Skip to main content
SpringerLink
Log in
Book cover

Oxidative Stress in Aging pp 191–211Cite as

Oxidative Stress in Type 2 Diabetes Mellitus

  • Chapter

Part of the book series: Aging Medicine ((AGME))

Summary

Type 2 diabetes (T2DM) is associated with significant morbidity and mortality, which primarily results from vascular damage. Two major defects contribute to the pathogenesis of T2DM: (1) impaired insulin secretion in response to glucose and other stimuli, i.e., β cell failure; and (2) impaired insulin action in the liver and peripheral (muscle and adipose) tissues, i.e., insulin resistance. In this review, we summarize the molecular mechanisms that contribute to insulin resistance, β cell failure, and vascular damage in T2DM, with emphasis on the contribution of oxidative stress to these mechanisms.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. King H, Aubert RE, Herman WH, Global burden of diabetes, 1995–2025:prevalence, numerical estimates, and projections Diabetes Care 1998;21:1414.

    Google Scholar 

  2. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006;444:840–6.

    Article  PubMed  CAS  Google Scholar 

  3. Schalkwijk CG, Stehouwer CD. Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clin Sci (Lond) 2005;109:143–59.

    Article  CAS  Google Scholar 

  4. He Z, King GL. Microvascular complications of diabetes. Endocrinol Metab Clin North Am 2004;33:215–38.

    Article  PubMed  CAS  Google Scholar 

  5. Harris MI, Klein R, Welborn TA, Knutman MW. Onset of NIDDM occurs at least 4–7 yr before clinical diagnosis. Diabetes Care 1992;15:815–9.

    Article  PubMed  CAS  Google Scholar 

  6. Morgan CL, Currie CJ, Stott NCH, Smithers M, Butler CC, Peters JR. The prevalence of multiple diabetes-related complications. Diabet Med 2000; 17:146–51.

    Article  PubMed  CAS  Google Scholar 

  7. Huse DM, Oster G, Killen AR, Lacey MJ, Colditz GA. The economic costs of non-insulin-dependent diabetes mellitus. JAMA 1989;262:2708.

    Article  PubMed  CAS  Google Scholar 

  8. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus: metabolic and molecular implications for identifying diabetes genes. Diabetes Rev 1997;5:117–269.

    Google Scholar 

  9. Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeogenesis. Its importance in human glucose homeostasis. Diabetes Care 2001;24:382–391.

    Article  PubMed  CAS  Google Scholar 

  10. DeFronzo RA, Ferrannini E. Regulation of hepatic glucose metabolism in humans. Diabetes Metab Rev 1987;3:415–59.

    Article  PubMed  CAS  Google Scholar 

  11. Katz LD, Glickman MG, Rapoport S, Ferrannini E, DeFronzo RA. Splanchnic and peripheral disposal of oral glucose in man. Diabetes 1983;32:675–679.

    Article  PubMed  CAS  Google Scholar 

  12. Mari A, Wahren J, DeFronzo RA, Ferrannini E. Glucose absorption and production following oral glucose: comparison of compartmental and arteriovenous-difference methods. Metabolism 1994;43:1419–25.

    Article  PubMed  CAS  Google Scholar 

  13. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 2004;8:787–835.

    Article  CAS  Google Scholar 

  14. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus: metabolic and molecular implications for identifying diabetes genes. Diabetes Rev 1997;5:117–269.

    Google Scholar 

  15. DeFronzo RA. Lilly Lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988;37:667–87.

    PubMed  CAS  Google Scholar 

  16. Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, DeFronzo RA; San Antonio metabolism study. beta-Cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Diabetologia 2004;47:31–9.

    Article  PubMed  CAS  Google Scholar 

  17. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 2004;46:3–19.

    Google Scholar 

  18. DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest 1985;76:149–55.

    Article  PubMed  CAS  Google Scholar 

  19. DeFronzo RA and Ferrannini E Regulation of hepatic glucose metabolism in humans. Diabetes Metab Rev 1987;3:415–59.

    Article  PubMed  CAS  Google Scholar 

  20. Ferrannini E, Bjorkman O, Reichard GA Jr et al. The disposal of an oral glucose load in healthy subjects. A quantitative study. Diabetes 1985;34:580–8.

    Article  PubMed  CAS  Google Scholar 

  21. Groop LC, Bonadonna RC, DelPrato S et al. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest 1989;84:205–13.

    Article  PubMed  CAS  Google Scholar 

  22. Saltiel AR, Kahn CR. Insulin signaling and the regulation of glucose and lipid metabolism. Nature 2001;414:799–806.

    Article  PubMed  CAS  Google Scholar 

  23. Shepherd PR, Kahn BB. Glucose transporters and insulin action. Implications for insulin resistance and diabetes mellitus. N Engl J Med 1999;341:248–257.

    Article  PubMed  CAS  Google Scholar 

  24. Virkamaki A, Ueki K, Kahn CR. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest 1999;103:931–943.

    Article  PubMed  CAS  Google Scholar 

  25. White MF, Livingston JN, Backer JM et al. Mutation of the insulin receptor at tyrosine 960 inhibits signal transmission but does not affect its tyrosine kinase activity. Cell 1992;54:641–649.

    Article  Google Scholar 

  26. Kerouz NJ, Horsch D, Pons S, Kahn CR. Differential regulation of insulin receptor sub-strates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. J Clin Invest 1997;100:3164–3172.

    Article  PubMed  CAS  Google Scholar 

  27. Sun XJ, Miralpeix M, Myers MG Jr et al. The expression and function of IRS-1 in insulin signal transmission. J Biol Chem 1993;267:22662–22672.

    Google Scholar 

  28. Ruderman N, Kapeller R, White MF, and Cantley LC. Activation of phosphatidylinosi-tol-3-kinase by insulin. Proc Natl Acad Sci U S A 1990;87:1411–1415.

    Article  PubMed  CAS  Google Scholar 

  29. Cross DA, Alessi DR, Cohen P, Andjelkovich M, and Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995;378:785–789.

    Article  PubMed  CAS  Google Scholar 

  30. Brady MJ, Nairn AC, Saltiel AR. The regulation of glycogen synthase by protein phos-phatase 1 in 3T3-L1 adipocytes. Evidence for a potential role for DARPP-32 in insulin action. J Biol Chem 1997;272:29698–29703.

    Article  PubMed  CAS  Google Scholar 

  31. Okada T, Sakuma L, Fukui Y, Hazeki O, and Ui M. Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. J Biol Chem 1994;269:3568–3573.

    PubMed  CAS  Google Scholar 

  32. Cross D, Alessi D, Vandenheed J et al. The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin but not rapamycin. Biochem J 1994;303:21–26.

    PubMed  CAS  Google Scholar 

  33. Osawa H, Sutherland C, Robey R, Printz R, Granner D, Analysis of the signaling pathway involved in the regulation of hexokinase II gene transcription by insulin. J Biol Chem 1996;271:16690–16694.

    Article  PubMed  CAS  Google Scholar 

  34. Kashyap SR, Defronzo RA. The insulin resistance syndrome: physiological considerations. Diab Vasc Dis Res 2007;4:13–9.

    Article  PubMed  Google Scholar 

  35. Mothe I, Van Obberghen E. Phosphorylation of insulin receptor substrate-1 on multiple serine residues, 612, 632, 662, and 731, modulates insulin action. J Biol Chem 1996;271:11222–11227.

    Article  PubMed  CAS  Google Scholar 

  36. Petersen KF, Shulman GI. Etiology of insulin resistance. Am J Med 2006;119(5 Suppl 1): S10–6.

    Article  PubMed  CAS  Google Scholar 

  37. Kim JK, Fillmore JJ, Sunshine MJ et al. PKC-theta knockout mice are protected from fat-induced insulin resistance. J Clin Invest 2004;114:823–827.

    PubMed  CAS  Google Scholar 

  38. Um SH, Frigerio F, Watanabe M et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 2004;431:200–205.

    Article  PubMed  CAS  Google Scholar 

  39. Furukawa N, Ongusaha P, Jahng WJ et al. Role of Rho-kinase in regulation of insulin action and glucose homeostasis. Cell Metab 2005;2:119–129.

    Article  PubMed  CAS  Google Scholar 

  40. Hirosumi J, Tuncman G, Chang LF et al. A central role for JNK in obesity and insulin resistance. Nature 2002;420:333–336.

    Article  PubMed  CAS  Google Scholar 

  41. Morino K, Petersen KF, Dufour S et al. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest 2005;115:3587–3593.

    Article  PubMed  CAS  Google Scholar 

  42. Yuan MS, Konstantopoulos N, Lee JS et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of IKK beta. Science 2001;293:1673–1677.

    Article  PubMed  CAS  Google Scholar 

  43. Morino K, Petersen KF, Shulman GI. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 2006;55 Suppl 2:S9–S15.

    Article  PubMed  CAS  Google Scholar 

  44. Yu CL, Chen Y, Cline GW et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 2002;277:50230–50236.

    Article  PubMed  CAS  Google Scholar 

  45. Czech MP, Fain JN. Cu++-dependent thiol stimulation of glucose metabolism in white fat cells. J Biol Chem 1972;247:6218–23.

    PubMed  CAS  Google Scholar 

  46. Evans JL, Maddux BA, Goldfine ID. The molecular basis for oxidative stress-induced insulin resistance. Antioxid Redox Signal 2005;7:1040–52.

    Article  PubMed  CAS  Google Scholar 

  47. Hayes GR, Lockwood DH. Role of insulin receptor phosphorylation in the insulinomimetic effects of hydrogen peroxide. Proc Natl Acad Sci U S A 1987;84:8115–9.

    Article  PubMed  CAS  Google Scholar 

  48. Mahadev K, Zilbering A, Zhu L, Goldstein BJ. Insulin-stimulated hydrogen peroxide reversi-bly inhibits protein-tyrosine phosphatase 1b in vivo and enhances the early insulin action cascade. J Biol Chem 2001;276:21938–42.

    Article  PubMed  CAS  Google Scholar 

  49. Mahadev K, Wu X, Zilbering A, Zhu L, Lawrence JT, Goldstein BJ. Hydrogen peroxide generated during cellular insulin stimulation is integral to activation of the distal insulin signaling cascade in 3T3-L1 adipocytes. J Biol Chem 2001;276:48662–9.

    Article  PubMed  CAS  Google Scholar 

  50. Paolisso G, D'Amore A, Volpe C et al. Evidence for a relationship between oxidative stress and insulin action in non-insulin-dependent (type II) diabetic patients. Metabolism 1994;43:1426–9.

    Article  PubMed  CAS  Google Scholar 

  51. Wittmann I, Nagy J. Are insulin resistance and atherosclerosis the consequences of oxidative stress? Diabetologia 1996;39:1002–3.

    Article  PubMed  CAS  Google Scholar 

  52. Urakawa H, Katsuki A, Sumida Y et al. Oxidative stress is associated with adiposity and insulin resistance in men. J Clin Endocrinol Metab 2003;88:4673–6.

    Article  PubMed  CAS  Google Scholar 

  53. Lee KU. Oxidative stress markers in Korean subjects with insulin resistance syndrome. Diabetes Res Clin Pract 2001;54 Suppl 2:S29–33.

    Article  PubMed  CAS  Google Scholar 

  54. Hitsumoto T, Iizuka T, Takahashi M et al. Relationship between insulin resistance and oxida-tive stress in vivo. J Cardiol 2003;42:119–27.

    PubMed  Google Scholar 

  55. Jacob S, Streeper RS, Fogt DL et al. Henriksen, the antioxidant a-lipoic acid enhances insulin stimulated glucose metabolism in insulin-resistant rat skeletal muscle, Diabetes 1996;45:1024–1029.

    Article  PubMed  CAS  Google Scholar 

  56. Jacob S, Henriksen EJ, Schiemann AL et al. Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid. Drug Res 1995;45:872–874.

    CAS  Google Scholar 

  57. Jacob S, Ruus P, Hermann R et al. Oral administration of rac-α-lipoic acid modulates insulin sensitivity in patients with type 2 diabetes mellitus-a placebo controlled pilot trial. Free Radic Biol Med 1999;27:309–314.

    Article  PubMed  CAS  Google Scholar 

  58. Hirashima O, Kawano H, Motoyama T et al. Improvement of endothelial function and insulin sensitivity with vitamin C in patients with coronary spastic angina: possible role of reactive oxygen species. J Am Coll Cardiol 2000;35:1860–6.

    Article  PubMed  CAS  Google Scholar 

  59. Paolisso G, Di Maro G, Pizza G et al. Plasma GSH/GSSG affects glucose homeostasis in healthy subjects and non-insulin-dependent diabetics. Am J Physiol 1992;263(3 Pt 1):E435–40.

    PubMed  CAS  Google Scholar 

  60. Bloch-Damti A, Potashnik R, Gual P et al. Differential effects of IRS1 phosphorylated on Ser307 or Ser632 in the induction of insulin resistance by oxidative stress. Diabetologia 2006;49(10):2463–73.

    Article  PubMed  CAS  Google Scholar 

  61. Rudich A, Tirosh A, Potashnik R, Hemi R, Kanety H, Bashan N. Prolonged oxidative stress impairs insulin-induced GLUT4 translocation in 3T3-L1 adipocytes. Diabetes 1998;47:1562–9.

    Article  PubMed  CAS  Google Scholar 

  62. Gardner CD, Eguchi S, Reynolds CM, Eguchi K, Frank GD, Motley ED. Hydrogen peroxide inhibits insulin signaling in vascular smooth muscle cells. Exp Biol Med (Maywood) 2003;228:836–42.

    CAS  Google Scholar 

  63. Maddux BA, See W, Lawrence JC Jr, Goldfine AL, Goldfine ID, Evans JL. Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by mircomolar concentrations of alpha-lipoic acid. Diabetes 2001;50:404–10.

    Article  PubMed  CAS  Google Scholar 

  64. Rudich A, Tirosh A, Potashnik R, Khamaisi M, Bashan N. Lipoic acid protects against oxidative stress induced impairment in insulin stimulation of protein kinase B and glucose transport in 3T3-L1 adipocytes. Diabetologia 1999;42:949–57.

    Article  PubMed  CAS  Google Scholar 

  65. Ogihara T, Asano T, Katagiri H et al. Oxidative stress induces insulin resistance by activating the nuclear factor-kappa B pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase. Diabetologia 2004;47:794–805.

    Article  PubMed  CAS  Google Scholar 

  66. Haber CA, Lam TK, Yu Z et al. N-Acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stress. Am J Physiol 2003;285: E744–53.

    CAS  Google Scholar 

  67. Bloch-Damti A, Bashan N. Proposed mechanisms for the induction of insulin resistance by oxidative stress. Antioxid Redox Signal 2005;7:1553–67.

    Article  PubMed  CAS  Google Scholar 

  68. Kaneki M, Shimizu N, Yamada D, Chang K. Nitrosative stress and pathogenesis of insulin resistance. Antioxid Redox Signal 2007;9:319–29.

    Article  PubMed  CAS  Google Scholar 

  69. Nomiyama T, Igarashi Y, Taka H et al. Reduction of insulin-stimulated glucose uptake by peroxynitrite is concurrent with tyrosine nitration of insulin receptor substrate-1. Biochem Biophys Res Commun 2004;320:639–47.

    Article  PubMed  CAS  Google Scholar 

  70. Carvalho-Filho MA, Ueno M, Hirabara SM et al. S-Nitrosation of the insulin receptor, insulin receptor substrate 1, and protein kinase B/Akt: a novel mechanism of insulin resistance. Diabetes 2005;54:959–67.

    Article  PubMed  CAS  Google Scholar 

  71. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979;237:E214–23.

    PubMed  CAS  Google Scholar 

  72. Bergman RN, Finegood DT, Kahn SE. The evolution of β-cell dysfunction and insulin resistance in type 2 diabetes. Eur J Clin Invest 2002;32:35–45.

    Article  PubMed  CAS  Google Scholar 

  73. Kahn SE. Clinical review 135. The importance of β-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab 2001;86:4047–4058.

    Article  PubMed  CAS  Google Scholar 

  74. Godsland IF, Jeffs JA, Johnston DG. Loss of beta cell function as fasting glucose increases in the non-diabetic range. Diabetologia 2004;47:1157–66.

    Article  PubMed  CAS  Google Scholar 

  75. Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, DeFronzo RA; San Antonio metabolism study. Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Diabetologia 2004;47:31–9.

    Article  PubMed  CAS  Google Scholar 

  76. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52:102–10.

    Article  PubMed  CAS  Google Scholar 

  77. Prentki M, Nolan CJ. Islet beta cell failure in type 2 diabetes. J Clin Invest 2006; 116:18020–1812.

    Article  CAS  Google Scholar 

  78. Gautier J-F, Wilson C, Weyer C et al. Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes. Diabetes 2001;50:1828–1833.

    Article  PubMed  CAS  Google Scholar 

  79. Vauhkonen N, Niskanen L, Vanninen E, Kainulainen S, Uusitupa M, Laakso M. Defects in insulin secretion and insulin action in non-insulin-dependent diabetes mellitus are inherited. Metabolic studies on offspring of diabetic probands. J Clin Invest 1997;100:86–96.

    Google Scholar 

  80. Vaag A, Henriksen JE, Madsbad S, Holm N, and Beck-Nielsen H. Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus. J Clin Invest 1995;95:690–698.

    Article  PubMed  CAS  Google Scholar 

  81. Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity. Diabetes Care 1990;13:610–630.

    Article  PubMed  CAS  Google Scholar 

  82. McGarry JD. Banting Lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 2002;51:7–18.

    Article  PubMed  CAS  Google Scholar 

  83. Shimabukuro M, Zhou Y-T, Levi M, Unger RH. Fatty acid induced β cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci U S A 1998;95:2498–2502.

    Article  PubMed  CAS  Google Scholar 

  84. Vague P, Moulin J-P. The defective glucose sensitivity of the B cell in insulin dependent diabetes. Improvement after twenty hours of normoglycaemia. Metabolism 1982;31:139–142.

    Article  PubMed  CAS  Google Scholar 

  85. Kosaka K, Kuzuya T, Akanuma Y, Hagura R. Increase in insulin response after treatment of overt maturity onset diabetes mellitus is independent of the mode of treatment. Diabetologia 1980;18:23–28.

    Article  PubMed  CAS  Google Scholar 

  86. Toschi E, Camastra S, Sironi AM et al. Effect of acute hyperglycemia on insulin secretion in humans. Diabetes 2002;51 Suppl 1:S130–3.

    Article  PubMed  CAS  Google Scholar 

  87. Rossetti L, Shulman GI, Zawalich W, DeFronzo RA. Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats. J Clin Invest 1987;80:1037–1044.

    Article  PubMed  CAS  Google Scholar 

  88. McGarry JD, Dobbins RL. Fatty acids, lipotoxicity and insulin secretion. Diabetologia 1999;42:128–38.

    Article  PubMed  CAS  Google Scholar 

  89. Iizuka K, Nakajima H, Namba M, Miyagawa J, Miyazaki J, Hanafusa T, Matsuzawa Y. Metabolic consequence of long-term exposure of pancreatic beta cells to free fatty acid with special reference to glucose insensitivity. Biochim Biophys Acta 2002;1586:23–31.

    PubMed  CAS  Google Scholar 

  90. Gremlich S, Bonny C, Waeber G, Thorens B. Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels. J Biol Chem 1997;272:30261–30269.

    Article  PubMed  CAS  Google Scholar 

  91. Jacqueminet S, Briaud I, Rouault C, Reach G, Poitout V. Inhibition of insulin gene expression by long-term exposure of pancreatic β-cells to palmitate is dependent upon the presence of a stimulatory glucose concentration. Metabolism 2000;49:532–536.

    Article  PubMed  CAS  Google Scholar 

  92. Maedler K, Spinas GA, Dyntar D, Moritz W, Kaiser N, Donath MY. Distinct effects of saturated and monounsaturated fatty acids on ß-cell turnover and function. Diabetes 2001;50:69–76.

    Article  PubMed  CAS  Google Scholar 

  93. Cnop M, Hannaert JC, Hoorens A, Eizirik DL, Pipeleers DG. Inverse relationship between cytotoxicity of free fatty acids in pancreatic islet cells and cellular triglyceride accumulation. Diabetes 2001;50:1771–1777.

    Article  PubMed  CAS  Google Scholar 

  94. Kashyap S, Belfort R, Gastaldelli A et al. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes 2003;52:2461–74.

    Article  PubMed  CAS  Google Scholar 

  95. Okuyama R, Fujiwara T, Ohsumi J. High glucose potentiates palmitate-induced NO-mediated cytotoxicity through generation of superoxide in clonal beta-cell HIT-T15. FEBS Lett 2003;545:219–23.

    Article  PubMed  CAS  Google Scholar 

  96. Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem 2004;279:42351–4.

    Article  PubMed  CAS  Google Scholar 

  97. Tiedge M, Lortz S, Drinkgern J, Lenzen S. Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells Diabetes 1997;46:1733–1742.

    Article  PubMed  CAS  Google Scholar 

  98. Olson LK, Redmon JB, Towle HC, Robertson RP. Chronic exposure of HIT cells to high glucose concentrations paradoxically decreases insulin gene transcription and alters binding of insulin gene regulatory protein. J Clin Invest 1993;92:514–9.

    Article  PubMed  CAS  Google Scholar 

  99. Sharma A, Olson LK, Robertson RP, Stein R. The reduction of insulin gene transcription in HIT-T15 beta cells chronically exposed to high glucose concentration is associated with the loss of RIPE3b1 and STF-1 transcription factor expression. Mol Endocrinol 1995;9:1127–34.

    Article  PubMed  CAS  Google Scholar 

  100. Matsuoka TA, Kajimoto Y, Watada H et al. Glycation-dependent, reactive oxygen species mediated suppression of the insulin gene promoter activity in HIT cells. J Clin Invest 1997;99:144–150.

    Article  PubMed  CAS  Google Scholar 

  101. Tanaka Y, Gleason CE, Tran POT, Harmon JS, Robertson RP Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc Natl Acad Sci USA 1999;96:10857–10862.

    Article  PubMed  CAS  Google Scholar 

  102. 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 2002;277:30010–8.

    Article  PubMed  CAS  Google Scholar 

  103. Krauss S, Zhang CY, Scorrano L et al. Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction. J Clin Invest 2003;112:1831–42.

    PubMed  CAS  Google Scholar 

  104. Zraika S, Aston-Mourney K, Laybutt DR et al. The influence of genetic background on the induction of oxidative stress and impaired insulin secretion in mouse islets. Diabetologia 2006;49:1254–63.

    Article  PubMed  CAS  Google Scholar 

  105. Uchiyama K, Naito Y, Hasegawa G, Nakamura N, Takahashi J, Yoshikawa T. Astaxanthin protects beta-cells against glucose toxicity in diabetic db/db mice. Redox Rep 2002;7:290–3.

    Article  PubMed  CAS  Google Scholar 

  106. Paolisso G, Giugliano D, Pizza G et al. Glutathione infusion potentiates glucose-induced insulin secretion in aged patients with impaired glucose tolerance. Diabetes Care 1992;15:1–7.

    Article  PubMed  CAS  Google Scholar 

  107. Federici M, Hribal M, Perego L et al. 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 2001;50:1290–301.

    Article  PubMed  CAS  Google Scholar 

  108. Ortega-Camarillo C, Guzman-Grenfell AM, Garcia-Macedo R et al. Hyperglycemia induces apoptosis and p53 mobilization to mitochondria in RINm5F cells. Mol Cell Biochem 2006;281:163–71.

    Article  PubMed  CAS  Google Scholar 

  109. Martens GA, Van de Casteele M. Glycemic control of apoptosis in the pancreatic beta cell: danger of extremes? Antioxid Redox Signal 2007;9:309–17.

    Article  PubMed  CAS  Google Scholar 

  110. The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986.

    Article  Google Scholar 

  111. UK Prospective Diabetes Study (UKPDS) Group: intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853.

    Article  Google Scholar 

  112. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005;54:1615–25.

    Article  PubMed  CAS  Google Scholar 

  113. Lee AY, Chung SS. Contributions of polyol pathway to oxidative stress in diabetic cataract. FASEB J 1999;13:23–30.

    PubMed  CAS  Google Scholar 

  114. Degenhardt TP, Thorpe SR, Baynes JW. Chemical modification of proteins by methylglyoxal. Cell Mol Biol 1998;44, 1139–1145.

    Google Scholar 

  115. Giardino I, Edelstein D, Brownlee M. Nonenzymatic glycosylation in vitro and in bovine endothelial cells alters basic fibroblast growth factor activity: a model for intracellular glyco-sylation in diabetes. J Clin Invest 1994;94:110–117.

    Article  PubMed  CAS  Google Scholar 

  116. Shinohara M, Thornalley PJ, Giardino I et al. Overexpression of glyoxalase-I in bovine endothelial cells inhibits intracellular advanced glycation endproduct formation and prevents hyperglycemia-induced increases in macromolecular endocytosis. J Clin Invest 1998;101:1142–1147.

    Article  PubMed  CAS  Google Scholar 

  117. Koya D, King GL. Protein kinase C activation and the development of diabetic complications. Diabetes 1998;47:859–866.

    Article  PubMed  CAS  Google Scholar 

  118. Xia P, Inoguchi T, Kern TS, Engerman RL, Oates PJ, King GL: Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia. Diabetes 1994;43:1122–1129.

    Article  PubMed  CAS  Google Scholar 

  119. Koya D, Jirousek MR, Lin YW, Ishii H, Kuboki K, King GL. Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats. J Clin Invest 1997;100:115–126.

    Article  PubMed  CAS  Google Scholar 

  120. Ishii H, Jirousek MR, Koya D et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 1996;272:728–731.

    Article  PubMed  CAS  Google Scholar 

  121. Kuboki K, Jiang Z Y, Takahara N et al. Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: a specific vascular action of insulin. Circulation 2000;101:676–681.

    PubMed  CAS  Google Scholar 

  122. Studer RK, Craven PA, Derubertis FR. Role for protein kinase C in the mediation of increased fibronectin accumulation by mesangial cells grown in high-glucose medium. Diabetes 1993;42:118–126.

    Article  PubMed  CAS  Google Scholar 

  123. Feener EP, Xia P, Inoguchi T, Shiba T, Kunisaki M, King GL. Role of protein kinase C in glucose- and angiotensin II-induced plasminogen activator inhibitor expression. Contrib Nephrol 1996;118:180–187.

    PubMed  CAS  Google Scholar 

  124. Du XL, Edelstein D, Rossetti L et al. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA 2000;97:12222–12226.

    Article  PubMed  CAS  Google Scholar 

  125. Du XL, Edelstein D, Rossetti L et al. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad. Sci USA 2000;97, 12222–12226.

    Article  Google Scholar 

  126. Nishikawa T, Edelstein D, Du XL et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000;404:787–790.

    Article  PubMed  CAS  Google Scholar 

  127. Du X, Matsumura T, Edelstein D et al. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest 2003;112:1049–1057.

    PubMed  CAS  Google Scholar 

  128. Triggiani V, Resta F, Guastamacchia E et al. Role of antioxidants, essential fatty acids, carnitine, vitamins, phytochemicals and trace elements in the treatment of diabetes mellitus and its chronic complications. Endocr Metab Immune Disord Drug Targets 2006;6:77–93.

    PubMed  CAS  Google Scholar 

  129. Ziegler D, Hanefeld M, Ruhnau KJ et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. alpha-Lipoic acid in diabetic neuropathy. Diabetes Care 1999;22:1296–301.

    Article  PubMed  CAS  Google Scholar 

  130. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:154–60.

    Article  PubMed  CAS  Google Scholar 

  131. Levy AP, Gerstein HC, Miller-Lotan R et al. The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes. Diabetes Care 2004;27:2767.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX

    Muhammad A. Abdul-Ghani & Ralph A. DeFronzo

Authors
  1. Muhammad A. Abdul-Ghani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ralph A. DeFronzo
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK

    Satomi Miwa PhD

  2. Functional Genomics Core, Children's Hospital Oakland Research Institute, Oakland, CA, USA

    Kenneth B. Beckman PhD

  3. Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Florian L. Muller PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Humana Press, a part of Springer Science + Business Media, LLC

About this chapter

Cite this chapter

Abdul-Ghani, M.A., DeFronzo, R.A. (2008). Oxidative Stress in Type 2 Diabetes Mellitus. In: Miwa, S., Beckman, K.B., Muller, F.L. (eds) Oxidative Stress in Aging. Aging Medicine. Humana Press. https://doi.org/10.1007/978-1-59745-420-9_11

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-420-9_11

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-991-8

  • Online ISBN: 978-1-59745-420-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation