Skip to main content
Log in

Hyperglycemia-induced oxidative stress in diabetic complications

  • Review
  • Published:
Histochemistry and Cell Biology Aims and scope Submit manuscript

Abstract

Reactive oxygen species are increased by hyperglycemia. Hyperglycemia, which occurs during diabetes (both type 1 and type 2) and, to a lesser extent, during insulin resistance, causes oxidative stress. Free fatty acids, which may be elevated during inadequate glycemic control, may also be contributory. In this review, we will discuss the role of oxidative stress in diabetic complications. Oxidative stress may be important in diabetes, not just because of its role in the development of complications, but because persistent hyperglycemia, secondary to insulin resistance, may induce oxidative stress and contribute to beta cell destruction in type 2 diabetes. The focus of this review will be on the role of oxidative stress in the etiology of diabetic complications.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Baynes JW, Thorpe SR (1999) Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48:1–9

    CAS  PubMed  Google Scholar 

  • Beckman JA, Goldfine AB, Gordon MB, Creager MA (2001) Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation 103:1618–1623

    CAS  PubMed  Google Scholar 

  • Benigni A, Perico N, Remuzzi G (2000) Endothelin antagonists and renal protection. J Cardiovasc Pharmacol 35:S75–S78

    Article  CAS  PubMed  Google Scholar 

  • Boaz M, Smetana S, Weinstein T, Matas Z, Gafter U, Iaina A, Knecht A, Weissgarten Y, Brunner D, Fainaru M, Green MS (2000) Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet 356:1213–1218

    Article  CAS  PubMed  Google Scholar 

  • Bursell SE, Clermont AC, Aiello LP, Aiello LM, Schlossman DK, Feener EP, Laffel L, King GL (1999) High-dose vitamin E supplementation normalizes retinal blood flow and creatinine clearance in patients with type 1 diabetes. Diabetes Care 22:1245–1251

    CAS  PubMed  Google Scholar 

  • Cederberg J, Galli J, Luthman H, Eriksson UJ (2000) Increased mRNA levels of Mn-SOD and catalase in embryos of diabetic rats from a malformation-resistant strain. Diabetes 49:101–107

    CAS  PubMed  Google Scholar 

  • Chang TI, Horal M, Jain S, Wang F, Patel R, Loeken MR (2003) Oxidant regulation of gene expression and neural tube development: insights gained from diabetic pregnancy on molecular causes of neural tube defects. Diabetologia 46:538–545

    Article  CAS  PubMed  Google Scholar 

  • Du X, Matsumura T, Edelstein D, Rossetti L, Zsengeller Z, Szabo C, Brownlee M (2003) Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest 112:1049–1057

    Article  CAS  PubMed  Google Scholar 

  • Dunlop M (2000) Aldose reductase and the role of the polyol pathway in diabetic nephropathy. Kidney Int Suppl 77:S3–S12

    Article  CAS  PubMed  Google Scholar 

  • Eriksson U, Siman CM (1996) Pregnant diabetic rats fed the antioxidant butylated hydroxytoluene show decreased occurrence of malformations in offspring. Diabetes 45:1497–1502

    CAS  PubMed  Google Scholar 

  • Feldman EL, Stevens MJ, Greene DA (1997) Pathogenesis of diabetic neuropathy. Clin Neurosci 4:365–370

    CAS  PubMed  Google Scholar 

  • Fine E, Horal M, Chang T, Fortin G, Loeken M (1999) Hyperglycemia is responsible for altered gene expression, apoptosis, and neural tube defects associated with diabetic pregnancy. Diabetes 48:2454–2462

    CAS  PubMed  Google Scholar 

  • Forsberg H, Borg LA, Cagliero E, Eriksson UJ (1996) Altered levels of scavenging enzymes in embryos subjected to a diabetic environment. Free Radic Res 24:451–459

    CAS  PubMed  Google Scholar 

  • Gaede P, Poulsen HE, Parving HH, Pedersen O (2001) Double-blind, randomised study of the effect of combined treatment with vitamin C and E on albuminuria in type 2 diabetic patients. Diabet Med 18:756–760

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Ruiz C, Colell A, Morales A, Kaplowitz N, Fernandez-Checa JC (1995) Role of oxidative stress generated from the mitochondrial electron transport chain and mitochondrial glutathione status in loss of mitochondrial function and activation of transcription factor nuclear factor-kappa B: studies with isolated mitochondria and rat hepatocytes. Mol Pharmacol 48:825–834

    CAS  PubMed  Google Scholar 

  • Giugliano D, Ceriello A (1996) Oxidative stress and diabetic vascular complications. Diabetes Care 19:257–267

    CAS  PubMed  Google Scholar 

  • Goldberg HJ, Whiteside CI, Fantus IG (2002) The hexosamine pathway regulates the plasminogen activator inhibitor-1 gene promoter and Sp1 transcriptional activation through protein kinase C-beta I and -delta. J Biol Chem 277:33833–33841

    Article  CAS  PubMed  Google Scholar 

  • Greene EL, Nelson BA, Robinson KA, Buse MG (2001) Alpha-lipoic acid prevents the development of glucose-induced insulin resistance in 3T3-L1 adipocytes and accelerates the decline in immunoreactive insulin during cell incubation. Metabolism 50:1063–1069

    Article  CAS  PubMed  Google Scholar 

  • Griendling KK, FitzGerald GA (2003) Oxidative stress and cardiovascular injury. I. basic mechanisms and in vivo monitoring of ROS. Circulation 108:1912–1916

    Article  PubMed  Google Scholar 

  • Hagay ZJ, Weiss Y, Zusman I, Peled-Kamar M, Reece EA, Eriksson UJ, Groner Y (1995) Prevention of diabetes-associated embryopathy by overexpression of the free radical scavenger copper zinc superoxide dismutase in transgenic mouse embryos. Am J Obstet Gynecol 173:1036–1041

    Article  CAS  PubMed  Google Scholar 

  • Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M (2003) Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 9:294–299

    Article  CAS  PubMed  Google Scholar 

  • Hancock JT, Desikan R, Neill SJ (2001) Role of reactive oxygen species in cell signalling pathways. Biochem Soc Trans 29:345–350

    Article  CAS  PubMed  Google Scholar 

  • Hoffman BB, Sharma K, Ziyadeh FN (1998) Potential role of TGF-beta in diabetic nephropathy. Miner Electrolyte Metab 24:190–196

    Article  CAS  PubMed  Google Scholar 

  • Hounsom L, Corder R, Patel J, Tomlinson DR (2001) Oxidative stress participates in the breakdown of neuronal phenotype in experimental diabetic neuropathy. Diabetologia 44:424–428

    Article  CAS  PubMed  Google Scholar 

  • 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 49:1939–1945

    CAS  PubMed  Google Scholar 

  • Ishii H, Jirousek MR, Koya D, Takagi C, Xia P, Clermont A, Bursell SE, Kern TS, Ballas LM, Heath WF, Stramm LE, Feener EP, King GL (1996) Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 272:728–731

    CAS  PubMed  Google Scholar 

  • Itani SI, Ruderman NB, Schmieder F, Boden G (2002) Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 51:2005–2011

    CAS  PubMed  Google Scholar 

  • Kanji MI, Toews ML, Carper WR (1976) A kinetic study of glucose-6-phosphate dehydrogenase. J Biol Chem 251:2258–2262

    CAS  PubMed  Google Scholar 

  • Kashiwagi A, Asahina T, Nishio Y, Motoyoshi I, Tanaka Y, Kikkawa R, Shigeta Y (1996) Glycation, oxidative stress, and scavenger activity. Glucose metabolism and radical scavenger dysfunction in endothelial cells. Diabetes 45:S84–S86

    CAS  PubMed  Google Scholar 

  • King GL, Kunisaki M, Nishio Y, Inoguchi T, Shiba T, Xia P (1996) Biochemical and molecular mechanisms in the development of diabetic vascular complications. Diabetes 45(suppl 3):S105–S108

    Google Scholar 

  • Konrad D, Somwar R, Sweeney G, Yaworsky K, Hayashi M, Ramlal T, Klip A (2001) The antihyperglycemic drug alpha-lipoic acid stimulates glucose uptake via both GLUT4 translocation and GLUT4 activation: potential role of p38 mitogen-activated protein kinase in GLUT4 activation. Diabetes 50:1464–1471

    CAS  PubMed  Google Scholar 

  • Kowluru RA, Kennedy A (2001) Therapeutic potential of anti-oxidants and diabetic retinopathy. Expert Opin Investig Drugs 10:1665–1676

    CAS  PubMed  Google Scholar 

  • Kunisaki M, Bursell S-E, Clermont AC, Ishii H, Ballas LM, Jirousek MR, Umeda F, Naata H, King GL (1995) Vitamin E prevents diabetes-induced abnormal retinal blood flow via the diacylglycerol-protein kinase C pathway. Am J Physiol Endocrinol Metab 269:E239–E246

    CAS  Google Scholar 

  • Kunisaki M, Fumio U, Nawata H, King GL (1996) Vitamin E normalizes diacylglycerol-protein kinase C activation induced by hyperglycemia in rat vascular tissues. Diabetes 45(suppl 3):117–119

    Google Scholar 

  • Liu PK, Grossman RG, Hsu CY, Robertson CS (2001) Ischemic injury and faulty gene transcripts in the brain. Trends Neurosci 24:581–588

    Article  CAS  PubMed  Google Scholar 

  • Lonn E, Yusuf S, Hoogwerf B, Pogue J, Yi Q, Zinman B, Bosch J, Dagenais G, Mann JF, Gerstein HC (2002) Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy. Diabetes Care 25:1919–1927

    CAS  PubMed  Google Scholar 

  • Marshall HE, Merchant K, Stamler JS (2000) Nitrosation and oxidation in the regulation of gene expression. FASEB J 14:1889–1900

    Article  CAS  PubMed  Google Scholar 

  • McDonagh PF, Hokama JY (2000) Microvascular perfusion and transport in the diabetic heart. Microcirculation 7:163–181

    Article  CAS  PubMed  Google Scholar 

  • Napoli C, de Nigris F, Palinski W (2001) Multiple role of reactive oxygen species in the arterial wall. J Cell Biochem 82:674–682

    Article  CAS  PubMed  Google Scholar 

  • Natarajan R, Bai W, Lanting L, Gonzales N, Nadler J (1997) Effects of high glucose on vascular endothelial growth factor expression in vascular smooth muscle cells. Am J Physiol 273:H2224–H2231

    CAS  PubMed  Google Scholar 

  • Nemoto S, Takeda K, Yu ZX, Ferrans VJ, Finkel T (2000) Role for mitochondrial oxidants as regulators of cellular metabolism. Mol Cell Biol 20:7311–7318

    Article  CAS  PubMed  Google Scholar 

  • Nicoletti VG, Stella AM (2003) Role of PARP under stress conditions: cell death or protection? Neurochem Res 28:187–194

    Article  CAS  PubMed  Google Scholar 

  • Nishikawa T, Edelstein D, Du XL, Yamagishi S-I, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes H-P, Giardino I, Brownlee M (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790

    Article  CAS  PubMed  Google Scholar 

  • Oren M (2003) Decision making by p53: life, death and cancer. Cell Death Differ 10:431–442

    Article  CAS  PubMed  Google Scholar 

  • Owuor ED, Kong AN (2002) Antioxidants and oxidants regulated signal transduction pathways. Biochem Pharmacol 64:765–770

    Article  CAS  PubMed  Google Scholar 

  • Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB (1999) NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401:82–85

    Article  CAS  PubMed  Google Scholar 

  • Packer L, Kraemer K, Rimbach G (2001) Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition 17:888–895

    Article  CAS  PubMed  Google Scholar 

  • Phelan SA, Ito M, Loeken MR (1997) Neural tube defects in embryos of diabetic mice: role of the Pax-3 gene and apoptosis. Diabetes 46:1189–1197

    CAS  PubMed  Google Scholar 

  • Ruggiero D, Lecomte M, Michoud E, Lagarde M, Wiernsperger N (1997) Involvement of cell-cell interactions in the pathogenesis of diabetic retinopathy. Diabetes Metab 23:30–42

    CAS  Google Scholar 

  • Rutter J, Reick M, Wu LC, McKnight SL (2001) Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science 293:510–514

    Article  CAS  PubMed  Google Scholar 

  • Savitsky PA, Finkel T (2002) Redox regulation of Cdc25C. J Biol Chem 277:20535–20540

    Article  CAS  PubMed  Google Scholar 

  • Sharpe PC, Liu W-H, Yue KKM, McMasgter D, Catherwood MA, McGinty AM, Trimble ER (1998) Glucose-induced oxidative stress in vascular contractile cells: comparison of aortic smooth muscle cells and retinal pericytes. Diabetes 47:801–809

    CAS  PubMed  Google Scholar 

  • Shin SJ, Lee YJ, Lin SR, Tan MS, Lai YH, Tsai JH (1995) Decrease of renal endothelin 1 content and gene expression in diabetic rats with moderate hyperglycemia. Nephron 70:486–493

    CAS  PubMed  Google Scholar 

  • Siman CM, Eriksson UJ (1997a) Vitamin E decreases the occurrence of malformations in the offspring of diabetic rats. Diabetes 46:1054–1061

    CAS  PubMed  Google Scholar 

  • Siman CM, Eriksson UJ (1997b) Vitamin C supplementation of the maternal diet reduces the rate of malformation in the offspring of diabetic rats. Diabetologia 40:1416–1424

    Article  CAS  PubMed  Google Scholar 

  • Sivan E, Reece EA, Wu Y-K, Homko CJ, Polansky M, Borenstein M (1996) Dietary vitamin E prophylaxis and diabetic embryopathy: morphologic and biochemical analysis. Am J Obstet Gynecol 175:793–799

    CAS  PubMed  Google Scholar 

  • Stepanovic V, Awad O, Jiao C, Dunnwald M, Schatteman GC (2003) Leprdb diabetic mouse bone marrow cells inhibit skin wound vascularization but promote wound healing. Circ Res 92:1247–1253

    Article  CAS  PubMed  Google Scholar 

  • Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ, Brown MJ (1996) Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge heart antioxidant study (CHAOS). Lancet 347:781–786

    Article  CAS  PubMed  Google Scholar 

  • Sugimoto H, Shikata K, Makino H, Ota K, Ota Z (1996) Increased gene expression of insulin-like growth factor-I receptor in experimental diabetic rat glomeruli. Nephron 72:648–653

    CAS  PubMed  Google Scholar 

  • Sundaresan M, Yu ZX, Ferrans VJ, Irani K, Finkel T (1995) Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270:296–299

    CAS  PubMed  Google Scholar 

  • Trocino RA, Akazawa S, Ishibashi M, Matsumoto K, Matsuo H, Yamamoto H, Goto S, Urata Y, Kondo T, Nagataki S (1995) Significance of glutathione depletion and oxidative stress in early embryogenesis in glucose-induced rat embryo culture. Diabetes 44:992–998

    CAS  PubMed  Google Scholar 

  • Viana M, Herrera E, Bonet B (1996) Terotogenic effects of diabetes mellitus in the rat. Prevention by vitamin E. Diabetologia 39:1041–1046

    Article  CAS  PubMed  Google Scholar 

  • Vinik AI, Park TS, Stansberry KB, Pittenger GL (2000) Diabetic neuropathies. Diabetologia 43:957–973

    Article  CAS  PubMed  Google Scholar 

  • Wentzel P, Eriksson UJ (1998) Antioxidants diminish developmental damage induced by high glucose and cyclooxygenase inhibitors in rat embryos in vitro. Diabetes 47:677–684

    CAS  PubMed  Google Scholar 

  • Wentzel P, Thunberg L, Eriksson UJ (1997) The teratogenic effect of diabetic serum is prevented by supplementation of superoxide dismutase and N-acetylcysteine in rat embryo culture. Diabetologia 40:7–14

    Article  CAS  PubMed  Google Scholar 

  • Wentzel P, Welsh N, Eriksson UJ (1999) Developmental damage, increased lipid peroxidation, diminished cyclooxygenase-2 gene expression, and lowered prostaglandin E2 levels in rat embryos exposed to a diabetic environment. Diabetes 48:813–820

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Xia P, Aiello LP, Ishii H, Jiang ZY, Park DJ, Robinson GS, Takagi H, Newsome WP, Jirousek MR, King GL (1996) Characterization of vascular endothelial growth factor’s effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J Clin Invest 98:2018–2026

    CAS  PubMed  Google Scholar 

  • Yamamoto Y, Gaynor RB (2001) Role of the NF-kappaB pathway in the pathogenesis of human disease states. Curr Mol Med 1:287–296

    CAS  PubMed  Google Scholar 

  • Yang X, Borg LA, Eriksson UJ (1997) Altered metabolism and superoxide generation in neural tissue of rat embryos exposed to high glucose. Am J Physiol 272:E173–E180

    CAS  PubMed  Google Scholar 

  • Zheng L, Roeder RG, Luo Y (2003) S phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component. Cell 114:255–266

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Institutes of Health, (DK58300) to M.R.L. and (EY5110 and DK53105) to G.K.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mary R. Loeken.

Rights and permissions

Reprints and permissions

About this article

Cite this article

King, G.L., Loeken, M.R. Hyperglycemia-induced oxidative stress in diabetic complications. Histochem Cell Biol 122, 333–338 (2004). https://doi.org/10.1007/s00418-004-0678-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00418-004-0678-9

Keywords

Navigation