Reviews/Commentaries/Position Statements

New Insights on Oxidative Stress and Diabetic Complications May Lead to a “Causal” Antioxidant Therapy

  1. Antonio Ceriello, MD
  1. From the Department of Pathology and Medicine, Experimental and Clinical, Chair of Internal Medicine, University of Udine, Udine, Italy
    Diabetes Care 2003 May; 26(5): 1589-1596. https://doi.org/10.2337/diacare.26.5.1589

    Abstract

    Evidence implicates hyperglycemia-derived oxygen free radicals as mediators of diabetic complications. However, intervention studies with classic antioxidants, such as vitamin E, failed to demonstrate any beneficial effect. Recent studies demonstrate that a single hyperglycemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain seems to be the first and key event in the activation of all other pathways involved in the pathogenesis of diabetic complications. These include increased polyol pathway flux, increased advanced glycosylation end product formation, activation of protein kinase C, and increased hexosamine pathway flux. Superoxide overproduction is accompanied by increased nitric oxide generation, due to an endothelial NOS and inducible NOS uncoupled state, a phenomenon favoring the formation of the strong oxidant peroxynitrite, which in turn damages DNA. DNA damage is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP-ribose) polymerase. Poly(ADP-ribose) polymerase activation in turn depletes the intracellular concentration of its substrate NAD+, slowing the rate of glycolysis, electron transport, and ATP formation, and produces an ADP-ribosylation of the GAPDH. These processes result in acute endothelial dysfunction in diabetic blood vessels that, convincingly, also contributes to the development of diabetic complications. These new findings may explain why classic antioxidants, such as vitamin E, which work by scavenging already-formed toxic oxidation products, have failed to show beneficial effects on diabetic complications and may suggest new and attractive “causal” antioxidant therapy. New low–molecular mass compounds that act as SOD or catalase mimetics or l-propionyl-carnitine and lipoic acid, which work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such a strategy, and preliminary studies support this hypothesis. This “causal” therapy would also be associated with other promising tools such as LY 333531, PJ34, and FP15, which block the protein kinase β isoform, poly(ADP-ribose) polymerase, and peroxynitrite, respectively. While waiting for these focused tools, we may have other options: thiazolinediones, statins, ACE inhibitors, and angiotensin 1 inhibitors can reduce intracellular oxidative stress generation, and it has been suggested that many of their beneficial effects, even in diabetic patients, are due to this property.

    The relationship between diabetes and premature vascular disease is well established (1). Recent prospective studies indicate that long-term glycemic control is an important predictor not only of microvascular disease (2,3), but also of macrovascular complications (4).

    Vascular endothelial cells are an important target of hyperglycemic damage, but the mechanisms underlying this damage are not fully understood (5).

    It has been suggested that, in diabetes, oxidative stress plays a key role in the pathogenesis of vascular complications, both microvascular and macrovascular (6), and an early marker of such damage is the development of an endothelial dysfunction (6,7). However, the role of oxidative stress in diabetes is questioned by the results of intervention studies with antioxidants, which are elusive or unsuccessful (8).

    Recent basic and clinical studies have uncovered new insights into the role of oxidative stress in diabetic complications, suggesting a different and innovative approach to a possible “causal” antioxidant therapy. The aim of this review is to give an update on this topic.

    HYPERGLYCEMIA, OXIDATIVE STRESS, AND ENDOTHELIAL DYSFUNCTION

    Vascular function in diabetes has been studied extensively in both animal models and humans. Impaired endothelium-dependent vasodilation has been a consistent finding in animal models of diabetes induced by alloxan or streptozotocin (9,10). Similarly, studies in humans with type 1 or type 2 diabetes have found endothelial dysfunction when compared with vascular function in nondiabetic subjects (11,12).

    In vitro, the direct role of hyperglycemia has been suggested by evidence that arteries isolated from normal animals, which are subsequently exposed to exogenous hyperglycemia, also exhibit attenuated endothelium-dependent relaxation (13). Consistently, in vivo studies have also demonstrated that hyperglycemia directly induces, both in diabetic and normal subjects, an endothelial dysfunction (14,15).

    The role of free radicals generation in producing the hyperglycemia-dependent endothelial dysfunction is suggested by studies showing that both in vitro (16,17) and in vivo (18,19–21), the acute effects of hyperglycemia is counterbalanced by antioxidants.

    Increased superoxide production in endothelial cells during hyperglycemia: the unifying hypothesis for the development of diabetic complications

    Brownlee (22) recently pointed out the key role of superoxide production in endothelial cells at the mitochondrial level during hyperglycemia in the pathogenesis of diabetic complications. This new insight is consistent with the four pathways suggested to be involved in the development of diabetic complications (increased polyol pathway flux, increased advanced glycosylation end product formation, activation of protein kinase C, and increased hexosamine pathway flux) and with a unifying hypothesis regarding the effects of hyperglycemia on cellular dysfunction (23,24). The authors used endothelial cells subjected to physiologically relevant glucose concentrations as a model system for analyzing the vascular response to hyperglycemia because the non-insulin-dependent glucose transporter GLUT1 facilitates diffusion of high levels of glucose into the endothelium. In the presence of increased glucose, endothelial generation of reactive oxygen species, particularly superoxide anion, was shown to be enhanced (23). Several pathways can be considered as likely candidates for oxygen free radical formation in cells. These include NAD(P)H oxidase, the mitochondrial respiratory chain, xantine oxidase, the arachidonic cascade (lipoxygenase and cycloxygenase), and microsomal enzymes (25). Brownlee et al. (23) have determined that the source of free radicals in endothelial cells incubated in high glucose is the transport of glycolysis-derived pyruvate in mitochondria at the level of complex II (succinate:ubiquinone oxidoreductase), one of the four inner membrane–associated complexes central to oxidative phosphorylation. The data in the papers (23) indicate that, at least in the cell culture, endothelium in an environment mimicking physiological hyperglycemia cannot control its appetite for glucose. Accelerated flux of glucose through glycolysis and feeding of pyruvate (thus formed) to the tricarboxylic acid cycle overloads mitochondria, causing excessive generation of free radicals. Although oxygen free radicals have been shown to have a physiological role in signal transduction, their sustained generation at the levels shown in endothelial cells exposed to high glucose can be expected to have substantial effects on cellular properties. Each of the pathways implicated in secondary complications of diabetes has been shown to arise by a single unifying mechanism (22). A central contribution of the works of Brownlee et al. (23) is to demonstrate that suppression of intracellular free radicals, using low molecular inhibitors or by expression of the antioxidant enzyme manganese-superoxide dismutase, prevents each of these events (i.e., glucose-induced formation of oxidants is a proximal step in cell perturbation).

    Furthermore, activation of nuclear factor (NF)-κB by this mechanism ties hyperglycemia to the expression of multiple genes related to vascular stress response (26). Figure 1 summarizes this finding.

    SUPEROXIDE, NITRIC OXIDE, PEROXYNITRITE, AND NITROTYROSINE FORMATION

    Even increased superoxide generation in hyperglycemia is a key event in activating the other pathways involved in the pathogenesis of diabetic complications; it represents only a first step in the production of the endothelial dysfunction in diabetes.

    Nitric oxide (NO) production plays a central role in modulating endothelial function (27). NO is generated from the metabolism of l-arginine by the enzyme nitric oxide synthase (NOS), of which there are three isoforms: the constitutive types, brain (bNOS) and endothelial (eNOS), and the inducible type, iNOS (28). iNOS is induced de novo by various stimuli, including hyperglycemia (29), while the mitochondrial-generated superoxide can inhibit eNOS, although enough NO is still produced (30).

    The superoxide anion may quench NO, thereby reducing the efficacy of a potent endothelium-derived vasodilator system that participates in the general homeostasis of the vasculature (31), and evidence suggests that during hyperglycemia, reduced NO availability exists (14).

    The activation of protein kinase C, due to superoxide overproduction, induces a de novo synthesis of the enzyme NAD(P)H oxidase, which significantly contributes to produce more superoxide anions (32).

    Hyperglycemia also favors, through the activation of NF-κB, an increased expression of both NAD(P)H and iNOS (33). Overexpression of iNOS is accompanied by increased generation of NO (33).

    Superoxide overproduction, when accompanied by increased NO generation, favors the formation of the strong oxidant peroxynitrite (34), which in turn avidly oxidizes tetrahydrobiopterin, an iNOS cofactor, to dihydrobiopterin (35). Under conditions of tetrahydrobiopterin deficiency, iNOS is in an uncoupled state, which means that electrons flowing from the iNOS reductase domain to the oxygenase domain are diverted to molecular oxygen rather than to l-arginine, resulting in production of superoxide rather than NO (36,37). Exposure to peroxynitrite during hyperglycemia also produces an uncoupling state of eNOS, presumably via a zinc depletion of the enzyme, favoring superoxide overproduction (38). Consistently, in hyperglycemic conditions, an overproduction of both superoxide and NO has been reported, with a threefold increase in superoxide generation (37). As previously reported, the simultaneous overgeneration of NO and superoxide favors the production of a toxic reaction product, the peroxynitrite anion (34). The peroxynitrite anion is cytotoxic because it oxidizes sulfydryl groups in proteins, initiates lipid peroxidation, and nitrates amino acids such as tyrosine, which affects many signal transduction pathways (34). The production of peroxynitrite can be indirectly inferred by the presence of nitrotyrosine (39).

    The possibility that diabetes is associated with increased nitrotyrosine formation is supported by the recent detection of increased nitrotyrosine plasma levels in type 2 diabetic patients (40). Several pieces of evidence support a direct role of hyperglycemia in favoring this phenomenon. Nitrotyrosine formation is detected in the artery wall of monkeys during hyperglycemia (41) and also in the plasma of healthy subjects during a hyperglycemic clamp (42) and in diabetic patients during an increase of postprandial hyperglycemia (43). Hyperglycemia is also accompanied by nitrotyrosine deposition in a perfused working heart from rats, and it is reasonably related to unbalanced production of NO and superoxide through iNOS overexpression (44). Nitrotyrosine formation is followed by the development of an endothelial dysfunction in both healthy subjects (41) and in coronaries of perfused hearts (44), and this effect is not surprising because it has been shown that nitrotyrosine can also be directly harmful to endothelial cells (45).

    The toxic action of nitrotyrosine, and therefore perhaps of peroxynitrite, is supported by study evidence. Increased apoptosis of myocytes, endothelial cells, and fibroblasts in heart biopsies from diabetic patients (46), in hearts from streptozotocin-induced diabetic rats (47), and in working hearts from rats during hyperglycemia (44) is selectively associated with levels of nitrotyrosine found in those cells.

    PEROXYNITRITE, DNA DAMAGE, AND ENDOTHELIAL DYSFUNCTION: THE ROLE OF POLY(ADP-RIBOSE) POLYMERASE ACTIVATION

    Peroxynitrite is a potent initiator of DNA single-strand breakage, which is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP-ribose) polymerase (48). As described above, when endothelial cells respond to high glucose, reactive nitrogen and oxygen species generation occurs (49). These reactive species trigger DNA single-strand breakage, which induces a rapid activation of poly(ADP-ribose) polymerase (49). The role of hyperglycemia and related oxidative stress in producing DNA damage is supported by the recent findings that increased amounts of 8-hydroxyguanine and 8-hydroxydeoxyguanosine (markers of oxidative damage to DNA) can be found in both the plasma and tissues of streptozotocin diabetic rats (50). These concentrations are correlated and can be reduced by the control of hyperglycemia and by the use of the antioxidants probucol and vitamin E (50).

    Poly(ADP-ribose) polymerase activation in turn depletes the intracellular concentration of its substrate NAD+, slowing the rate of glycolysis, electron transport, and ATP formation, and produces the ADP-rybosylation of GAPDH (51). This process results in acute endothelial dysfunction in diabetic blood vessels (48). The possibility of normalizing diabetic endothelial dysfunction using a specific of poly(ADP-ribose) polymerase inhibitor, PJ34, supports this evidence (52,53).

    A NEW THERAPEUTIC APPROACH: THE “CAUSAL” ANTIOXIDANT THERAPY

    As previously stated, convincing evidence is now available about the possible role of oxidative stress in the development of diabetic complications (6). However, clinical trials with antioxidants, in particular with vitamin E, have failed to demonstrate any beneficial effect (8).

    On this matter, it has recently been suggested that antioxidant therapy with vitamin E or other antioxidants is limited to scavenging already-formed oxidants and may therefore be considered a more “symptomatic” rather than a causal treatment for vascular oxidative stress (54). Figure 2 helps explain this concept.

    According to the evidence discussed in this article, it is suggested that interrupting the overproduction of superoxide by the mitochondrial electron-transport chain would normalize the pathways involved in the development of diabetic complications. It might, however, be difficult to accomplish this using conventional antioxidants, because these scavenge reactive oxygen species in a stechiometric manner. New low–molecular mass compounds that act as SOD or catalase mimetics have the theoretical advantage of scavenging reactive oxygen species continuously by acting as catalysts with efficiencies approaching those of native enzymes (54). Such compounds normalize endothelial dysfunction in streptozotocin-induced diabetic rats (55) and improve diabetes-induced decreases in endoneurial blood flow and motor nerve conduction velocity (56). Another interesting compound is l-propionyl-carnitine. This substance has been shown to act as an intracellular superoxide scavenger, improving mitochondrial function and reducing DNA damage (57–60). These properties have been shown to have beneficial effects on diabetic heart function, peripheral nerve function, and vascular blood flow in experimental diabetes (58,60,61).

    In the last years, another substance has received much attention: lipoic acid (62). It may have a unique self-regenerating capacity as a mitochondrial antioxidant (62), and the possibility that it restores endothelial dysfunction in both animal models of diabetes and in diabetic patients has been reported (63,64).

    Other promising tools are LY 333531, PJ34, and FP15, which block the protein kinase β isoform, poly(ADP-ribose) polymerase, and peroxynitrite, respectively. Not surprisingly, they have been shown to ameliorate the endothelial dysfunction induced by hyperglycemia (52,53,65,66). LY 333531 has been demonstrated to reduce oxidative stress generation in the retina: this is consistent with the evidence that protein kinase C activation may increase superoxide generation through NAD(P)H (67). PJ34 is not an antioxidant and does not directly interfere with the reactivity of peroxynitrite (48); however, poly(ADP-ribose) polymerase−/− mice show that after coronary occlusion and reperfusion, nitrotyrosine staining is markedly reduced by PJ34 (68). There is evidence that poly(ADP-ribose) polymerase inhibition can suppress the expression of iNOS (69,70) and that poly(ADP-ribose) polymerase can regulate the function of mitochondria in oxidatively challenged cells: poly(ADP-ribose) polymerase inhibitors or poly(ADP-ribose) polymerase deficiency can suppress mitochondrial permeability transition and mitochondrial oxidant generation (71). Because mitochondria represent a principal source of reactive oxidants in endothelial cells placed in high glucose (22) may be that poly(ADP-ribose) polymerase inhibition suppresses nitrotyrosine generation preserving mitochondrial integrity.

    FP15 is a potent peroxynitrite decomposition catalyst (66). It inhibits tyrosine nitration and reduces the toxicity of peroxynitrite for β-cells and vascular endothelium during the development of diabetes in rats (66). Therefore, in the near future, a causal antioxidant therapy may include SOD and catalase mimetics, l-propionyl-carnitine, lipoic acid, protein kinase Cβ and poly(ADP-ribose) polymerase inhibitors, and peroxynitrite catalysts. This combination would aim to block the noxious cascade activated by hyperglycemia through the overproduction of superoxide and NO.

    However, while waiting for these focused tools, we may already have other possibilities. It is now evident that thiazolinediones (72), statins (73), ACE inhibitors (74), and ATI inhibitors (75,76) have a strong intracellular antioxidant activity, and it has been suggested that many of their beneficial ancillary effects are due to this property. Thiazolinediones have an inhibiting effect on iNOS and significantly reduce peroxynitrite generation (72). An animal study supports the efficacy of thiazolidinediones in reducing the harmful effect of peroxynitrite (77). Indeed, statins increase NO bioavailability and decrease superoxide production (78), probably interfering with NAD(P)H activity (79), and improve endothelial dysfunction (73), even in diabetic patients (80,81). This hypothesis is supported by the evidence that the action of statins is independent of the cholesterol-lowering effect (73,80,81) and that studies show that (at least) simvastatin ameliorates diabetic retinopathy (82) and reduces cardiovascular disease as primary prevention in diabetic patients (83). Moreover, statins reduce nitrotyrosine formation in diabetic patients (81) and attenuate angiotensin II–induced free radical production (84). This effect is of particular interest because it is now well recognized that angiotensin II and activated angiotensin 1 (AT-1) receptors produce intracellular oxidative stress (85,86), and evidence shows that hyperglycemia is able to directly modulate cellular angiotensin production (87). Therefore, it is not surprising that the possible use of both ACE inhibitors and ATI receptor blockers should be of particular interest in the prevention of hyperglycemia-derived oxidative stress.

    Important trials have shown that these compounds are particularly efficacious in preventing diabetic complications such as retinopathy (88), nephropathy (89–93), and cardiovascular disease (91,93). ACE inhibitors and ATI blockers have been demonstrated to act as causal antioxidants (85,86), and it has recently been suggested that this property may account for their beneficial effect on diabetic complications (94). This hypothesis is strongly supported by the recent evidence that treatment with either ACE inhibitors or AT-1 blockers prevents nitrotyrosine deposition in the kidney and the development of proteinuria in diabetic rats (95). A summary of the various options proposed as causal antioxidant therapy is reported in Fig. 3.

    In conclusion, a large body of evidence suggests a possible role of oxidative stress in the pathogenesis of diabetic complications. This raises the concept that an antioxidant therapy may be of great interest in these patients. It has recently been suggested that diabetic subjects with complications may have a defective cellular antioxidant response against the oxidative stress generated by hyperglycemia, which can predispose the patient to organ damage (96). New insights into the mechanisms leading to the generation of oxidative stress in diabetes are now available. Presumably these findings have led to the discovery and to the evaluation of new antioxidant molecules, such as SOD and catalase mimetics, that hopefully may inhibit, at an early stage, the mechanism leading to diabetic complications. While waiting for these new and specific compounds, it is reasonable to suggest that already-available substances, such as thiazolinediones, statins, ACE inhibitors, and ATI blockers, should also be used because they are effective causal antioxidants.

    Figure 1—
    Figure 1—

    In endothelial cells, glucose can pass freely through the cell membrane in an insulin-independent manner via GLUT1. Intracellular hyperglycemia induces overproduction of superoxide at the mitochondrial level. Overproduction of superoxide is the first and key event in the activation of all other pathways involved in the pathogenesis of diabetic complications, such as polyol pathway flux, increased advanced glycosylation end product (AGE) formation, activation of protein kinase C (PKC) and NF-κB, and increased hexosamine pathway flux.

    Figure 2—
    Figure 2—

    O2− reacting with NO produces peroxynitrite (ONOO−) (see Fig. 3 for details). The radical scavenging antioxidant vitamin E is active only against certain components of oxidative stress, particularly lipid peroxidation products, leaving other consequences of O2− untouched.

    Figure 3—
    Figure 3—

    Superoxide overproduction reduces eNOS activity, but through NF-κB and protein kinase C (PKC) activates NAD(P)H and increases iNOS expression: the final effect is an increased NO generation. This condition favors the formation of the strong oxidant peroxynitrite, which in turn produces, in iNOS and eNOS, an uncoupled state, resulting in the production of superoxide rather than NO, and damages DNA. DNA damage is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP). Poly(ADP-ribose) polymerase activation in turn depletes the intracellular concentration of its substrate NAD+, slowing the rate of glycolysis, electron transport, and ATP formation, and produces an ADP-ribosylation of the GAPDH. This process results in acute endothelial dysfunction in diabetic blood vessels, which contributes to the development of diabetic complications. NF-κB activation also induces a proinflammatory conditions and adhesion molecule overexpression. All these alterations produce the final picture of diabetic complications. SOD or catalase mimetics, l-propionyl-carnitine and lipoic acid, reducing mitochondrial overproduction of superoxide, and reducing DNA damage may be good candidates for causal intracellular antioxidants. This causal therapy would also be associated with LY 333531, PJ34, and FP15, which block protein kinase β isoform, poly(ADP-ribose) polymerase, and peroxynitrite, respectively. Other current options may be thiazolinediones, statins, ACE inhibitors, and ATI inhibitors, which also have, at different levels, intracellular causal antioxidant activity. AGE, advanced glycosylation end product.

    Footnotes

    • Address correspondence and reprint requests to Prof. Antonio Ceriello, Chair of Internal Medicine, University of Udine, P.le S. Maria della Misericordia, 33100 Udine, Italy. E-mail: antonio.ceriello{at}dpmsc.uniud.it.

      Received for publication 2 May 2002 and accepted in revised form 12 February 2003.

      A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

    References

    1. ↵
      Kannel WB, McGee DL: Diabetes and cardiovascular diseases: the Framingham Study. JAMA 241:2035–2038, 1979
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      UK Prospective Diabetes Study 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 352:837–853, 1998
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      The Diabetes Control and Complications Trials (DCCT) 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 329:977–986, 1993
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      Laakso M: Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes 48:937–942, 1999
      OpenUrlAbstract
    5. ↵
      De Vriese AS, Verbeuren TJ, Van de Voorde J, Lameire NH, Vanhoutte PM: Endothelial dysfunction in diabetes. Br J Pharmacol 130:963–974, 2000
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      Giugliano D, Ceriello A, Paolisso G: Oxidative stress and diabetic vascular complications. Diabetes Care 19:257–267, 1996
      OpenUrlFREE Full Text
    7. ↵
      Cai H, Harrison DG: Endothelial dysfunction in cardiovascular disease: the role of oxidant stress. Circ Res 87:840–844, 2000
      OpenUrlAbstract/FREE Full Text
    8. ↵
      Marchioli R, Schweiger C, Levantesi G, Gavazzi L, Valagussa F: Antioxidant vitamins and prevention of cardiovascular disease: epidemiological and clinical trial data. Lipids 36:S53–S63, 2001
    9. ↵
      Meraji S, Jayakody L, Senaratne PJ, Thomson ABR, Kappagoda T: Endothelium-dependent relaxation in aorta of BB rat. Diabetes 36:978–981, 1987
      OpenUrlAbstract/FREE Full Text
    10. ↵
      Mayhan WG: Impairment of endothelium-dependent dilatation of cerebral arterioles during diabetes mellitus. Am J Physiol 256:H621–H625, 1989
    11. ↵
      Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA: Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 88:2510–2516, 1993
      OpenUrlAbstract/FREE Full Text
    12. ↵
      McVeigh GE, Brennan GM, Johnston GD, McDermott BJ, McGrath LT, Henry WR, Andrews JW, Hayes JR: Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin dependent) diabetes mellitus. Diabetologia 35:771–776, 1992
      OpenUrlPubMedWeb of Science
    13. ↵
      Bohlen HG, Lash JM: Topical hyperglycemia rapidly suppresses EDRF-mediated vasodilatation of normal rat arterioles. Am J Physiol 265:H219–H225, 1993
    14. ↵
      Giugliano D, Marfella R, Coppola L, Verrazzo G, Acampora R, Giunta R, Nappo F, Lucarelli C, D’Onofrio F: Vascular effects of acute hyperglycemia in humans are reversed by L-arginine: evidence for reduced availability of nitric oxide during hyperglycemia. Circulation 95:1783–1790, 1997
      OpenUrlAbstract/FREE Full Text
    15. ↵
      Kawano H, Motoyama T, Hirashima O, Hirai N, Miyao Y, Sakamoto T, Kugiyama K, Ogawa H, Yasue H: Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery. J Am Coll Cardiol 34:146–154, 1999
      OpenUrlCrossRefPubMedWeb of Science
    16. ↵
      Tesfamariam B, Cohen RA: Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Physiol 263:H321–H326, 1992
    17. ↵
      Diederich D, Skopec J, Diederich A, Dai F: Endothelial dysfunction in mesenteric resistance arteries of diabetic rats: role of free radicals. Am J Physiol 266:H1153–H1161, 1994
    18. ↵
      Marfella R, Verrazzo G, Acampora R, La Marca C, Giunta R, Lucarelli C, Paolisso G, Ceriello A, Giugliano D: Glutathione reverses systemic hemodynamic changes by acute hyperglycemia in healthy subjects. Am J Physiol 268:E1167–E1173, 1995
    19. ↵
      Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA: Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 97:22–28, 1996
      OpenUrlCrossRefPubMedWeb of Science
    20. Ceriello A, Motz E, Giugliano D: Vitamin C and hypertension. Lancet 355:1271–1272, 2000
      OpenUrlCrossRef
    21. ↵
      Beckman JA, Goldfine AB, Gordon MB, Creager MA: Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation 103:1618–1623, 2001
      OpenUrlAbstract/FREE Full Text
    22. ↵
      Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820, 2001
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      Nishikawa T, Edelstein D, Du X-L, Yamagishi S, Matsumura T, Kaneda Y, Yorek M, Beebe D, Oates P, Hammes HP, Giardino I, Brownlee M: Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790, 2000
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu J, Brownlee M: Hyperglycemia-induced mitochondrial superoxide overproduction activates the exosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci U S A 97:12222–12226, 2002
      OpenUrlAbstract/FREE Full Text
    25. ↵
      Cross A, Jones O: Enzymic mechanisms of superoxide production. Biochim Biophys Acta 1057:281–198, 1991
      OpenUrlPubMed
    26. ↵
      Collins T: Endothelial nuclear factor kB and the initiation of the atherosclerotic lesion. Lab Invest 68:499–508, 1993
      OpenUrlPubMedWeb of Science
    27. ↵
      Moncada S, Palmer RMJ, Higgs EA: Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 43:109–142, 1991
      OpenUrlPubMedWeb of Science
    28. ↵
      Nathan C, Xie QW: Nitric oxide synthases:roles, tolls, and controls. Cell 78:915–918, 1994
      OpenUrlCrossRefPubMedWeb of Science
    29. ↵
      Baox KJ, Thiel BA, Stuehr DJ: Macrophage nitric oxide synthase subunits. J Biol Chem 268:21120–21129, 1993
      OpenUrlAbstract/FREE Full Text
    30. ↵
      Du XL, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M: Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest 108:1341–1348, 2001
      OpenUrlCrossRefPubMedWeb of Science
    31. ↵
      Benz D, Cadet P, Mantione K, Zhu W, Stefano GB: Tonal nitric oxide and health: a free radical and scavenger of free radicals. Med Sci Monit 8:RA1–RA4, 2002
      OpenUrlPubMed
    32. ↵
      Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, Skatchkov M, Thaiss F, Stahl RAK, Warnholtz A, Meinertz T, Griendling K, Harrison DG, Forstermann U, Munzel T: Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 88:14–22, 2001
      OpenUrlCrossRef
    33. ↵
      Spitaler MM, Graier WF: Vascular targets of redox signalling in diabetes mellitus. Diabetologia 45:476–494, 2002
      OpenUrlCrossRefPubMedWeb of Science
    34. ↵
      Beckman JS, Koppenol WH: Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271:C1424–C1437, 1996
    35. ↵
      Guzik TJ, Mussa S, Gastaldi D, Sadowski J, Ratnatuga C, Pillai R, Channon KM: Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 105:1656–1662, 2002
      OpenUrlAbstract/FREE Full Text
    36. ↵
      Brodsky SV, Gao S, Li H, Goligorsky MS: Hyperglycemic switch from mitochondrial nitric oxide to superoxide production in endothelial cells. Am J Physiol 283:H2130–H2139, 2002
      OpenUrl
    37. ↵
      Cosentino F, Hishikawa K, Katusic ZS, Lüscher TF: High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation 96:25–28, 1997
      OpenUrlAbstract/FREE Full Text
    38. ↵
      Zou MH, Shi C, Cohen RA: Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Invest 109:817–826, 2002
      OpenUrlCrossRefPubMedWeb of Science
    39. ↵
      Ischiropoulos H: Biological tyrosine nitration: a pathophysiological function of nitric oxide and reactive oxygen species. Arch Biochem Biophys 356:1–11, 1998
      OpenUrlCrossRefPubMedWeb of Science
    40. ↵
      Ceriello A, Mercuri F, Quagliaro L, Assaloni R, Motz E, Tonutti L, Taboga C: Detection of nitrotyrosine in the diabetic plasma: evidence of oxidative stress. Diabetologia 44:834–838, 2001
      OpenUrlCrossRefPubMedWeb of Science
    41. ↵
      Pennathur S, Wagner JD, Leeuwenburgh C, Litwak C, Heinecke JW: A hydroxyl radical-like species oxidizes cynomolgus monkey artery wall proteins in early diabetic vascular disease. J Clin Invest 107:853–860, 2001
      OpenUrlCrossRefPubMedWeb of Science
    42. ↵
      Marfella R, Quagliaro L, Nappo F, Ceriello A, Giugliano D: Acute hyperglycemia induces an oxidative stress in healthy subjects (Letter). J Clin Invest 108:635–636, 2001
      OpenUrlCrossRefPubMedWeb of Science
    43. ↵
      Ceriello A, Quagliaro L, Catone B, Pascon R, Piazzola M, Bais B, Marra G, Tonutti L, Taboga C, Motz E: The role of hyperglycemia in nitrotyrosine postprandial generation. Diabetes Care 25:1439–1443, 2002
      OpenUrlAbstract/FREE Full Text
    44. ↵
      Ceriello A, Quagliaro L, D’Amico M, Di Filippo C, Martella R, Nappo F, Berrino L, Rossi F, Giugliano D: Acute hyperglycemia induces nitrotyrosine formation and apoptosis in perfused heart from rat. Diabetes 51:1076–1082, 2002
      OpenUrlAbstract/FREE Full Text
    45. ↵
      Mihm MJ, Jing L, Bauer JA: Nitrotyrosine causes selective vascular endothelial dysfunction and DNA damage. J Cardiovasc Pharmacol 36:182–187, 2000
      OpenUrlCrossRefPubMedWeb of Science
    46. ↵
      Frustaci A, Kajstura J, Cimenti C, Jakoniuk I, Leri A, Maseri A, Nadal-Ginard B, Anversa P: Myocardial cell death in human diabetes. Circ Res 87:1123–1132, 2000
      OpenUrlAbstract/FREE Full Text
    47. ↵
      Kajstura J, Fiordaliso F, Andreoli AM, Li B, Cimenti S, Medow MS, Limana F, Nadal-Ginard B, Leri A, Anversa P: IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II–mediated oxidative stress. Diabetes 50:1414–1424, 2001
      OpenUrlAbstract/FREE Full Text
    48. ↵
      Garcia Soriano F, Virag L, Jagtap P, Szabo E, Mabley JG, Liaudet L, Marton A, Hoyt DG, Murthy KG, Salzman AL, Southan GJ, Szabo C: Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat Med 7:108–113, 2001
      OpenUrlCrossRefPubMedWeb of Science
    49. ↵
      Garcia Soriano F, Viràg L, Szabo C: Diabetic endothelial dysfunction: role of reactive oxygen and nitrogen species production and poly(ADP-ribose) polymerase activation. J Mol Med 79:437–448, 2001
      OpenUrlCrossRefPubMedWeb of Science
    50. ↵
      Park KS, Kim JH, Kim MS, Kim JM, Kim SK, Choi JY, Chung MH, Han B, Kim SY, Lee HK: Effects of insulin and antioxidant on plasma 8-hydroxyguanine and tissue 8-hydroxydeoxyguanosine in streptozotocin-induced diabetic rats. Diabetes 50:2837–2841, 2001
      OpenUrlAbstract/FREE Full Text
    51. ↵
      Kamoshima W, Kitamura Y, Nomura Y, Taniguchi T: Possible involvement of ADP-ribosylation of particular enzymes in cell death induced by nitric oxide-donors in human neuroblastoma cells. Neurochem Int 30:305–311, 1997
      OpenUrlPubMed
    52. ↵
      Garcia Soriano F, Pacher P, Mabley JG, Liaudet L, Szabo E, Szabo C: Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly(ADP-ribose) polymerase activation. Circ Res 89:684–691, 2001
      OpenUrlAbstract/FREE Full Text
    53. ↵
      Pacher P, Liaudet L, Garcia Soriano F, Mabley JG, Szabo E, Szabo C: The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes. Diabetes 51:514–521, 2002
      OpenUrlAbstract/FREE Full Text
    54. ↵
      Cuzzocrea S, Riley DP, Caputi AP, Salvemini D: Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury. Pharmacol Reviews 53:135–159, 2001
      OpenUrlAbstract/FREE Full Text
    55. ↵
      Nassar T, Kadery B, Lotan C, Da’as N, Kleinman Y, Haj-Yehia A: Effects of the superoxide dismutase mimetic compound tempol on endothelial dysfunction in streptozotocin-induced diabetic rats. Eur J Pharmacol 436:111–118, 2002
      OpenUrlCrossRefPubMedWeb of Science
    56. ↵
      Coppey LJ, Gellett JS, Davidson EP, Dunlap JA, Lund DD, Salvemini D, Yorek MA: Effect of M40403 treatment of diabetic rats on endoneurial blood flow, motor nerve conduction velocity and vascular function of epineurial arterioles of the sciatic nerve. Br J Pharmacol 134:21–29, 2001
      OpenUrlCrossRefPubMedWeb of Science
    57. ↵
      Packer L, Valenza M, Serbinova E, Starke-Reed P, Frost K, Kagan V: Free radical scavenging is involved in the protective affect of L-propionyl-carnitine against ischemia-reperfusion injury of the heart. Arch Biochem Biophys 288:533–537, 1991
      OpenUrlCrossRefPubMedWeb of Science
    58. ↵
      Broderick TL, Haloftis G, Paulson DJ: L-propionyl-carnitine enhancement of substrate oxidation and mitochondrial respiration in the diabetic rat heart. J Mol Cell Cardiol 2:331–340, 1996
    59. Vanella A, Russo A, Acquaviva R, Campisi A, Di Giacomo Sorrenti V, Barcellona ML: L-propionyl-carnitine as superoxide scavenger, antioxidant, and DNA cleavage protector. Cell Biol Toxicol 16:99–104, 2000
      OpenUrlCrossRefPubMedWeb of Science
    60. ↵
      Felix C, Gillis M, Driedzic WR, Paulson DJ, Broderick TL: Effects of propionyl-L-carnitine on isolated mitochondrial function in the reperfused diabetic rat heart. Diabetes Res Clin Pract 53:17–24, 2001
      OpenUrlCrossRefPubMed
    61. ↵
      Cotter MA, Cameron NE, Keegan A, Dines KC: Effects of acetyl and propionyl-L-carnitine on peripheral nerve function and vascular supply in experimental diabetes. Metabolism 44:1209–1214, 1995
      OpenUrlCrossRefPubMedWeb of Science
    62. ↵
      Packer L, Kraemer K, Rimbach G: Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition 17:888–895, 2001
      OpenUrlCrossRefPubMedWeb of Science
    63. ↵
      Coppey LJ, Gellett JS, Davidson EP, Dunlap JA, Lund DD, Yorek MA: Effect of antioxidant treatment of streptozotocin-induced diabetic rats on endoneurial blood flow, motor nerve conduction velocity, and vascular reactivity of epineurial arterioles of the sciatic nerve. Diabetes 50:1927–1937, 2001
      OpenUrlAbstract/FREE Full Text
    64. ↵
      Hetizer T, Finckh B, Albers S, Krohn K, Kohlschutter A, Meinertz T: Beneficial effects of alpha-lipoic acid and ascorbic acid on endothelium-dependent, nitric oxide-mediated vasodilation in diabetic patients:relation to parameters of oxidative stress. Free Radic Biol Med 31:53–61, 2001
      OpenUrlCrossRefPubMedWeb of Science
    65. ↵
      Beckman JA, Goldfine AB, Gordon MB, Garrett LA, Creager MA: Inhibition of protein kinase Cbeta prevents impairedendothelium-dependent vasodilationcaused by hyperglycemia in humans. Circ Res 90:107–111, 2002
      OpenUrlAbstract/FREE Full Text
    66. ↵
      Szabo C, Mabley JG, Moeller SM, Shimanovich R, Pacher Virag L, Soriano FG, Van Duzer JH, Williams W, Salzman, Groves JT: Part I: Pathogenetic role of peroxynitrite in the development of diabetes and diabetic vascular complications: studies with FP15, a novel potent peroxynitrite decomposition catalyst. Mol Med 8:571–580, 2002
      OpenUrlPubMedWeb of Science
    67. ↵
      Kowluru RA: Diabetes-induced elevations in retinal oxidative stress, protein kinase C and nitric oxide are interrelated. Acta Diabetol 38:179–185, 2001
      OpenUrlCrossRefPubMedWeb of Science
    68. ↵
      Zingarelli B, Salzman AL, Szabo C: Genetic disruption of poly (ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury. Circ Res 13:85–94, 1998
    69. ↵
      Szabo C, Virag L, Cuzzocrea S, Scott GS, Hake P, O’Connor MP, Zingarelli B, Salzman A, Kun E: Protection against peroxynitrite-induced fibroblast injury and arthritis development by inhibition of poly(ADP-ribose) synthase. Proc Natl Acad Sci U S A 95:3867–3872, 1998
      OpenUrlAbstract/FREE Full Text
    70. ↵
      Oliver FJ, Menissier-de Murcia J, Nacci C, Decker P, Andriantsitohaina R, Muller S, de la Rubia G, Stoclet JC, de Murcia G: Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP-ribose) polymerase-1 deficient mice. EMBO J 18:4446–4454, 1999
      OpenUrlAbstract
    71. ↵
      Virag L, Salzman AL, Szabo C: Poly(ADP-ribose) synthetase activation mediates mitochondrial injury during oxidant-induced cell death. J Immunol 161:3753–3759, 1998
      OpenUrlAbstract/FREE Full Text
    72. ↵
      Li M, Pascual G, Glass CK: Peroxisome proliferator-activated receptor gamma-dependent repression of the inducible nitric oxide synthase gene. Mol Cell Biol 20:4699–4707, 2000
      OpenUrlAbstract/FREE Full Text
    73. ↵
      Takemoto M, Liao JK: Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arterioscler Thromb Vasc Biol 21:1712–1719, 2001
      OpenUrlAbstract/FREE Full Text
    74. ↵
      Varin R, Mulder P, Tamion F, Richard V, Henry JP, Lallemand F, Lerebours G, Thuillez C: Improvement of endothelial function by chronic angiotensin-converting enzyme inhibition in heart failure: role of nitric oxide, prostanoids, oxidant stress, and bradykinin. Circulation 102:351–356, 2000
      OpenUrlAbstract/FREE Full Text
    75. ↵
      Zhang H, Schmeisser A, Garlichs CD, Plotze K, Damme U, Mugge A, Daniel WG:Angiotensin II-induced superoxide anion generation in human vascular endothelial cells: role of membrane-bound NADH-/NADPH-oxidases. Cardiovasc Res 44:215–222, 1999
      OpenUrlAbstract/FREE Full Text
    76. ↵
      Wassmann S, Baumer AT, Strehlow K, van Eickels M, Grohe C, Ahlbory K, Ro-sen R, Bohm M, Nickenig G: Endothelial dysfunction and oxidative stress during estrogen deficiency in spontaneously hypertensive rats. Circulation 103:435–441, 2001
      OpenUrlAbstract/FREE Full Text
    77. ↵
      Shiojiri T, Wada K, Nakajima A, Katayama K, Shibuya A, Kudo C, Kadowaki T, Mayumi T, Yura Y, Kamisaki Y: PPARgamma ligands inhibit nitrotyrosine formation and inflammatory mediator expressions in adjuvant-induced rheumatoid arthritis mice. Eur J Pharmacol 448:231–238, 2002
      OpenUrlCrossRefPubMedWeb of Science
    78. ↵
      Dobrucki LW, Kalinowski L, Dobrucki IT, Malinski T: Statin-stimulated nitric oxide release from endothelium. Med Sci Monit 7:622–627, 2001
      OpenUrlPubMed
    79. ↵
      Christ M, Bauersachs J, Liebetrau C, Heck M, Gunther A, Wehling M: Glucose increases endothelial-dependent superoxide formation in coronary arteries by NAD(P)H oxidase activation: attenuation by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin. Diabetes 51:2648–2652, 2002
      OpenUrlAbstract/FREE Full Text
    80. ↵
      Tsunekawa T, Hayashi T, Kano H, Sumi D, Matsui-Hirai H, Thakur NK, Egashira K, Iguchi A: Cerivastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, improves endothelial function in elderly diabetic patients within 3 days. Circulation 104:376–379, 2001
      OpenUrlAbstract/FREE Full Text
    81. ↵
      Ceriello A, Taboga C, Tonutti L, Quagliaro L, Piconi L, Bais B, Da Ros R, Motz E: Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment. Circulation 106:1211–1218, 2002
      OpenUrlAbstract/FREE Full Text
    82. ↵
      Sen K, Misra A, Kumar A, Pandey RM: Simvastatin retards progression of retinopathy in diabetic patients with hypercholesterolemia. Diabetes Res Clin Pract 56:1–11, 2002
      OpenUrlPubMedWeb of Science
    83. ↵
      Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360:7–22, 2002
      OpenUrlCrossRefPubMedWeb of Science
    84. ↵
      Takemoto M, Node K, Nakagami H, Liao Y, Grimm M, Takemoto Y, Kitakaze M, Liao JK: Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest 108:1429–1437, 2001
      OpenUrlCrossRefPubMedWeb of Science
    85. ↵
      Münzel T, Keaney JF: Are ACE inhibitors a “magic bullet” against oxidative stress? Circulation 104:1571–1574, 2001
      OpenUrlFREE Full Text
    86. ↵
      Nickenig G, Harrison DG: The AT1-type angiotensin receptor in oxidative stress and atherogenesis. Part I: oxidative stress and atherogenesis. Circulation 105:393–396, 2002
      OpenUrlFREE Full Text
    87. ↵
      Gabriely I, Yang XM, Cases JA, Ma XH, Rossetti L, Barzilai N: Hyperglycemia modulates angiotensinogen gene expression. Am J Physiol 281:R795–R802, 2001
      OpenUrl
    88. ↵
      Chaturvedi N, Sjolie AK, Stephenson JM, Abrahamian H, Keipes M, Castellarin A, Rogulja-Pepeonik Z, Fuller JH: Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. Lancet 351:28–31, 1998
      OpenUrlCrossRefPubMedWeb of Science
    89. ↵
      Heart Outcomes Prevention Evaluation Study Investigators: Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 355:253–259, 2000
      OpenUrlCrossRefPubMedWeb of Science
    90. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I, Collaborative Study Group:Renoprotective effect of the angiotensin receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851–860, 2001
      OpenUrlCrossRefPubMedWeb of Science
    91. ↵
      Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S, RENAAL Study Investigators: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861–869, 2001
      OpenUrlCrossRefPubMedWeb of Science
    92. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P: Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria Study Group. N Engl J Med 345:870–878, 2001
      OpenUrlCrossRefPubMedWeb of Science
    93. ↵
      Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristiansson K, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wedel H, Aurup P, Edelman J, Snapinn S, the LIFE Study Group: Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 359:1004–1010, 2002
      OpenUrlCrossRefPubMedWeb of Science
    94. ↵
      Ceriello A, Motz E: Angiotensin-receptor blockers, type 2 diabetes, and renoprotection (Letter). N Engl J Med 346:705–707, 2002
      OpenUrlCrossRefPubMed
    95. ↵
      Onozato ML, Tojo A, Goto A, Fujita T, Wilcox CS: Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB. Kidney Int 61:186–194, 2002
      OpenUrlCrossRefPubMedWeb of Science
    96. ↵
      Ceriello A, Morocutti A, Mercuri L, Quagliaro L, Moro M, Damante G, Viberti GC: Defective intracellular antioxidant enzyme production in type 1 diabetic patients with nephropathy. Diabetes 49:2170–2177, 2000
      OpenUrlAbstract/FREE Full Text
    Back to top
    View Selected Citations (0)
    Print
    Download PDF
    Article Alerts
    Email Article
    Citation Tools
    Add to Selected Citations

    New Insights on Oxidative Stress and Diabetic Complications May Lead to a “Causal” Antioxidant Therapy
    Antonio Ceriello
    Diabetes Care May 2003, 26 (5) 1589-1596; DOI: 10.2337/diacare.26.5.1589
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

    Jump to section