Diabetes and Metabolism Journal

Korean Diabetes Association (대한당뇨병학회)
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Glucose Toxicity and Pancreatic Beta Cell Dysfunction in Type 2 Diabetes

제2형 당뇨병에서 포도당독성과 췌도베타세포 기능저하

Won, Kyu-Chang;Yoon, Ji-Sung
원규장;윤지성

  • Published : 2008.06.01
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Abstract

The adverse effects of prolonged exposure of pancreatic islets to supraphysiologic glucose concentrations(i.e. glucose toxicity) is mediated at least in part by glucose oxidation and the subsequent generation of reactive oxygen species(ROS) that can impair insulin gene expression and β cell function. Multiple biochemical pathways and mechanisms of action for glucose toxicity have been suggested. These include glucose autoxidation, protein kinase C activation, methylglyoxal formation and glycation, hexosamine metabolism, sorbitol formation, and oxidative phosphorylation. There are many potential mechanisms whereby excess glucose metabolites traveling along these pathways might cause β cell damage. However, all these pathways have in common the formation of reactive oxygen species that, in excess and over time, cause chronic oxidative stress, which in turn causes defective insulin gene expression and insulin secretion as well as increased apoptosis. The intracellular peroxide levels of the pancreatic islets(INS-1 cells, rat islets) by flow cytometry were increased in the high glucose media compared to 5.6 mM glucose media. The insulin, MafA, PDX-1 mRNA levels and glucose stimulated insulin secretion(GSIS) were decreased in high glucose media compared to 5.6 mM glucose media. The HO-1 seems to mediate the protective response of pancreatic islets against the oxidative stress that is due to high glucose conditions. Also, we observed decreased glutathione level, γ-GCS expression and increased oxidized LDL, malondialdehyde level at leukocytes and mesothelial cells from patients with Korean Type 2 Diabetes(esp, poorly controlled patients). In conclusion, this pathophysiologic sequence sets the scene for considering antioxidant therapy as an adjunct in the management of diabetes, especially type 2 Diabetes.(KOREAN DIABETES J 32:175-181, 2008)

Keywords

References

  1. Robertson RP, Zhang HJ, Pyzdrowski KL, Walseth TF: Preservation of insulin mRNA levels and insulin secretion in HIT cells by avoidance of chronic exposure to high glucose concentration. J Cin Inves 1990:320-5, 1992
  2. Robertson RP, Harmon J, Tran PO, Tanaka Y, Takahashi H: Glucose Toxicity in beta-Cells: Type 2 Diabetes, Good Radicals Gone Bad, and the Glutathione Connection. Diabetes 52:581-7, 2003 https://doi.org/10.2337/diabetes.52.3.581
  3. Robertson RP, Harmon J, Tran PO, Poitout V: b-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. Diabetes 53(S1):S119-24, 2004 https://doi.org/10.2337/diabetes.53.2007.S119
  4. Won KC, Moon JS, Eun MJ, Yoon JS, Kim YW, Lee HW: A protective role for Heme-oxygenase-1 in INS-1 cells and rat islets that are exposed to high glucose conditions. J Korean Med Sci 21;418-24, 2006 https://doi.org/10.3346/jkms.2006.21.3.418
  5. 원규장: 고농도 포도당에 노출된 췌장 소도 베타 세포에서 산화스트레스. 당뇨병 28:250-4, 2004
  6. Park KG, Lee KM, Seo HY, Won KC, Lee HW, Park JY, Lee KU, Kim BW, Lee IK: Glucotoxicity in the NS-1 rat insulinoma cell line is mediated by the orphan nuclear receptor small heterodimer partner. Diabetes 56:431-7, 2007 https://doi.org/10.2337/db06-0753
  7. 김재홍, 이찬희, 문준성, 윤지성, 원규장, 이형우: 고농도 포도당에 노출된 INS-1 세포와 제2형 당뇨병환자에서 gamma-GCS mRNA의 발현. 당뇨병 31:302-9, 2007 https://doi.org/10.4093/jkda.2007.31.4.302
  8. Yoshida K, Hirokawa J, Tagami S, Kawakami Y, Urata Y, Kondo T: Weakened cellular scavenging activity against oxidative stress in diabetes mellitus : regulation of glutathione synthesis and efflux. Diabetologia 38:201-10, 1995 https://doi.org/10.1007/BF00400095
  9. Dandona P, Thusu K, Cook S, Snyder B, Makowski J, Armstrong D, Nicotera T: Oxidative damage to DNA in diabetes mellitus. Lancet 347:444-5, 1996 https://doi.org/10.1016/S0140-6736(96)90013-6
  10. Ceriello A, Falleti E, Bortolotti N, Motz E, Cavarape A, Russo A, Gonano F, Bartoli E: Increased circulating intercellular adhesion molecule-1 levels in type II diabetic patients: the possible role of metabolioc control and oxidative stress. Metabolism 45:498-501, 1996 https://doi.org/10.1016/S0026-0495(96)90226-7
  11. Leinonen J, Lehtimaki T, Toyokuni S, Okada K, Tanaka T, Hiai H, Ochi H, Laippala P, Ranatalaiho V, Wirta O: New biomarker evidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitus. FEBS Lett 417:150-2, 1997 https://doi.org/10.1016/S0014-5793(97)01273-8
  12. Rehman A, Nourooz-Zadeh J, Moller W, Tritschler H, Pereira P, Halliwell B: Increased oxidative damage to all DNA bases in patients with type II diabetes mellitus. FEBS Lett 488:120-2, 1999
  13. Santerre RF, Cook RA, Crisel RM, Sharp JD, Schmidt RJ, Williams DC, Wilson CP: Insulin synthesis in a clonal cell line of simian virus 40-transformed hamster pancreatic beta cell. Proc Natl Acad Sci USA 78:4339-43, 1981
  14. Wolff SP, Dean RT: Glucose autoxidation and protein modification. The potential role of autoxidative glycosylation in diabetes. Biochem J 245:243-50, 1987 https://doi.org/10.1042/bj2450243
  15. Lenzen S, Drinkgern J, Tiedge M: Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radic Biol Med 20:463-6, 1996 https://doi.org/10.1016/0891-5849(96)02051-5
  16. Seufert J, Weir GC, Habener JF: Differential expression of the insulin gene transcriptional repressor CCAAT/enhancer-binding protein beta and transactivator islet duodenum homeobox-1 in rat pancreatic beta cells during the development of diabetes mellitus. J Clin Invest 101:2528-39, 1998 https://doi.org/10.1172/JCI2401
  17. Kaneto H, Sharma A, Suzuma K, Laybutt DR, Bonner-Weir S, Weir GC: Induction of c-Myc Expression Suppresses Insulin Gene Transcription by Inhibiting NeuroD/ETA2-mediated Transcriptional Activation. J Biol Chem 277:12998-3006, 2002 https://doi.org/10.1074/jbc.M111148200
  18. Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu J, Brownlee M: Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci U S A 97:12222-6, 2000
  19. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M: Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787-90, 2000 https://doi.org/10.1038/35008121
  20. 윤지성, 원규장, 이형우: 고농도 포도당에 노출된 INS-1 세포와 백서 췌장 소도 세포에서 포도당 산화 및 ROS 생성. 당뇨병 30:246-53, 2006 https://doi.org/10.4093/jkda.2006.30.4.246
  21. Ohlsson H , Karlsson K , Edlund T: IPF1, a homeodomain-containing transactivator of the insulin gene. EMBO J 12:4251-9, 1993
  22. Miller CP, McGehee RE Jr, Habener JF: IDX-1: a new homeodomain transcription factor expressed in rat pancreatic islets and duodenum that transactivates the somatostatin gene. EMBO J 13:1145-56, 1994
  23. Jonsson J, Carlsson L, Edlund T, Edlund H: Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 371:606-9, 1994 https://doi.org/10.1038/371606a0
  24. Sharma A, Zangen DH, Reitz P, Taneja M, Lissauer ME, Miller CP, Weir GC, Habener JF, Bonner-Weir S: The homeodomain protein IDX-1 increases after an early burst of proliferation during pancreatic regeneration. Diabetes 48:507-13, 1999 https://doi.org/10.2337/diabetes.48.3.507
  25. Yoshida S, Kajimoto Y, Yasuda T, Watada H, Fujitani Y, Kosaka H, Gotow T, Miyatsuka T, Umayahara Y, Yamasaki Y, Hori M: PDX-1 induces differentiation of intestinal epithelioid IEC-6 into insulin-producing cells. Diabetes 51:2505-13, 2002 https://doi.org/10.2337/diabetes.51.8.2505
  26. Wang H, Maechler P, Ritz-Laser B, Hagenfeldt KA, Ishihara H, Philippe J, Wollheim CB: Pdx1 level defines pancreatic gene expression pattern and cell lineage differentiation. J Biol Chem 276:25279-86, 2001 https://doi.org/10.1074/jbc.M101233200
  27. Watada H, Kajimoto Y, Umayahara Y, Matsuoka T, Kaneto H, Fujitani Y, Kamada T, Kawamori R, Yamasaki Y: The human glucokinase gene beta-cell -type promoter: an essential role of insulin promoter factor 1/PDX-1 in its activation in HIT-T15 cells. Diabetes 45:1478-88, 1996 https://doi.org/10.2337/diabetes.45.11.1478
  28. Kaneto H, Xu G, Fujii N, Kim S, Bonner-Weir S, Weir GC: Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression. J Biol Chem 277:30010-8, 2002 https://doi.org/10.1074/jbc.M202066200
  29. Matsuoka T, Kajimoto Y, Watada H, Kaneto H, Kishimoto M, Umayahara Y, Fujitani Y, Kamada T, Kawamori R, Yamasaki Y: Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells. J Clin Invest 99:144-50, 1997 https://doi.org/10.1172/JCI119126
  30. Ye J, Laychock SG: A protective role for heme oxygenase expression jn pancreatic islets exposed to interleukin-1beta. Endocrinology 139:4155-63, 1998 https://doi.org/10.1210/en.139.10.4155
  31. 원규장, 은미정, 이시형, 김재홍, 오정현, 남상엽, 윤지성, 윤현대, 조인호, 이형우: Interleukin-1$\beta$에 노출된 흰쥐 췌장소도의 nitric oxide생성, 인슐린 분비 및 heat shock protein 70 발현에 미치는 aminoguanidine의 효과. 당뇨병 25:273-85, 2001
  32. Lortz S, Tiedge M, Nachtwey T, Karlsen AE, Nerup J, Lenzen S: Protection of insulin-producing RINm5F cells against cytokine-mediated toxicity through overexpression of antioxidant enzymes. Diabetes 49:1123-30, 2000 https://doi.org/10.2337/diabetes.49.7.1123
  33. Gunther L, Berberat PO, Haga M, Brouard S, Smith RN, Soares MP, Bach FH, Tobiasch E: Carbon monoxide protects pancreatic beta-cells from apoptosis and improves islet function/survival after transplantation.Diabetes 51:994-9, 2002 https://doi.org/10.2337/diabetes.51.4.994
  34. Tiedge M, Lortz S, Munday R, Lenzen S: Complementary action of antioxidant enzymes in the protection of bioengineered insulin-producing RINm5F cells against the toxicity of reactive oxygen species. Diabetes 47:1578-85, 1998 https://doi.org/10.2337/diabetes.47.10.1578
  35. Tiedge M, Lortz S, Munday R, Lenzen S: Protection against the co-operative toxicity of nitric oxide and oxygen free radicals by overexpression of antioxidant enzymes in bioengineered insulin-producing RINm5F cells. Diabetologia 42:849-55, 1999 https://doi.org/10.1007/s001250051237
  36. Hohmeier HE, Thigpen A, Tran VV, Davis R, Newgard CB: Stable expression of manganese superoxide dismutase (MnSOD) in insulinoma cells prevents IL-1beta-induced cytotoxicity and reduces nitric oxide production. J Clin Invest 101:1811-20, 1998 https://doi.org/10.1172/JCI1489
  37. Moriscot C, Pattou F, Kerr-Conte J, Richard MJ, Lemarchand P, Benhamou PY: Contribution of adenoviral-mediated superoxide dismutase gene transfer to the reduction in nitric oxide-induced cytotoxicity on human islets and INS-1 insulinsecreting cells. Diabetologia 43:625-31, 2000 https://doi.org/10.1007/s001250051351