN, Kakkar R, Singh GP (2000) Evaluation of oxidative stress before and after control of glycemia and after vitamin E supplementation in diabetic patients. Metabolism 49:160–162PubMedCrossRefGoogle Scholar
  68. 68.
    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 41:177–184PubMedCrossRefGoogle Scholar
  69. 69.
    Del Guerra S, Lupi R, Marselli L, Masini M, Bugliani M, Sbrana S, Torri S, Pollera M, Boggi U, Mosca F, Del Prato S, Marchetti P (2005) Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes 54:727–735PubMedCrossRefGoogle Scholar
  70. 70.
    Federici M, Hribal M, Perego L, Ranalli M, Caradonna Z, Perego C, Usellini L, Nano R, Bonini P, Bertuzzi F, Marlier LN, Davalli AM, Carandente O, Pontiroli AE, Melino G, Marchetti P, Lauro R, Sesti G, Folli F (2001) High glucose causes apoptosis in cultured human pancreatic islets of Langerhans: a potential role for regulation of specific Bcl family genes toward an apoptotic cell death program. Diabetes 50:1290–1301PubMedCrossRefGoogle Scholar
  71. 71.
    Herson PS, Lee K, Pinnock RD, Hughes J, Ashford ML (1999) Hydrogen peroxide induces intracellular calcium overload by activation of a non-selective cation channel in an insulin-secreting cell line. J Biol Chem 274:833–841PubMedCrossRefGoogle Scholar
  72. 72.
    Nakazaki M, Kakei M, Yaekura K, Koriyama N, Morimitsu S, Ichinari K, Yada T, Tei C (2000) Diverse effects of hydrogen peroxide on cytosolic Ca2+ homeostasis in rat pancreatic beta-cells. Cell Struct Funct 25:187–193PubMedCrossRefGoogle Scholar
  73. 73.
    Maechler P, Jornot L, Wollheim CB (1999) Hydrogen peroxide alters mitochondrial activation and insulin secretion in pancreatic beta cells. J Biol Chem 274:27905–27913PubMedCrossRefGoogle Scholar
  74. 74.
    Drews G, Krämer C, Düfer M, Krippeit-Drews P (2000) Contrasting effects of alloxan on islets and single mouse pancreatic beta-cells. Biochem J 352 Pt 2:389–397PubMedCrossRefGoogle Scholar
  75. 75.
    Holohan C, Szegezdi E, Ritter T, O'Brien T, Samali A (2008) Cytokine-induced beta-cell apoptosis is NO-dependent, mitochondria-mediated and inhibited by BCL-XL. J Cell Mol Med 12:591–606PubMedCrossRefGoogle Scholar
  76. 76.
    Laffranchi R, Gogvadze V, Richter C, Spinas GA (1995) Nitric oxide (nitrogen monoxide, NO) stimulates insulin secretion by inducing calcium release from mitochondria. Biochem Biophys Res Commun 217:584–591PubMedCrossRefGoogle Scholar
  77. 77.
    Zoratti M, Szabo I (1995) The mitochondrial permeability transition. Biochim Biophys Acta 1241:139–176PubMedGoogle Scholar
  78. 78.
    Duchen MR (1999) Contributions of mitochondria to animal physiology: from homeostatic sensor to calcium signalling and cell death. J Physiol 516 Pt 1:1–17PubMedCrossRefGoogle Scholar
  79. 79.
    Ichas F, Jouaville LS, Mazat JP (1997) Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell 89:1145–1153PubMedCrossRefGoogle Scholar
  80. 80.
    Krippeit-Drews P, Krämer C, Welker S, Lang F, Ammon HP, Drews G (1999) Interference of H2O2 with stimulus-secretion coupling in mouse pancreatic beta-cells. J Physiol 514 Pt 2:471–481PubMedCrossRefGoogle Scholar
  81. 81.
    Detmer SA, Chan DC (2007) Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 8:870–879PubMedCrossRefGoogle Scholar
  82. 82.
    Fex M, Nitert MD, Wierup N, Sundler F, Ling C, Mulder H (2007) Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6 J mice fed a high-fat diet. Diabetologia 50:74–83PubMedCrossRefGoogle Scholar
  83. 83.
    Park KS, Wiederkehr A, Kirkpatrick C, Mattenberger Y, Martinou JC, Marchetti P, Demaurex N, Wollheim CB (2008) Selective actions of mitochondrial fission/fusion genes on metabolism-secretion coupling in insulin-releasing cells. J Biol Chem 283:33347–33356PubMedCrossRefGoogle Scholar
  84. 84.
    Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27:433–446PubMedCrossRefGoogle Scholar
  85. 85.
    Molina AJ, Wikstrom JD, Stiles L, Las G, Mohamed H, Elorza A, Walzer G, Twig G, Katz S, Corkey BE, Shirihai OS (2009) Mitochondrial networking protects beta-cells from nutrient-induced apoptosis. Diabetes 58:2303–2315PubMedCrossRefGoogle Scholar
  86. 86.
    Anello M, Lupi R, Spampinato D, Piro S, Masini M, Boggi U, Del Prato S, Rabuazzo AM, Purrello F, Marchetti P (2005) Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients. Diabetologia 48:282–289PubMedCrossRefGoogle Scholar
  87. 87.
    Fernandez AM, Kim JK, Yakar S, Dupont J, Hernandez-Sanchez C, Castle AL, Filmore J, Shulman GI, Le Roith D (2001) Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes. Genes Dev 15:1926–1934PubMedCrossRefGoogle Scholar
  88. 88.
    Ichas F, Mazat JP (1998) From calcium signaling to cell death: two conformations for the mitochondrial permeability trancdsfsition pore. Switching from low- to high-conductance state. Biochim Biophys Acta 1366:33–50PubMedCrossRefGoogle Scholar
  89. 89.
    Zamzami N, Kroemer G (2001) The mitochondrion in apoptosis: how Pandora's box opens. Nat Rev Mol Cell Biol 2:67–71PubMedCrossRefGoogle Scholar
  90. 90.
    Brady NR, Elmore SP, van Beek JJ, Krab K, Courtoy PJ, Hue L, Westerhoff HV (2004) Coordinated behavior of mitochondria in both space and time: a reactive oxygen species-activated wave of mitochondrial depolarization. Biophys J 87:2022–2034PubMedCrossRefGoogle Scholar
  91. 91.
    Zorov DB, Juhaszova M, Sollott SJ (2006) Mitochondrial ROS-induced ROS release: an update and review. Biochim Biophys Acta 1757:509–517PubMedCrossRefGoogle Scholar
  92. 92.
    Szabadkai G, Duchen MR (2009) Mitochondria mediated cell death in diabetes. Apoptosis 14:1405–1423PubMedCrossRefGoogle Scholar
  93. 93.
    Gupta S, Kass GE, Szegezdi E, Joseph B (2009) The mitochondrial death pathway: a promising therapeutic target in Diseases. J Cell Mol Med 13(6):1004–1033PubMedCrossRefGoogle Scholar
  94. 94.
    Saxena G, Chen J, Shalev A (2010) Intracellular shuttling and mitochondrial function of thioredoxin-interacting protein. J Biol Chem 285:3997–4005PubMedCrossRefGoogle Scholar
  95. 95.
    Henquin JC, Meissner HP, Schmeer W (1982) Cyclic variations of glucose-induced electrical activity in pancreatic B cells. Pflugers Arch 393:322–327PubMedCrossRefGoogle Scholar
  96. 96.
    Ashcroft FM, Harrison DE, Ashcroft SJ (1984) Glucose induces closure of single potassium channels in isolated rat pancreatic beta-cells. Nature 312:446–448PubMedCrossRefGoogle Scholar
  97. 97.
    Drews G, Krippeit-Drews P, Düfer M (2010) Electrophysiology of islet cells. Adv Exp Med Biol 654:115–163PubMedCrossRefGoogle Scholar
  98. 98.
    Dukes ID, McIntyre MS, Mertz RJ, Philipson LH, Roe MW, Spencer B, Worley JF 3rd (1994) Dependence on NADH produced during glycolysis for beta-cell glucose signaling. J Biol Chem 269:10979–10982PubMedGoogle Scholar
  99. 99.
    Eto K, Tsubamoto Y, Terauchi Y, Sugiyama T, Kishimoto T, Takahashi N, Yamauchi N, Kubota N, Murayama S, Aizawa T, Akanuma Y, Aizawa S, Kasai H, Yazaki Y, Kadowaki T (1999) Role of NADH shuttle system in glucose-induced activation of mitochondrial metabolism and insulin secretion. Science 283:981–985PubMedCrossRefGoogle Scholar
  100. 100.
    Gerbitz KD, Gempel K, Brdiczka D (1996) Mitochondria and diabetes. Genetic, biochemical, and clinical implications of the cellular energy circuit. Diabetes 45:113–126PubMedCrossRefGoogle Scholar
  101. 101.
    Krippeit-Drews P, Bäcker M, Düfer M, Drews G (2003) Phosphocreatine as a determinant of KATP channel activity in pancreatic beta-cells. Pflugers Arch 445:556–562PubMedGoogle Scholar
  102. 102.
    Schulze DU, Düfer M, Wieringa B, Krippeit-Drews P, Drews G (2007) An adenylate kinase is involved in KATP channel regulation of mouse pancreatic beta cells. Diabetologia 50:2126–2134PubMedCrossRefGoogle Scholar
  103. 103.
    Worley JF 3rd, McIntyre MS, Spencer B, Dukes ID (1994) Depletion of intracellular Ca2+ stores activates a maitotoxin-sensitive nonselective cationic current in beta-cells. J Biol Chem 269:32055–32058PubMedGoogle Scholar
  104. 104.
    Miura Y, Henquin JC, Gilon P (1997) Emptying of intracellular Ca2+ stores stimulates Ca2+ entry in mouse pancreatic beta-cells by both direct and indirect mechanisms. J Physiol 503 Pt 2:387–398PubMedCrossRefGoogle Scholar
  105. 105.
    Krippeit-Drews P, Düfer M, Drews G (2000) Parallel oscillations of intracellular calcium activity and mitochondrial membrane potential in mouse pancreatic B-cells. Biochem Biophys Res Commun 267:179–183PubMedCrossRefGoogle Scholar
  106. 106.
    Rolland JF, Henquin JC, Gilon P (2002) Feedback control of the ATP-sensitive K+ current by cytosolic Ca2+ contributes to oscillations of the membrane potential in pancreatic beta-cells. Diabetes 51:376–384PubMedCrossRefGoogle Scholar
  107. 107.
    Kindmark H, Köhler M, Brown G, Bränström R, Larsson O, Berggren PO (2001) Glucose-induced oscillations in cytoplasmic free Ca2+ concentration precede oscillations in mitochondrial membrane potential in the pancreatic beta-cell. J Biol Chem 276:34530–34536PubMedCrossRefGoogle Scholar
  108. 108.
    Maechler P, Wollheim CB (1998) Role of mitochondria in metabolism-secretion coupling of insulin release in the pancreatic beta-cell. Biofactors 8:255–262PubMedCrossRefGoogle Scholar
  109. 109.
    Grapengiesser E, Gylfe E, Hellman B (1988) Dual effect of glucose on cytoplasmic Ca2+ in single pancreatic beta-cells. Biochem Biophys Res Commun 150:419–425PubMedCrossRefGoogle Scholar
  110. 110.
    Krippeit-Drews P, Lang F, Häussinger D, Drews G (1994) H2O2 induced hyperpolarization of pancreatic B-cells. Pflugers Arch 426:552–554PubMedCrossRefGoogle Scholar
  111. 111.
    Nakazaki M, Kakei M, Koriyama N, Tanaka H (1995) Involvement of ATP-sensitive K+ channels in free radical-mediated inhibition of insulin secretion in rat pancreatic beta-cells. Diabetes 44:878–883PubMedCrossRefGoogle Scholar
  112. 112.
    Krippeit-Drews P, Britsch S, Lang F, Drews G (1994) Effects of SH-group reagents on Ca2+ and K+ channel currents of pancreatic B-cells. Biochem Biophys Res Commun 200:860–866PubMedCrossRefGoogle Scholar
  113. 113.
    Krippeit-Drews P, Britsch S, Lang F, Drews G (1997) Effects of oxidants on membrane potential, K+ and Ca2+ currents of mouse pancreatic B-cells. Adv Exp Med Biol 426:355–359PubMedGoogle Scholar
  114. 114.
    Maechler P, Kennedy ED, Sebo E, Valeva A, Pozzan T, Wollheim CB (1999) Secretagogues modulate the calcium concentration in the endoplasmic reticulum of insulin-secreting cells. Studies in aequorin-expressing intact and permeabilized ins-1 cells. J Biol Chem 274:12583–12592PubMedCrossRefGoogle Scholar
  115. 115.
    Rebelato E, Abdulkader F, Curi R, Carpinelli AR (2010) Low doses of hydrogen peroxide impair glucose-stimulated insulin secretion via inhibition of glucose metabolism and intracellular calcium oscillations. Metabolism 59:409–413PubMedCrossRefGoogle Scholar
  116. 116.
    Gier B, Krippeit-Drews P, Sheiko T, Aguilar-Bryan L, Bryan J, Düfer M, Drews G (2009) Suppression of KATP channel activity protects murine pancreatic beta cells against oxidative stress. J Clin Invest 119:3246–3256PubMedGoogle Scholar
  117. 117.
    Qian F, Huang P, Ma L, Kuznetsov A, Tamarina N, Philipson LH (2002) TRP genes: candidates for nonselective cation channels and store-operated channels in insulin-secreting cells. Diabetes 51 Suppl 1:S183–S189PubMedCrossRefGoogle Scholar
  118. 118.
    Togashi K, Hara Y, Tominaga T, Higashi T, Konishi Y, Mori Y, Tominaga M (2006) TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion. EMBO J 25:1804–1815PubMedCrossRefGoogle Scholar
  119. 119.
    Lange I, Yamamoto S, Partida-Sanchez S, Mori Y, Fleig A, Penner R (2009) TRPM2 functions as a lysosomal Ca2+-release channel in beta cells. Sci Signal 2:ra23PubMedCrossRefGoogle Scholar
  120. 120.
    Rerup CC (1970) Drugs producing diabetes through damage of the insulin secreting cells. Pharmacol Rev 22:485–518PubMedGoogle Scholar
  121. 121.
    Henquin JC, Malvaux P, Lambert AE (1979) Alloxan-induced alteration of insulin release, rubidium efflux and glucose metabolism in rat islets stimulated by various secretagogues. Diabetologia 16:253–260PubMedCrossRefGoogle Scholar
  122. 122.
    Takasu N, Komiya I, Asawa T, Nagasawa Y, Yamada T (1991) Streptozocin- and alloxan-induced H2O2 generation and DNA fragmentation in pancreatic islets. H2O2 as mediator for DNA fragmentation. Diabetes 40:1141–1145PubMedCrossRefGoogle Scholar
  123. 123.
    Park BH, Rho HW, Park JW, Cho CG, Kim JS, Chung HT, Kim HR (1995) Protective mechanism of glucose against alloxan-induced pancreatic beta-cell damage. Biochem Biophys Res Commun 210:1–6PubMedCrossRefGoogle Scholar
  124. 124.
    Islam MS, Berggren PO, Larsson O (1993) Sulfhydryl oxidation induces rapid and reversible closure of the ATP-regulated K+ channel in the pancreatic beta-cell. FEBS Lett 319:128–132PubMedCrossRefGoogle Scholar
  125. 125.
    Krippeit-Drews P, Kröncke KD, Welker S, Zempel G, Roenfeldt M, Ammon HP, Lang F, Drews G (1995) The effects of nitric oxide on the membrane potential and ionic currents of mouse pancreatic B cells. Endocrinology 136:5363–5369PubMedCrossRefGoogle Scholar
  126. 126.
    Trapp S, Tucker SJ, Ashcroft FM (1998) Mechanism of ATP-sensitive K channel inhibition by sulfhydryl modification. J Gen Physiol 112:325–332PubMedCrossRefGoogle Scholar
  127. 127.
    Islam MS, Kindmark H, Larsson O, Berggren PO (1997) Thiol oxidation by 2,2'-dithiodipyridine causes a reversible increase in cytoplasmic free Ca2+ concentration in pancreatic beta-cells. Role for inositol 1,4,5-trisphosphate-sensitive Ca2+ stores. Biochem J 321 (Pt 2):347–354Google Scholar
  128. 128.
    Tsuura Y, Ishida H, Hayashi S, Sakamoto K, Horie M, Seino Y (1994) Nitric oxide opens ATP-sensitive K+ channels through suppression of phosphofructokinase activity and inhibits glucose-induced insulin release in pancreatic beta cells. J Gen Physiol 104:1079–1098PubMedCrossRefGoogle Scholar
  129. 129.
    Sunouchi T, Suzuki K, Nakayama K, Ishikawa T (2008) Dual effect of nitric oxide on ATP-sensitive K+ channels in rat pancreatic beta cells. Pflugers Arch 456:573–579PubMedCrossRefGoogle Scholar
  130. 130.
    Feelisch M (1998) The use of nitric oxide donors in pharmacological studies. Naunyn-Schmiedebergs Arch Pharmacol 358:113–122PubMedCrossRefGoogle Scholar
  131. 131.
    Dimmeler S, Ankarcrona M, Nicotera P, Brune B (1993) Exogenous nitric oxide (NO) generation or IL-1 beta-induced intracellular NO production stimulates inhibitory auto-ADP-ribosylation of glyceraldehyde-3-phosphate dehydrogenase in RINm5F cells. J Immunol 150:2964–2971PubMedGoogle Scholar
  132. 132.
    Scheuner D, Kaufman RJ (2008) The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes. Endocr Rev 29:317–333PubMedCrossRefGoogle Scholar
  133. 133.
    Li X, Chen H, Epstein PN (2006) Metallothionein and catalase sensitize to diabetes in nonobese diabetic mice: reactive oxygen species may have a protective role in pancreatic beta-cells. Diabetes 55:1592–1604PubMedCrossRefGoogle Scholar
  134. 134.
    Nakata M, Yada T (2003) Endocrinology: nitric oxide-mediated insulin secretion in response to citrulline in islet beta-cells. Pancreas 27:209–213PubMedCrossRefGoogle Scholar
  135. 135.
    Li X, Chen H, Epstein PN (2004) Metallothionein protects islets from hypoxia and extends islet graft survival by scavenging most kinds of reactive oxygen species. J Biol Chem 279:765–771PubMedCrossRefGoogle Scholar
  136. 136.
    Mysore TB, Shinkel TA, Collins J, Salvaris EJ, Fisicaro N, Murray-Segal LJ, Johnson LE, Lepore DA, Walters SN, Stokes R, Chandra AP, O'Connell PJ, d'Apice AJ, Cowan PJ (2005) Overexpression of glutathione peroxidase with two isoforms of superoxide dismutase protects mouse islets from oxidative injury and improves islet graft function. Diabetes 54:2109–2116PubMedCrossRefGoogle Scholar
  137. 137.
    Pi J, Bai Y, Daniel KW, Liu D, Lyght O, Edelstein D, Brownlee M, Corkey BE, Collins S (2009) Persistent oxidative stress due to absence of uncoupling protein 2 associated with impaired pancreatic beta-cell function. Endocrinology 150:3040–3048PubMedCrossRefGoogle Scholar
  138. 138.
    Li LX, Skorpen F, Egeberg K, Jorgensen IH, Grill V (2001) Uncoupling protein-2 participates in cellular defense against oxidative stress in clonal beta-cells. Biochem Biophys Res Commun 282:273–277PubMedCrossRefGoogle Scholar
  139. 139.
    Produit-Zengaffinen N, Davis-Lameloise N, Perreten H, Becard D, Gjinovci A, Keller PA, Wollheim CB, Herrera P, Muzzin P, Assimacopoulos-Jeannet F (2007) Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species. Diabetologia 50:84–93PubMedCrossRefGoogle Scholar
  140. 140.
    Zhang CY, Parton LE, Ye CP, Krauss S, Shen R, Lin CT, Porco JA Jr, Lowell BB (2006) Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced beta cell dysfunction in isolated pancreatic islets. Cell Metab 3:417–427PubMedCrossRefGoogle Scholar
  141. 141.
    Zhang CY, Baffy G, Perret P, Krauss S, Peroni O, Grujic D, Hagen T, Vidal-Puig AJ, Boss O, Kim YB, Zheng XX, Wheeler MB, Shulman GI, Chan CB, Lowell BB (2001) Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell 105:745–755PubMedCrossRefGoogle Scholar
  142. 142.
    Joseph JW, Koshkin V, Zhang CY, Wang J, Lowell BB, Chan CB, Wheeler MB (2002) Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet. Diabetes 51:3211–3219PubMedCrossRefGoogle Scholar
  143. 143.
    De Souza CT, Araujo EP, Stoppiglia LF, Pauli JR, Ropelle E, Rocco SA, Marin RM, Franchini KG, Carvalheira JB, Saad MJ, Boschero AC, Carneiro EM, Velloso LA (2007) Inhibition of UCP2 expression reverses diet-induced diabetes mellitus by effects on both insulin secretion and action. FASEB J 21:1153–1163PubMedCrossRefGoogle Scholar
  144. 144.
    Cunningham GA, McClenaghan NH, Flatt PR, Newsholme P (2005) L-Alanine induces changes in metabolic and signal transduction gene expression in a clonal rat pancreatic beta-cell line and protects from pro-inflammatory cytokine-induced apoptosis. Clin Sci (Lond) 109:447–455CrossRefGoogle Scholar
  145. 145.
    Saitoh Y, Hongwei W, Ueno H, Mizuta M, Nakazato M (2009) Telmisartan attenuates fatty-acid-induced oxidative stress and NAD(P)H oxidase activity in pancreatic beta-cells. Diabetes Metab 35:392–397PubMedCrossRefGoogle Scholar
  146. 146.
    Chu KY, Leung PS (2007) 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. Antioxid Redox Signal 9:869–878PubMedCrossRefGoogle Scholar
  147. 147.
    Shao J, Iwashita N, Ikeda F, Ogihara T, Uchida T, Shimizu T, Uchino H, Hirose T, Kawamori R, Watada H (2006) Beneficial effects of candesartan, an angiotensin II type 1 receptor blocker, on beta-cell function and morphology in db/db mice. Biochem Biophys Res Commun 344:1224–1233PubMedCrossRefGoogle Scholar
  148. 148.
    Cheng Q, Law PK, de Gasparo M, Leung PS (2008) Combination of the dipeptidyl peptidase IV inhibitor LAF237 [(S)-1-[(3-hydroxy-1-adamantyl)ammo]acetyl-2-cyanopyrrolidine] with the angiotensin II type 1 receptor antagonist valsartan [N-(1-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]methyl]-L- valine] enhances pancreatic islet morphology and function in a mouse model of type 2 diabetes. J Pharmacol Exp Ther 327:683–691PubMedCrossRefGoogle Scholar
  149. 149.
    Ehses JA, Perren A, Eppler E, Ribaux P, Pospisilik JA, Maor-Cahn R, Gueripel X, Ellingsgaard H, Schneider MK, Biollaz G, Fontana A, Reinecke M, Homo-Delarche F, Donath MY (2007) Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56:2356–2370PubMedCrossRefGoogle Scholar
  150. 150.
    Pirot P, Cardozo AK, Eizirik DL (2008) Mediators and mechanisms of pancreatic beta-cell death in type 1 diabetes. Arq Bras Endocrinol Metabol 52:156–165PubMedGoogle Scholar
  151. 151.
    Eizirik DL, Mandrup-Poulsen T (2001) A choice of death—the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia 44:2115–2133PubMedCrossRefGoogle Scholar
  152. 152.
    Salehi A, Meidute Abaraviciene S, Jimenez-Feltstrom J, Ostenson CG, Efendic S, Lundquist I (2008) Excessive islet NO generation in type 2 diabetic GK rats coincides with abnormal hormone secretion and is counteracted by GLP-1. PLoS ONE 3:e2165PubMedCrossRefGoogle Scholar
  153. 153.
    Shimabukuro M, Ohneda M, Lee Y, Unger RH (1997) Role of nitric oxide in obesity-induced beta cell disease. J Clin Invest 100:290–295PubMedCrossRefGoogle Scholar
  154. 154.
    Flodstrom M, Tyrberg B, Eizirik DL, Sandler S (1999) Reduced sensitivity of inducible nitric oxide synthase-deficient mice to multiple low-dose streptozotocin-induced diabetes. Diabetes 48:706–713PubMedCrossRefGoogle Scholar
  155. 155.
    McCabe C, Samali A, O'Brien T (2006) Beta cell cytoprotective strategies: establishing the relative roles for iNOS and ROS. Biochem Biophys Res Commun 342:1240–1248PubMedCrossRefGoogle Scholar
  156. 156.
    McCabe C, O'Brien T (2007) Beta cell cytoprotection using lentiviral vector-based iNOS-specific shRNA delivery. Biochem Biophys Res Commun 357:75–80PubMedCrossRefGoogle Scholar
  157. 157.
    Kato Y, Miura Y, Yamamoto N, Ozaki N, Oiso Y (2003) Suppressive effects of a selective inducible nitric oxide synthase (iNOS) inhibitor on pancreatic beta-cell dysfunction. Diabetologia 46:1228–1233PubMedCrossRefGoogle Scholar
  158. 158.
    Rao VS, Santos FA, Silva RM, Teixiera MG (2002) Effects of nitric oxide synthase inhibitors and melatonin on the hyperglycemic response to streptozotocin in rats. Vascul Pharmacol 38:127–130PubMedCrossRefGoogle Scholar
  159. 159.
    Li L, El-Kholy W, Rhodes CJ, Brubaker PL (2005) Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B. Diabetologia 48:1339–1349PubMedCrossRefGoogle Scholar
  160. 160.
    Hahm E, Lee YS, Jun HS (2008) Suppressive effects of glucagon-like peptide-1 on interferon-gamma-induced nitric oxide production in insulin-producing cells is mediated by inhibition of tumor necrosis factor-alpha production. J Endocrinol Investig 31:334–340Google Scholar
  161. 161.
    Lacraz G, Figeac F, Movassat J, Kassis N, Coulaud J, Galinier A, Leloup C, Bailbe D, Homo-Delarche F, Portha B (2009) Diabetic beta-cells can achieve self-protection against oxidative stress through an adaptive up-regulation of their antioxidant defenses. PLoS ONE 4:e6500PubMedCrossRefGoogle Scholar
  162. 162.
    Gandy SE, Buse MG, Crouch RK (1982) Protective role of superoxide dismutase against diabetogenic drugs. J Clin Invest 70:650–658PubMedCrossRefGoogle Scholar
  163. 163.
    Robbins MJ, Sharp RA, Slonim AE, Burr IM (1980) Protection against streptozotocin-induced diabetes by superoxide dismutase. Diabetologia 18:55–58PubMedCrossRefGoogle Scholar
  164. 164.
    Asplund K, Grankvist K, Marklund S, Taljedal IB (1984) Partial protection against streptozotocin-induced hyperglycaemia by superoxide dismutase linked to polyethylene glycol. Acta Endocrinol (Copenh) 107:390–394Google Scholar
  165. 165.
    Moriscot C, Pattou F, Kerr-Conte J, Richard MJ, Lemarchand P, Benhamou PY (2000) Contribution of adenoviral-mediated superoxide dismutase gene transfer to the reduction in nitric oxide-induced cytotoxicity on human islets and INS-1 insulin-secreting cells. Diabetologia 43:625–631PubMedCrossRefGoogle Scholar
  166. 166.
    Kubisch HM, Wang J, Bray TM, Phillips JP (1997) Targeted overexpression of Cu/Zn superoxide dismutase protects pancreatic beta-cells against oxidative stress. Diabetes 46:1563–1566PubMedCrossRefGoogle Scholar
  167. 167.
    Harmon JS, Bogdani M, Parazzoli SD, Mak SS, Oseid EA, Berghmans M, Leboeuf RC, Robertson RP (2009) beta-Cell-specific overexpression of glutathione peroxidase preserves intranuclear MafA and reverses diabetes in db/db mice. Endocrinology 150:4855–4862PubMedCrossRefGoogle Scholar
  168. 168.
    Moriscot C, Richard MJ, Favrot MC, Benhamou PY (2003) Protection of insulin-secreting INS-1 cells against oxidative stress through adenoviral-mediated glutathione peroxidase overexpression. Diabetes Metab 29:145–151PubMedCrossRefGoogle Scholar
  169. 169.
    Benhamou PY, Moriscot C, Richard MJ, Beatrix O, Badet L, Pattou F, Kerr-Conte J, Chroboczek J, Lemarchand P, Halimi S (1998) Adenovirus-mediated catalase gene transfer reduces oxidant stress in human, porcine and rat pancreatic islets. Diabetologia 41:1093–1100PubMedCrossRefGoogle Scholar
  170. 170.
    Azevedo-Martins AK, Lortz S, Lenzen S, Curi R, Eizirik DL, Tiedge M (2003) Improvement of the mitochondrial antioxidant defense status prevents cytokine-induced nuclear factor-kappaB activation in insulin-producing cells. Diabetes 52:93–101PubMedCrossRefGoogle Scholar
  171. 171.
    Lortz S, Gurgul-Convey E, Lenzen S, Tiedge M (2005) Importance of mitochondrial superoxide dismutase expression in insulin-producing cells for the toxicity of reactive oxygen species and proinflammatory cytokines. Diabetologia 48:1541–1548PubMedCrossRefGoogle Scholar
  172. 172.
    Hohmeier HE, Thigpen A, Tran VV, Davis R, Newgard CB (1998) Stable expression of manganese superoxide dismutase (MnSOD) in insulinoma cells prevents IL-1beta- induced cytotoxicity and reduces nitric oxide production. J Clin Invest 101:1811–1820PubMedCrossRefGoogle Scholar
  173. 173.
    Moriscot C, Candel S, Sauret V, Kerr-Conte J, Richard MJ, Favrot MC, Benhamou PY (2007) MnTMPyP, a metalloporphyrin-based superoxide dismutase/catalase mimetic, protects INS-1 cells and human pancreatic islets from an in vitro oxidative challenge. Diabetes Metab 33:44–53PubMedCrossRefGoogle Scholar
  174. 174.
    Pedulla M, d'Aquino R, Desiderio V, de Francesco F, Puca A, Papaccio G (2007) MnSOD mimic compounds can counteract mechanical stress and islet beta cell apoptosis, although at appropriate concentration ranges. J Cell Physiol 212:432–438PubMedCrossRefGoogle Scholar
  175. 175.
    O'Brien RC, Luo M, Balazs N, Mercuri J (2000) In vitro and in vivo antioxidant properties of gliclazide. J Diabetes its Complicat 14:201–206CrossRefGoogle Scholar
  176. 176.
    Jennings PE, Belch JJ (2000) Free radical scavenging activity of sulfonylureas: a clinical assessment of the effect of gliclazide. Metabolism 49:23–26PubMedCrossRefGoogle Scholar
  177. 177.
    Sawada F, Inoguchi T, Tsubouchi H, Sasaki S, Fujii M, Maeda Y, Morinaga H, Nomura M, Kobayashi K, Takayanagi R (2008) Differential effect of sulfonylureas on production of reactive oxygen species and apoptosis in cultured pancreatic beta-cell line, MIN6. Metabolism 57:1038–1045PubMedCrossRefGoogle Scholar
  178. 178.
    Efanova IB, Zaitsev SV, Zhivotovsky B, Köhler M, Efendic S, Orrenius S, Berggren PO (1998) Glucose and tolbutamide induce apoptosis in pancreatic beta-cells. A process dependent on intracellular Ca2+ concentration. J Biol Chem 273:33501–33507PubMedCrossRefGoogle Scholar
  179. 179.
    Maedler K, Carr RD, Bosco D, Zuellig RA, Berney T, Donath MY (2005) Sulfonylurea induced beta-cell apoptosis in cultured human islets. J Clin Endocrinol Metab 90:501–506PubMedCrossRefGoogle Scholar
  180. 180.
    Del Guerra S, Grupillo M, Masini M, Lupi R, Bugliani M, Torri S, Boggi U, Del Chiaro M, Vistoli F, Mosca F, Del Prato S, Marchetti P (2007) Gliclazide protects human islet beta-cells from apoptosis induced by intermittent high glucose. Diabetes Metab Res Rev 23:234–238PubMedCrossRefGoogle Scholar
  181. 181.
    Feissner RF, Skalska J, Gaum WE, Sheu SS (2009) Crosstalk signaling between mitochondrial Ca2+ and ROS. Front Biosci 14:1197–1218PubMedCrossRefGoogle Scholar
  182. 182.
    Hopper RK, Carroll S, Aponte AM, Johnson DT, French S, Shen RF, Witzmann FA, Harris RA, Balaban RS (2006) Mitochondrial matrix phosphoproteome: effect of extra mitochondrial calcium. Biochemistry 45:2524–2536PubMedCrossRefGoogle Scholar
  183. 183.
    Schild L, Plumeyer F, Reiser G (2005) Ca2+ rise within a narrow window of concentration prevents functional injury of mitochondria exposed to hypoxia/reoxygenation by increasing antioxidative defence. FEBS J 272:5844–5852PubMedCrossRefGoogle Scholar
  184. 184.
    Shkryl VM, Martins AS, Ullrich ND, Nowycky MC, Niggli E, Shirokova N (2009) Reciprocal amplification of ROS and Ca2+ signals in stressed mdx dystrophic skeletal muscle fibers. Pflugers Arch 458:915–928PubMedCrossRefGoogle Scholar
  185. 185.
    Düfer M, Haspel D, Krippeit-Drews P, Kelm M, Ranta F, Nitschke R, Ullrich S, Aguilar-Bryan L, Bryan J, Drews G (2007) The KATP channel is critical for calcium sequestration into non-ER compartments in mouse pancreatic beta cells. Cell Physiol Biochem 20:65–74PubMedGoogle Scholar
  186. 186.
    Bukan N, Sancak B, Bilgihan A, Kosova F, Bugdayci G, Altan N (2004) The effects of the sulfonylurea glyburide on glutathione peroxidase, superoxide dismutase and catalase activities in the heart tissue of streptozotocin-induced diabetic rat. Methods Find Exp Clin Pharmacol 26:519–522PubMedCrossRefGoogle Scholar
  187. 187.
    Elmali E, Altan N, Bukan N (2004) Effect of the sulphonylurea glibenclamide on liver and kidney antioxidant enzymes in streptozocin-induced diabetic rats. Drugs R&D 5:203–208CrossRefGoogle Scholar
  188. 188.
    Nazaroglu NK, Sepici-Dincel A, Altan N (2009) The effects of sulfonylurea glyburide on superoxide dismutase, catalase, and glutathione peroxidase activities in the brain tissue of streptozotocin-induced diabetic rat. J Diab Complications 23:209–213CrossRefGoogle Scholar
  189. 189.
    Tankova T, Koev D, Dakovska L, Kirilov G (2003) The effect of repaglinide on insulin secretion and oxidative stress in type 2 diabetic patients. Diab Res Clin Pract 59:43–49CrossRefGoogle Scholar
  190. 190.
    Lindblad U, Lindwall K, Sjostrand A, Ranstam J, Melander A (2001) The NEPI antidiabetes study (NANSY). 1: short-term dose-effect relations of glimepiride in subjects with impaired fasting glucose. Diabetes Obes Metab 3:443–451PubMedCrossRefGoogle Scholar
  191. 191.
    Califf RM, Boolell M, Haffner SM, Bethel MA, McMurray J, Duggal A, Holman RR (2008) Prevention of diabetes and cardiovascular disease in patients with impaired glucose tolerance: rationale and design of the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial. Am Heart J 156:623–632PubMedCrossRefGoogle Scholar
  192. 192.
    Tanaka Y, Gleason CE, Tran PO, Harmon JS, Robertson RP (1999) Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc Natl Acad Sci USA 96:10857–10862PubMedCrossRefGoogle Scholar
  193. 193.
    Ho E, Chen G, Bray TM (1999) Supplementation of N-acetylcysteine inhibits NFkappaB activation and protects against alloxan-induced diabetes in CD-1 mice. FASEB J 13:1845–1854PubMedGoogle Scholar
  194. 194.
    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 48:2398–2406PubMedCrossRefGoogle Scholar
  195. 195.
    Muller JM, Rupec RA, Baeuerle PA (1997) Study of gene regulation by NF-kappa B and AP-1 in response to reactive oxygen intermediates. Methods 11:301–312PubMedCrossRefGoogle Scholar
  196. 196.
    Ho E, Bray TM (1999) Antioxidants, NFkappaB activation, and diabetogenesis. Proc Soc Exp Biol Med 222:205–213PubMedCrossRefGoogle Scholar
  197. 197.
    Evans JL, Goldfine ID, Maddux BA, Grodsky GM (2003) Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 52:1–8PubMedCrossRefGoogle Scholar
  198. 198.
    Robertson R, Zhou H, Zhang T, Harmon JS (2007) Chronic oxidative stress as a mechanism for glucose toxicity of the beta cell in type 2 diabetes. Cell Biochem Biophys 48:139–146PubMedCrossRefGoogle Scholar
  199. 199.
    Tabatabaie T, Kotake Y, Wallis G, Jacob JM, Floyd RA (1997) Spin trapping agent phenyl N-tert-butylnitrone protects against the onset of drug-induced insulin-dependent diabetes mellitus. FEBS Lett 407:148–152PubMedCrossRefGoogle Scholar
  200. 200.
    Schroeder MM, Belloto RJ Jr, Hudson RA, McInerney MF (2005) Effects of antioxidants coenzyme Q10 and lipoic acid on interleukin-1 beta-mediated inhibition of glucose-stimulated insulin release from cultured mouse pancreatic islets. Immunopharmacol Immunotoxicol 27:109–122PubMedGoogle Scholar
  201. 201.
    Lee BW, Kwon SJ, Chae HY, Kang JG, Kim CS, Lee SJ, Yoo HJ, Kim JH, Park KS, Ihm SH (2009) Dose-related cytoprotective effect of alpha-lipoic acid on hydrogen peroxide-induced oxidative stress to pancreatic beta cells. Free Radic Res 43:68–77PubMedCrossRefGoogle Scholar
  202. 202.
    D'Aleo V, Del Guerra S, Martano M, Bonamassa B, Canistro D, Soleti A, Valgimigli L, Paolini M, Filipponi F, Boggi U, Del Prato S, Lupi R (2009) The non-peptidyl low molecular weight radical scavenger IAC protects human pancreatic islets from lipotoxicity. Mol Cell Endocrinol 309:63–66PubMedCrossRefGoogle Scholar
  203. 203.
    Mohseni Salehi Monfared SS, Vahidi H, Abdolghaffari AH, Nikfar S, Abdollahi M (2009) Antioxidant therapy in the management of acute, chronic and post-ERCP pancreatitis: a systematic review. World J Gastroenterol 15:4481–4490PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Gisela Drews
    • 1
  • Peter Krippeit-Drews
    • 1
  • Martina Düfer
    • 1
  1. 1.Institute of Pharmacy, Department of Pharmacology and Clinical PharmacyUniversity of TübingenTübingenGermany

Personalised recommendations