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Diabetic complications: from oxidative stress to inflammatorycardiovascular disorders

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Antonio CERIELLO, MD, PhDInsititut dInvestigacions Biomdiques August Pii Sunyer (IDIBAPS)Barcelona, SPAIN

by A. Ceriello, SpainEvidence implicates hyperglycemia-derived oxygen free radicals as mediators of diabetic complications.However, intervention studies with classic antioxidants, such as vitamin E, have failed to demonstrateany beneficial effect. Recent studies demonstrate that a single hyperglycemiainduced process ofsuperoxide overproduction by the mitochondrial electron- transport chain seems to be the first and keyevent in the activation of all the other pathways involved in the pathogenesis of diabetic complications.These include increased polyol pathway flux, advanced glycation end product formation, andhexosamine pathway flux, and activation of protein kinase C. These processes result in acuteendothelial dysfunction in diabetic blood vessels that, convincingly, also contributes to thedevelopment of diabetic complications. While waiting for more focused tools, we will have to use otheroptions, particularly the oral hypoglycemic agent gliclazide, which reduces glycemia while exerting anantioxidant effect.

Medicographia. 2011;33:29-34 (see French abstract on page 34)

In the last few decades the occurrence of type 2 diabetes mellitus has rapidly increased internationally, and it

has been estimated that the number of diabetic patients will more than double within 15 years.1 As type 2diabetes is mainly characterized by the development of increased cardiovascular disease (CVD) morbidity and

mortality, it has been suggested that diabetes could be considered a CVD.1 However, diabetes is also

characterized by dramatic microangiopathic complications, such as retinopathy, nephropathy, and neuropathy.1

Recent evidence suggests that glucose overload may damage cells through oxidative stress.2 This is currentlythe basis of the unifying hypothesis, in which hyperglycemia- induced oxidative stress may account for the

pathogenesis of all diabetic complications.2

The central role of oxidative stress in the pathogenesis of diabetic complicationsIt has been suggested that four key biochemical changes induced by hyperglycemia( i) increased flux throughthe polyol pathway (in which glucose is reduced to sorbitol, lowering levels of both reduced nicotinamideadenine dinucleotide phosphate [NADPH] and reduced glutathione); (ii) increased formation of advancedglycation end products (AGEs); (iii) activation of protein kinase C (PKC) (with effects ranging from vascularocclusion to expression of proinflammatory genes); and (iv) increased shunting of excess glucose through thehexosamine pathway (mediating increased transcription of genes for inflammatory cytokines) are all activated

by a common mechanism: overproduction of superoxide radicals.2

Excess plasma glucose drives excess production of electron donors (mainly NADH/H+) from the tricarboxylicacid cycle; in turn, this surfeit results in the transfer of single electrons (instead of the usual electron pairs) tooxygen, producing superoxide radicals and other reactive oxygen species (instead of the usual end product,H2O). The superoxide anion itself inhibits the key glycolytic enzyme glyceraldehyde-3-phosphate

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dehydrogenase, and consequently, glucose and glycolytic intermediates spill into the polyol and hexosaminepathways, as well as additional pathways that culminate in PKC activation and intracellular AGE formation(Figure 1).

Figure 1. Potential mechanism by which hyperglycemia-induced mitochondrial superoxide overproductionactivates four pathways of hyperglycemic damage.

Excess superoxide partially inhibits the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), thereby divertingupstream metabolites from glycolysis into pathways of glucose overutilization. This results inincreased flux of dihydroxyacetonephosphate (DHAP) to diacylglycerol (DAG), an activator of protein kinase C (PKC), and of triose phosphates to methylglyoxal, themain intracellular advanced glycation end product (AGE) precursor. Increased flux of fructose-6-phosphate to uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) increases modification of proteins by O-linked N-acetylglucosamine (GlcNAc) and increasedglucose flux through the polyol pathway consumes nicotinamide dinucleotide phosphate (NADPH) and depletes glutathione.Abbreviations: AGE, advanced glycation end product; DAG, diacylglycerol; DHAP, dihydroxyacetone phosphate; GAPDH,glyceraldehyde-3-phosphate dehydrogenase; GFAT, glutamine: fructose-6-phosphate aminotransferase; Gln, glutamine; Glu,glutamate; NAD(P), nicotinamide dinucleotide (phosphate); P, phosphate; PKC, protein kinase C; UDP-GlcNAc, uridine diphosphate-N-acetylglucosamine.

However, superoxide overproduction is also accompanied by increased nitric oxide (NO) generation, due to the

uncoupled state of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS),3 a

phenomenon favoring the formation of the strong oxidant peroxynitrite, which in turn damages DNA.3 DNAdamage is an obligatory stimulus for the activation of the nuclear enzyme poly(adenosine diphosphate [ADP]-

ribose) polymerase (PARP).4 PARP activation in turn depletes the intracellular concentration of its substrateNAD+, slowing the rate of glycolysis, electron transport, and adenosine triphosphate formation, and producing

ADP-ribosylation of the glyceraldehyde-3-phosphate dehydrogenase.4 These processes result in endothelialdysfunction (Figure 2).

These pathways have been confirmed by at least one study on the perfusion for 2 hours of isolated rat heartswith solutions of 11.1 mmol/L glucose, 33.3 mmol/L glucose, or 33.1 mmol/L glucose plus glutathione. In thehearts perfused with high glucose concentrations, coronary perfusion pressure increased significantly; there wasa 40% increase in NO levels and an upregulation of iNOS, but a 300% increase in the production of superoxide

species; nitrotyrosine and cardiac cell apoptosis also increased significantly.5 All these effects were substantially

prevented by glutathione, which effectively removes reactive oxygen species, including peroxynitrite.5
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However, more recently, evidence from in vitro studies suggests that marked fluctuations in glucose levels, asseen in diabetic patients, have consequences that are even more deleterious than those of continuous highglucose levels, and that oxidative stress is convincingly involved. For example, in cultures of human umbilicalvein endothelial cells, levels of nitrotyrosine (a marker of oxidative stress), intercellular adhesion molecule 1(ICAM-1), vascular cellular adhesion molecule 1, E-selectin, interleukin 6 (IL-6), and 8-hydroxydeoxyguanosine(a marker of oxidative damage of DNA) all increased after incubation in a medium containing 20 mmol glucosecompared with incubation in a 5 mmol glucose medium, but alternating the two media caused even greater

increases.6-8 In addition, intermittent hyperglycemic conditions increased rates of cellular apoptosis, andstimulated the expression of caspase 3 (a proapoptotic protein), but decreased Bcl2 (an antiapoptotic protein).These effects were abolished by adding superoxide dismutase (SOD), which scavenges free radicals, orinhibitors of the mitochondrial electron-transport chain, suggesting that overproduction of free radicals in the

mitochondria mediates the apoptotic effects of increased glucose concentrations and fluctuations.9

Figure 2. Intracellular hyperglycemia induces overproduction of superoxideat the mitochondrial level.

Overproduction of superoxide is the first and key event in the activation of all other pathways involved in the pathogenesis of diabeticcomplications, such as polyol pathway flux, increased AGE formation, and increased hexosamine pathway flux. Gliclazide maycontribute to reducethe risk for complications because it shows, simultaneously, a glycemia-lowering effect andantioxidant action.Abbreviation: AGE, advanced glycation end product.

Oxidative stress in diabetes: in vivo evidenceThe response-to-injury hypothesis of atherosclerosis states that the initial damage affects the arterialendothelium, in terms of endothelial dysfunction. Notably, todays evidence confirms that endothelial dysfunction,

associated with oxidative stress, predicts CVD.10 Indeed, studies show that high glucose concentrations induceendothelial dysfunction in diabetic as well as normal subjects.3 The role of free radical generation in producinghyperglycemia-dependent endothelial dysfunction is also suggested by studies showing that the acute effects of

hyperglycemia are counterbalanced by antioxidants.11,12

Numerous studies have also noted the effect of hyperglycemia- induced oxidative stress on inflammation. Astudy in which insulin secretion was blocked, and subjects were maintained at plasma glucose levels of 15mmol/L for 5 hours, found that levels of IL-6, tumor necrosis factor ! (TNF-! ), and the proinflammatory cytokine

IL-18 rose significantly and returned to baseline within 3 hours in the control group.13 However, patients withimpaired glucose tolerance had significantly higher TNF-! and IL-6 levels at baseline, and cytokine levels

reached substantially higher peaks and stayed elevated for considerably longer than in the control subjects.13

All changes in plasma cytokine levels were abolished by infusion of the antioxidant glutathione, consistent withthe hypothesis that hyperglycemia, especially in the form of spikes, is linked to immune activation via an

oxidative mechanism.13 Another study matching diabetic patients and healthy controls found increases incirculating ICAM-1 in both groups during an oral glucose tolerance test (OGTT); these increases were also

abolished by glutathione.14 Glutathione administered without a glucose load decreased circulating ICAM-1levels in the diabetic group, but not in the control group, again suggesting that hyperglycemia increases ICAM-1

levels via an oxidative mechanism.14

More direct evidence for the central role of oxidative stress is derived from clinical studies that measuredmarkers. For example, among 20 diabetic patients, either a low-carbohydrate or a high-carbohydrate mealincreased levels of plasma glucose, insulin, triglycerides, and malondialdehyde (a marker for lipid peroxidation),and decreased nonsterified fatty acids and the total radical-trapping antioxidant parameter (TRAP), a global

measure of antioxidant capacity in the plasma.15 However, the high-carbohydrate meal (designed to producehigher postprandial glucose levels) increased glucose and malondialdehyde more, decreased TRAP significantly

more, and rendered low-density lipoprotein more susceptible to oxidation than the low-carbohydrate meal.15 Thedecrease in TRAP highlights the fact that oxidative stress may also ensue from the failure of normal antioxidantdefenses: the same group found that during the OGTT, TRAP was reduced from baseline in both well-controlled,nonsmoking diabetic subjects and healthy age-matched subjects, as were levels of protein-bound thiol (-SH)

groups, vitamins C and E, and uric acid.15

As aforementioned, a superoxide anion combines with NO to produce a peroxynitrite ion; this species is capableof peroxidating lipoproteins and damaging DNA, which then activates the nuclear enzyme poly(ADP-ribose)polymerase, depleting intracellular NAD+ and (among other effects) causing acute endothelial dysfunction.3 Inone study involving 12 healthy subjects, infusion of L-arginine (to supply NO) reversed hyperglycemia-inducedincreases in systolic and diastolic blood pressure, heart rate, plasma catecholamine levels, ADPinduced platelet
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aggregation, and blood viscosity.16 However, infusing NG-monomethyl-L-arginine, which inhibits the synthesis ofendogenous NO, produced effects that were very similar to those produced by hyperglycemia. Thus, decreasedNO availability may be one mechanism by which hyperglycemia induces hemodynamic and rheological changes

in blood.16 It has been shown, however, that unlike normal controls, patients with diabetes have significantlyelevated fasting nitrotyrosine levels, as well as postprandial increases after eating a standard mixed meal; theeffect was significantly normalized by insulin aspart (which targets postprandial glucose), but not by regular

insulin.17

Finally, consistent with the recent emerging role of glucose fluctuations, a new study confirms that in type 2

diabetes, diurnal glucose fluctuations are the most powerful predictors of oxidative stress generation.18

New perspectives: oxidative stress and hyperglycemia- induced metabolic memoryLarge randomized studies have established that early intensive glycemic control reduces the risk of diabetic

complications, both micro- and macrovascular.19 Moreover, epidemiological and prospective data support the

idea that early metabolic control has a long-term influence on clinical outcomes.19 This phenomenon has

recently been defined as metabolic memory. 19 Potential mechanisms for propagating this memory are thenonenzymatic glycation of cellular proteins and lipids and an excess of cellular reactive oxygen and nitrogenspecies, in particular those that originated at the level of glycated mitochondrial proteins, perhaps acting in

concert with one another to maintain stress signaling.19

_ Experimental evidence supporting the concept of metabolic memory and its possible link withoxidative stressSeveral years ago, there were preliminary reports of the possibility that hyperglycemic memory forhyperproduction of fibronectin and collagen in endothelial cells persists after glucose normalization.20 Using thesame design, ie, 14 days in high concentration glucose followed by 7 days of culture in normal concentrationglucose, it has been shown that the overproduction of free radicals in endothelial cells persists afternormalization of glucose concentration, and this is accompanied by a prolongation of the induction of PKC-" ,

NAD(P)H oxidase, Bax, collagen, and fibronectin, in addition to 3-nitrotyrosine.21 This suggests that oxidativestress may be involved in the metabolic memory effect.

The effect of reinstitution of good glucose control on hyperglycemia- induced increased oxidative stress andnitrative stress has also been previously evaluated in the retina of rats maintained with poor glucose control

before initiation of good control.22 In diabetic rats, 2 or 6 months of poor control (glycated hemoglobin [HbA1c]

>11.0%) was followed by 7months of good control (HbA1c 80% compared with normal rats or rats with good glucose control for

the duration.22 In a similar study, caspase 3 activity in diabetic rats with poor control for 13 months was higher

than in normal rats.23 Reinstitution of good glycemic control after 2 months of poor control partially normalizedthe hyperglycemia-induced activation of caspase 3 (to 140% of normal values), while reinstitution of good controlafter 6 months of poor control had no significant effect on the activation of caspase 3. In the same study, nuclearfactor-#B (NF#B) activity was 2.5-fold higher in diabetic rats with poor glucose control than in normal rats.

Reinstitution of good control after 2 months of poor control partially reversed this increase, but good control after6months of poor control had no effect. Initiation of good control soon after induction of diabetes in rats prevented

activation of retinal caspase 3 and NF#B.23 Similar results are available for the kidney. Diabetic rats weremaintained with good glycemic control (HbA1c = 5%) soon, or 6 months, after induction of diabetes, and were

sacrificed after 13 months.24 For rats in which good control was initiated soon after the induction of diabetes,oxidative stress (as measured by levels of lipid peroxides, 8- hydroxy-2-deoxyguanosine, and reducedglutathione) and NO levels in urine and renal cortex were no different from those observed in normal controlrats, but when the reinstitution of good control was delayed for 6 months after induction of diabetes, oxidative

stress and NO remained elevated in both urine and renal cortex.24 These data suggest that hyperglycemia-induced oxidative stress and NO, as well as activation of apoptosis and NF#B, can be prevented if goodglycemic control is initiated very early, but are not easily reversed if poor control is maintained for longerdurations. Therefore, these findings suggest the persistence of hyperglycemia-induced damage in such organs,even after glycemia normalization.

However, if excess reactive species are central to the development of hyperglycemia-related diabeticcomplications, could this excess explain the persistence of the risk of complications even when hyperglycemia isreduced or normalized?

The above reported studies suggest that long-lasting effects of hyperglycemia result in increased oxidative

stress, while inhibiting oxidative stress has preliminarily been shown to reverse these effects.21 Mitochondrialoverproduction of superoxide in hyperglycemia has been suggested as the unifying hypothesis for the

development of diabetic complications.2 Therefore, it is reasonable to assume that mitochondria are alsoimportant players in propagating metabolic memory. Chronic hyperglycemia is thought to alter mitochondrial



function through glycation of mitochondrial proteins.25 Levels of methylglyoxal, a highly-reactive alpha-dicarbonil

byproduct of glycolysis, increase in diabetes.26 Methylglyoxal readily reacts with arginine, lysine, and sulfhydryl

groups of proteins,26 in addition to nucleic acids,26 inducing the formation of a variety of structurally identified

AGEs in both target cells and plasma.26 Methylglyoxal has an inhibitory effect on mitochondrial respiration and

methylglyoxal-induced modifications are targeted to specific mitochondrial proteins.26 These premises areimportant because a recent study has described, for the first time, a direct relationship between formation ofintracellular AGEs on mitochondrial proteins and the decline in mitochondrial function and excess formation of

reactive species.25 Mitochondrial respiratory chain proteins that underwent glycation were prone to producemore superoxide, independent of the level of hyperglycemia. The glycation of mitochondrial proteins may be acontributing explanation for the phenomenon of metabolic memory. The glycation of mitochondrial proteins thatoverproduce free radicals, independent of actual glycemia, can also lead to a catastrophic cycle of mitochondrialDNA damage, as well as functional decline, cellular injury, further oxygen radical generation, and the continued

activation of pathways involved in the pathogenesis of diabetic complications.27 Furthermore, mitochondrialproteins become damaged or posttranslationally modified as a consequence of a major change in a cells redox

status.27 This may affect mitochondrially destined proteins that are imported into the mitochondrial outer

membrane, inner membrane, or matrix space via specific import machinery transport components.27

In other words, it may be postulated that the cascade of events in metabolic memory is the same as that

proposed by Brownlee2; the source of superoxide is still the mitochondria, but, in addition, the production ofreactive species is unrelated to the presence of hyperglycemia; it depends on the level of glycation ofmitochondrial proteins.

How could oxidative stress be reduced with pharmacological intervention?Antioxidant therapy may be of great value in diabetic patients. However, the classic antioxidants, like vitamins Eand C, do not seem to be helpful. New insights into the mechanisms leading to the generation of oxidative stressindiabetes are now available. Presumably, these findings will lead to the discovery and evaluation of newantioxidant molecules, such as superoxide dismutase (SOD) and catalase mimetics, that may hopefully inhibitthe mechanism leading to diabetic complications at an early stage. While waiting for these specific newcompounds, it is reasonable to suggest that substances already available, such as statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, should be used for their effectiveness ascausal and preventive antioxidants (for an up-to-date review, see reference 28).

The availability of compounds that simultaneously decrease hyperglycemia, restore insulin secretion, and inhibitoxidative stress produced by high glucose is an interesting therapeutic prospect for the prevention of vascularcomplications of diabetes. Gliclazide, an oral hypoglycemic agent that belongs to the sulfonylurea class, hasbeen demonstrated to be effective and safe in numerous clinical trials and in clinical practice. Several studieshave demonstrated, both in vitro and in vivo, that gliclazide shows antioxidative potential, independent of its

hyperglycemia-lowering effect.29 Gliclazide is a general free radical scavenger in vitroin contrast withglibenclamide, which fails to produce any effect below a concentration of 25 g/mL (gliclazide induced strong

concentration-dependent inhibition of free radical generation at therapeutic concentrations).29 Jennings et alconfirmed these effects of gliclazide on oxidative stress in clinical conditions. They found that gliclazide-treatedtype 2 patients with retinopathy had a highly significant and sustained decrease in peroxidized lipids and an

increase in erythrocyte SOD activity.30 Interestingly, glucose control did not differ between therapeutic groups,which supports the hypothesis that the effect results from the molecule gliclazide itself, rather than from ageneral improvement in metabolic control.

The antioxidative property of gliclazide convincingly impacts the vascular system in diabetes. Fava et al studied

both the antioxidative potential of gliclazide in vivo and its effect on vascular reactivity.31 In this experiment,blood glucose control remained unchanged from baseline and similar in both groups, as patients were alreadybeing treated, which excludes any glucose-related bias effect. Thirty type 2 diabetic patients receivedglibenclamide or gliclazide in a 12-week, randomized, observer-blinded, parallel study. Blood pressureresponses to an intravenous bolus of L-arginine were measured pre- and posttreatment. Gliclazide, but notglibenclamide, significantly reduced systolic and diastolic blood pressure in response to intravenous L-arginine.This provided the first demonstration that gliclazide significantly enhances NO-mediated vasodilatation and thusimproves vascular reactivity in type 2 diabetic patients.

Finally, and this could be of great relevance, in order to avoid the development of diabetic complications, it has

been shown that gliclazide can block the metabolic memory effect. 32 In my opinion, all these effects33 maycontribute to explaining why gliclazide prevented nephropathy in the Action in Diabetes and Vascular disease:

PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE).34 Conclusions

Our understanding of the molecular pathways activated inside the cell by hyperglycemia is growing, andevidence about the involvement of oxidative stress in the development of diabetic complications is becomingabundant, making the unifying hypothesis more persuasive every day. Against this background, the finding ofunexpected protective effects of drugs intended for different uses or different pathologies has given us anintriguing opportunity to elucidate their underlying mechanisms, to tune up these weapons to be more andmore effective, and to confirm the hypothesis formulated. These goals are becoming increasingly important dueto the massive spread in diabetic pathology that is expected to occur in the coming years. _



References1. Chaturvedi N. The burden of diabetes and its complications: trends and implications for intervention. DiabetesRes Clin Pract. 2007;76(suppl 1):S3-S12.2. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813-820.3. Ceriello A. New insights on oxidative stress and diabetic complications may lead to a causal antioxidanttherapy. Diabetes Care. 2003;26:1589-1596.4. Garcia Soriano F, Virag L, Jagtap P, et al. Diabetic endothelial dysfunction: the role of poly(ADP-ribose)polymerase activation. Nature Med. 2001;7:108-113.5. Ceriello A, Quagliaro L, DAmico M, et al. Acute hyperglycemia induces nitrotyrosine formation and apoptosisin perfused heart from rat. Diabetes. 2002; 51:1076-1082.6. Piconi L, Quagliaro L, Da Ros R, et al. Intermittent high glucose enhances ICAM-1, VCAM-1, E-selectin andinterleukin-6 expression in human umbilical endothelial cells in culture: the role of poly(ADP-ribose) polymerase.J Thromb Haemost. 2004;2:1453-1459.7. Quagliaro L, Piconi L, Assaloni R, Martinelli L, Motz E, Ceriello A. Intermittent high glucose enhancesapoptosis related to oxidative stress in human umbilical vein endothelial cells: the role of PKC and NAD(P)H-oxidase activation. Diabetes. 2003;52:2795-2804.8. Quagliaro L, Piconi L, Assaloni R, et al. Intermittent high glucose enhances ICAM-1, VCAM-1 and E-selectinexpression in human umbilical vein endothelial cells in culture: the distinct role of protein kinase C andmitochondrial superoxide production. Atherosclerosis. 2005;183:259-267.9. Quagliaro L, Piconi L, Assaloni R, et al. Constant and intermittent high glucose enhances endothelial cellapoptosis through mitochondrial superoxide overproduction. Diabetes Metab Res Rev. 2006;22:198-203.10. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk ofcardiovascular events in patients with coronary artery disease. Circulation. 2001;104:2673-2678.11. Marfella R, Verrazzo G, Acampora R, et al. Glutathione reverses systemic hemodynamic changes by acutehyperglycemia in healthy subjects. Am J Physiol. 1995;268:E1167-E1173.12. 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 Investig. 1996;97:22-28.13. Esposito K, Nappo F, Marfella R, et al. Inflammatory cytokine concentrations are acutely increased byhyperglycemia in humans: role of oxidative stress. Circulation. 2002;106:2067-2072.14. Ceriello A, Falleti E, Motz E, et al. Hyperglycemia-induced circulating ICAM-1 increase in diabetes mellitus:the possible role of oxidative stress. Horm Metab Res. 1998;30:146-149.15. Ceriello A, Bortolotti N, Motz E, et al. Meal-induced oxidative stress and lowdensity lipoprotein oxidation indiabetes: the possible role of hyperglycemia. Metabolism. 1999;48:1503-1508.16. Giugliano D, Marfella R, Coppola L, et al. Vascular effects of acute hyperglycemia in humans are reversedby L-arginine. Evidence for reduced availability of nitric oxide during hyperglycemia. Circulation. 1997;95:1783-1790.17. Ceriello A, Quagliaro L, Catone B, et al. Role of hyperglycemia in nitrotyrosine postprandial generation.Diabetes Care. 2002;25:1439-1443.18. Ceriello A, Esposito K, Piconi L, et al. Oscillating glucose is more deleterious to endothelial function andoxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes. 2008;57:1349-1354.19. Ceriello A, Ihnat MA, Thorpe JE. The metabolic memory: is more than just tight glucose control necessaryto prevent diabetic complications? J Clin Endocrinol Metab. 2009;94:410-415.20. Roy S, Sala R, Cagliero E, Lorenzi M. Overexpression of fibronectin induced by diabetes or high glucose:phenomenon with a memory. Proc Natl Acad Sci U S A. 1990;87:404-408.21. Ihnat MA, Thorpe JE, Kamat CD, et al. Reactive oxygen species mediate a cellular memory of high glucosestress signalling. Diabetologia. 2007;50:1523-1531.22. Kowluru RA. Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress indiabetic rats. Diabetes. 2003;52:818-823.23. Kowluru RA, Chakrabarti S, Chen S. Re-institution of good metabolic control in diabetic rats and activation ofcaspase-3 and nuclear transcriptional factor (NF-kappaB) in the retina. Acta Diabetol. 2004;41:194-199.24. Kowluru RA, Abbas SN, Odenbach S. Reversal of hyperglycemia and diabetic nephropathy: effect ofreinstitution of good metabolic control on oxidative stress in the kidney of diabetic rats. J DiabetesComplications. 2004;18:282-288.25. RoscaMG,Mustata TG, KinterMT, et al. Glycation ofmitochondrial proteins from diabetic rat kidney isassociated with excess superoxide formation. Am J Physiol Renal Physiol. 2005;289:F420-F430.26. Yan SF, Ramasamy R, Schmidt AM. Mechanisms of disease: advanced glycation end-products and theirreceptor in inflammation and diabetes complications. Nat Clin Pract Endocrinol Metab. 2008;4:285-293.27. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial ROS-induced ROS release: an update and review.Biochim Biophys Acta. 2006;1757:509-517.28. Ceriello A, Testa R. Antioxidant anti-inflammatory treatment in type 2 diabetes. Diabetes Care.2009;32(suppl 2):S232-S236.29. Jennings PE, Belch JJF. Free radical scavenging activity of sulfonylureas: a clinical assessment of the effectof gliclazide. Metabolism. 2000;49(S1):23-26.30. Jennings PE, Scott NA, Saniabadi AR, Belch JJF. Effects of gliclazide on platelet reactivity and free radicalsin type II diabetic patients: clinical assessment. Metabolism. 1992;41:36-39.31. Fava D, Cassone-Faldetta M, Laurenti O, De Luca O, Ghiselli A, De Mattia G. Gliclazide improves anti-oxidant status and nitric oxide-mediated vasodilation in type 2 diabetes. Diabet Med. 2002;19:752-757.32. Corgnali M, Piconi L, Ihnat M, Ceriello A. Evaluation of gliclazide ability to attenuate the hyperglycaemicmemory induced by high glucose in isolated human endothelial cells. Diabetes Metab Res Rev. 2008;24:301-309.33. Ceriello A. Effects of gliclazide beyond metabolic control. Metabolism. 2006; 55(5 suppl 1):S10-S15.



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34. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Intensive blood glucose controland vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.

Keywords : hyperglycemia; free radicals; antioxidants; superoxide; pathogenesis; polyol; advanced glycosylationend product; hexosamine pathway
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