The effect of Hyperglycemia and Oxidative Stress on the Development and Progress of Vascular Complications in Type 2 Diabetes

Open access

The effect of Hyperglycemia and Oxidative Stress on the Development and Progress of Vascular Complications in Type 2 Diabetes

Oxidative stress is the result of increased production of free radicals, which impair the cell function and cause many pathological conditions and diseases. The development of diabetes, its course and complications are closely associated with an imbalance in pro-antioxidative cell state and change of redox potential. Prolonged exposure to hyperglycemia is currently considered the major factor of the pathogenesis of atherosclerosis in diabetes. Atherosclerosis is the cause of about 80% of mortality in diabetics, and over 75% of all hospitalized diabetic patients have associated cardiovascular complications. Hyperglycemia induces different vascular tissue damage at the cellular level, which potentially accelerates the atherosclerotic processes. The most significant mechanisms responsible for acceleration of atherosclerotic processes in diabetic patients are: a) non-enzymatic protein and lipid glycosylation which interferes with normal function, in the way that it deranges molecular conformation, impairs enzymatic function, reduces the capacity of breakdown and interferes with recognition of protein structures by receptors; b) interaction of glycosylated proteins with their receptors resulting in induction of oxidative stress and pro-inflammatory reactions; c) polyol pathway; d) hexosamine pathway and e) activation of protein kinase C and impaired growth factor expression.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • Giugliano D Ceriello A. Oxidative stress and diabetic vascular complications. Diabetes 1996; 19: 257-67.

  • Bonnefont-Rousselot D Bastard JP Jaudon MC Delattre J. Consequences of the diabetic status on the oxidant-antioxidant balance. Diabetes & Metabolism 2000; 26: 163-74.

  • Aronson D Rayfield EJ. How hyperglycemia promotes atherosclerosis: molecular mechanisms. Cardiovascular Diabetology 2002; 1: 1-10.

  • Pavlović DD Đorđević BV Kocić MG. Ćelijska signalna transdukcija-modulacija slobodnim radikalima. Jugoslov Med Biohem 2002; 21: 69-84.

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

  • Wolff SP. Diabetes mellitus and free radicals. Free radicals transition metals and oxidative stress in the aetiology of diabetes mellitus and complications. Br Med Bull 1993; 49: 6425-2.

  • Laakso M. Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes 1999; 48: 937-42

  • Tuiyama Y Griendling KK. Reactive oxygen species in the vasculature. Hypertension 2003; 43: 10758-4.

  • Čolak E Dimitrijević-Srećković V Đorđević PB Stanković S Majkić-Singh N Lalić K et al. The influence of type and duration of cardiovascular complications on antioxidative parameter values in type 2 diabetic patients. Journal of Medical Biochemistry 2007; 1: 10-7.

  • Čolak E Majkić-Singh N Stanković S Srećković-Dimitrijević V Đorđević PB Lalić K et al. The effect of hyperglycemia on the values of antioxidative parameters in type 2 diabetic patients with cardiovascular complications. Jugoslov Med Biohem 2006; 25: 173-9.

  • Brownlee M. The pathobiology of diabetic complications. A unifying mechanism. Diabetes 2005; 54: 1615-25.

  • Maillard L. Action des acides amines sur les sucres: formation des melanoidines par voie methodique. C R Acad Sci (Paris) 1912; 154: 66-8.

  • Wautier JL Schmidt AM. Protein glycation - a firm link to endothelial dysfunction. Circulation Research 2004; 95: 233-8.

  • Brownlee M Cerami A Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complication. N Engl J Med 1988; 318: 1315-21.

  • Čolak E. New markers of oxidative damage to macro-molecules. Journal of Medical Biochemistry 2008; 27 (1): 1-16.

  • Berg TJ Clausen JT Torjesen PA Dohl-Jorgensen K Bangstad HJ Hanssen KF. The advanced glycation end product N epsilon-(carboxymethyl) lysine is increased in serum from children and adolescents with type 1 diabetes. Diabetes Care 1998; 21: 1997-2002.

  • Chellan P Nagaraj RH. Protein crosslinking by the Maillard reaction: dicarbonyl-derived imidazolium crosslinks in aging and diabetes. Arch Biochem Biophys 1999; 368: 98-104.

  • Lederer MO Klaiber RG. Cross-linking of proteins by Maillard processes: characterization and detection of lysine-arginine cross-links derived from glyoxal and methylglyoxal. Bioorg Med Chem 1999; 7: 24995-7.

  • Thornalley PJ Langborn A Minhas HS. Formation of glyoxal methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose. Biochem J 1999; 344: 109-16.

  • Oya T Hattori N Mizuno Y Miyata S Maeda S Osawa T et al. Methylglyoxal modification of protein. Chemical and immunochemical characterization of methylglyoxal-arginine adducts. J Biol Chem 1999; 274: 18492-502.

  • Paul RG Bailey AJ. The effect of advanced glycation end product formation upon cell-matrix interactions. Int J Biochem Cell Biol 1999; 31: 653-60.

  • Thornalley PJ. Glutathione-dependent detoxification of alpha-oxoaldehydes by the glyoxalase system: involve-

  • Ranganathan S Ciaccio PJ Walsh ES Tew KD. Genomic sequence of human glyoxalase-I: analysis of promoter activity and its regulation. Gene 1999; 240: 149-55.

  • Abordo EA Minhas HS Thornalley PJ. Accumulation of alpha-oxoaldehydes during oxidative stress: a role of cytotoxicity. Biochem Pharmacol 1999; 58: 641-8.

  • Ahmed N Thornalley PJ. Quantitative screening of protein biomarkers of early glycation advanced glycation oxidation and nitrozation in cellular and extra-cellular proteins by tandem mass spectrometry multiple reaction monitoring. Biochem Soc Trans 2003; 31: 1417-22.

  • Bucala R Makita Z Koschinsky T Cerami A Vlassara H. Lipid advanced glycosylation: pathway for lipid oxidation in vivo. Proc Natl Acad Sci USA 1993; 90: 6434-8.

  • Bucala R Mitchell R Arnold K Innerarity T Vlassara H Cerami A. Indentification of the major site of apolipoprotein B modification by advanced glycosylation end products blocking uptake by the low density lipo-protein receptor. J Biol Chem 1995; 270: 10828-32.

  • Bucala R Makita Z Vega G Grundy S Koschinsky T Cerami A Vlassara H. Modification of low density lipo-protein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency. Proc Natl Acad Sci USA 1994; 91: 9441-5.

  • Steinbrecher UP Witztum JL. Glucosylation of low-density lipoprotein to an extent comparable to that seen in diabetes slows their catabolism. Diabetes 1984; 33: 130-4.

  • Čolak E. Uticaj hiperglikemije na vrednosti antioksidativnih parametara kod dijabetičara tipa 2 sa kardio-vaskularnim komplikacijama. Farmaceutski fakultet Beograd 2005 magistarski rad.

  • Zamaklar M Lalić K Rajković N Trifunović D Draga-šević M Popović Lj et al. Oxidized LDL and other lipids as risk factors for cardiovascular disease in the patients with metabolic syndrome. Jugoslov Med Biohem 2005; 24 (2): 99-106.

  • Klein RL Laimins M Lopes-Virella MF. Isolation characterization and metabolism of the glycated and non-glycated subfractions of low-density lipoproteins isolated from type 1 diabetic patients and nondiabetic subjects. Diabetes 1995; 44: 1093-8.

  • Picard S Talussot C Serusclat A Ambrosio N Berthezene F. Minimaly oxidized LDL as estimated by a new method increase in plasma of type 2 diabetic patients with atherosclerosis or nephropathy. Diabetes Metab 1996; 22: 25-30.

  • Dimitrijević-Srećković V Đorđević P Gostiljac D Čolak E Srećković B Popović S et al. Quinquennial follow-up of prediabetic patients progressing into diabetics. Diabetes & Vascular Disease Research 2007;4: Suppl. l S105.

  • Dimitrijević-Srećković V Čolak E Đorđević P Gostiljac D Srećković B Popović S et al. Prothrombogenic factors and reduced antioxiative defense in children and adolescents with pre-metabolic and metabolic syndrome. Clin Chem Lab Med 2007; 45 (9): 1140-4.

  • Jain SK Mc Vie R Jaramillo JJ Chen Y. Hyperketonemia (acetoacetate) increases the oxidizability of LDL+VLDL in type 1 diabetic patients. Free Radic Biol Med 1998; 24; 175-81.

  • Leonhardt W Hanefeld M Muller G Hora C Meissner D Lattke P et al. Impact of concentration of glycated hemoglobin alpha-tocopherol copper and manganese on oxidation of low-density lipoprotein in patients with type 1 diabetes type 2 diabetes and control subjects. Clin Chim Acta 1996; 254: 173-86.

  • Oranje WA Rondas-Colbers GJ Swennen GN Jansen H Wolffenbuttel BH. Lack of effect on LDL oxidation and antioxidant status after improvement of metabolic control in type 2 diabetes. Diabetes Care 1999; 22: 2083-4.

  • Carantoni M Abbasi F Warmerdam F Klebanov M Wang PW Chen YD et al. Relationship between insulin resistance and partially oxidized LDL particles in healthy nondiabetic volunteers. Arterioscler Thromb Vasc Biol 1998; 18: 762-7.

  • Lopes-Virella MF Virella G. Cytokines modified lipo-proteins and arteriosclerosis in diabetes. Diabetes 1996; 45: S40-S44.

  • Lopes-Virella MF Virella G Orchard TJ Koskinen S Evans RW Becker DJ et al. Antibodies to oxidized LDL and LDL-containing immune complexes as risk factors for coronary artery disease in diabetes mellitus. Clin Immunol 1999; 90: 165-72.

  • Brett J. Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissue. Am J Pathol 1993; 143: 1699-712.

  • Ritthaler U Deng Y Zhang Y Greten J Abel M Sido B et al. Expression of receptors for advanced glycation end products in peripheral occlusive vascular disease. Am J Pathol 1995; 146: 688-94.

  • Schmidt AM Du Yau Shi Wautier JL Stern D. Activation of receptors for advanced glycation end products. Circulation Research 1999; 84: 489-97.

  • Kilhovd BK Juntilainen A Lehto S Rönnemaa T Torjensen PA Birkeland KJ et al. High serum levels of advanced glycation end products predict increased coronary heart disease mortality in nondiabetic women but not in nondiabetic men-a population based 18 years follow-up study. Arterioscler Thromb Vasc Biol 2005; 25 (4): 815-20.

  • Falcone C Emanuele E D'Angelo A Puzzi MP Belvito C Cuccia M et al. Plasma levels of soluble receptor for advanced glycation end products and coronary artery disease in nondiabetic men. Arterioscler Thromb Vasc Biol 2005; 25 (5): 1032-7.

  • Yan SD Schmidt AM Anderson GM Zhang J Brett J Zou YS et al. Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem 1994; 269: 9889-97.

  • Wautier JL Wautier MP Schmidt AM Anderson GM Hori O Zoukourian C et al. Advanced glycation end products (AGEs) on the surface of diabetic erythrocytes bind to the vessel wall via specific receptor inducing oxidant stress in the vasculature: a link between surface-associated AGEs and diabetic complications. Proc Natl Acad Sci USA 1994; 91: 7742-6.

  • Schmidt AM Hori O Chen JX Li JF Crandall J Zhang J et al. Advanced glycation end products interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells in mice. A potential mechanism for the accelerated vasculopathy of diabetes. J Clin Invest 1995; 96: 1395-403.

  • Schmidt AM Yan SD Brett J Mora R Nowygrod R Stern D. Regulation of human mononuclear phagocyte migration by cell surface binding proteins for advanced glycation end products. J Clin Invest 1993; 91: 2155-68.

  • Kirstein M Brett J Radoff S Ogawa S Stern D Vlassara H. Advanced protein glycosylation induces transendothelial human monocyte chemotaxis and secretion of platelet-derived growth factor: role in vascular disease of diabetes and aging. Proc Natl Acad Sci USA 1990; 87: 9010-4.

  • Vlassara H Brownlee M Manogue KR Dinarello CA Pasagian A. Cachectin/TNF and IL-1 induced by glucose-modified proteins: role in normal tissue remodeling. Science 1988; 240: 1546-8.

  • Kirstein M Aston C Hintz R Vlassara H. Receptor-specific induction of insulin-like growth factor I in human monocytes by advanced glycosylation end product-modified proteins. J Clin Invest 1992; 90: 439-46.

  • Ross R. Atherosclerosis - an inflammatory disease. N Engl J Med 1999; 340: 115-26.

  • Vlassara H Bucala R Striker L. Pathogenic effects of advanced glycosylation: biochemical biologic and clinical implications for diabetes and aging. Lab Invest 1994; 70: 138-51.

  • Lee AY Chung SS. Contributions of polyol pathway to oxidative stress in diabetic cataract. Faseb J 1999; 13: 23-30.

  • Tesfamariam B. Free radicals in diabetic endothelial cell dysfunction. Free Radic Biol Med 1994; 16: 383-91.

  • Greene DA Stevens MJ. The sorbitol-osmotic and sorbitol redox hypotheses. In: Le Roith D Taylor SI Olefsky JM eds. Diabetes Mellitus. Philadelphia: Lippincott-Raven Publishers 1996.

  • Bucala R Tracey KJ Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest 1991;87:432-8.

  • Kolni-Litty V Sauer U Nerlich A Lehman R Schleicher ED. High glucose-induced tranforming growth-factor beta 1 production is mediated by the hexozamine path-way in porcine glomerular mesangial cells. J Clin Invest 1998; 101: 160-9.

  • Wells L Hart G. O-GlcNAc turns twenty: functional implications for posttranslational modification of nuclear and cytosolic protein with a sugar. FEBS Lett 2003; 546: 154-8.

  • Du XL Edelstein D Rossetti L Fantus IG Goldberg H Ziyadeh T et al. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexozamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA 2000; 97: 12222-6.

  • Pressler D Rudich A Bashan N. Oxidative stress impairs nuclear proteins binding to the insulin responsive element in the GLUT 4 promoter. Diabetologia 2001; 44: 2156-64.

  • Tomkin GH. Diabetic vascular disease and the rising star of protein kinase C. Diabetologia 2001; 44: 657-8.

  • Tomlinson DR. Mitogen-activated protein kinases as glucose transducers for diabetic complications. Diabetologia 1999; 42: 1271-81.

  • Koya D King GL. Protein kinase C and the development of diabetic complications. Diabetes 1998; 47: 859-66.

  • Inoguchi T Battan R Handler E Sportsman JR Heath W King GL. Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation. Proc Natl Acad Sci USA 1992; 89: 11059-63.

  • Ikeda Y Olsen GS Ziv E Hansen LL Busch AK Hansen BF et al. Cellular mechanism of nutritionally induced insulin resistance in Psammomys obesus: over-expression of protein kinase C epsilon in skeletal muscle precedes the onset of hyperinsulinemia and hyperglycemia. Diabetes 2001; 50: 584-92.

  • Nabel E Shum L Pompili V Yang Z-Y San H Shu H et al. Direct transfer of transforming growth factor b1 gene into arteries stimulates fibrocellular hyperplasia. Proc Natl Acad Sci USA 1993; 90: 10759-63.

  • Koya D Jirousek MR Lin YW Issii H Kuboki K King GL. Characteristics of protein kinase C b isoform activation on gene expression of transforming growth factor b extracellular matrix components and prostanoids in the glomeruli of diabetic rats. J Clin Invest 1997; 100: 115-26.

  • Li PF Maasch C Haller H Dietz R Von Harsdorf R. Requirement for protein kinase C in reactive oxygen species-induced apoptosis of vascular smooth muscle cells. Circulation 1999; 100: 967-73.

  • Aiello LP Avery RL Arrigg PG Keyt BA Jampel HD Shah ST et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994; 331: 1480-7.

  • Tomlinson DR. Mitogen-activated protein kinases as glucose transducers for diabetic complications. Diabetologia 1999; 42: 1271-81.

  • Davis RJ. Transcriptional regulation bay MAP kinases. Mol Reprod Dev 1995; 42: 459-67.

  • Guyton KZ Liu Y Gorospe M XuQ Holbrook NJ. Activation of mitogen-activated protein kinase by h202. Role in cell survival following oxidant injury. J Biol Chem 1996; 271: 4138-42.

  • English JM Cobb MH. Pharmacological inhibitors of MAPK pathways. Trends Pharmacol Sci 2002; 23: 40-5.

  • Pavlović D Kocić R Kocić G Đorđević V Bjelaković G Koraćević D. Therapeutic effects of vitamin E and C on the serum lipid peroxidation and glycaemia in diabetic subjects. Diabetologia 1992; 35 (Suppl 1): A 201-2.

  • Pavlović D Bjelaković G. A possibile link between polyamines and thiol redox signaling pathway in diabetic liver. J Hepatology 2001; 34 (Suppl 1): 94-5.

Journal information
Impact Factor

IMPACT FACTOR 2018: 2.000
5-year IMPACT FACTOR: 1.075

CiteScore 2018: 1.47

SCImago Journal Rank (SJR) 2018: 0.523
Source Normalized Impact per Paper (SNIP) 2018: 0.581

Cited By
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 222 105 3
PDF Downloads 103 67 0