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Diabetes, Oxidative Stress, and Antioxidants

J BIOCHEM MOLECULAR TOXICOLOGY

Volume17,Number1,2003

Diabetes,Oxidative Stress,and Antioxidants:A Review A.C.Maritim,1R.A.Sanders,2and J.B.Watkins III2

1Moi University,College of Health Sciences,Eldoret,Kenya

2Medical Sciences Program,Indiana University School of Medicine,Bloomington,IN,USA;E-mail:watkins@https://www.wendangku.net/doc/bc10574268.html,

Received28September2002;revised8November2002;accepted12November2002

ABSTRACT:Increasing evidence in both experimen-tal and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of both types of diabetes mellitus.Free radicals are formed dispropor-tionately in diabetes by glucose oxidation,nonenzy-matic glycation of proteins,and the subsequent oxida-tive degradation of glycated proteins.Abnormally high levels of free radicals and the simultaneous decline of antioxidant defense mechanisms can lead to dam-age of cellular organelles and enzymes,increased lipid peroxidation,and development of insulin resistance.

These consequences of oxidative stress can promote the development of complications of diabetes melli-tus.Changes in oxidative stress biomarkers,including superoxide dismutase,catalase,glutathione reductase, glutathione peroxidase,glutathione levels,vitamins, lipid peroxidation,nitrite concentration,nonenzymatic glycosylated proteins,and hyperglycemia in diabetes, and their consequences,are discussed in this review.In vivo studies of the effects of various conventional and alternative drugs on these biomarkers are surveyed.

There is a need to continue to explore the relationship between free radicals,diabetes,and its complications, and to elucidate the mechanisms by which increased oxidative stress accelerates the development of diabetic complications,in an effort to expand treatment options.

C 2003Wiley Periodicals,Inc.J Biochem Mol Toxicol

17:24–38,2003;Published online in Wiley InterScience (https://www.wendangku.net/doc/bc10574268.html,).DOI10.1002/jbt.10058

KEYWORDS:Type1Diabetes Mellitus;Antioxidants;

Oxidative Stress;Catalase;Glutathione Peroxidase

INTRODUCTION

Diabetes mellitus is a metabolic disorder character-ized by hyperglycemia and insuf?ciency of secretion or action of endogenous insulin.Although the etiology of this disease is not well de?ned,viral infection,au-toimmune disease,and environmental factors have been implicated[1–5].While exogenous insulin and other medications can control many aspects of diabetes, Correspondence to:J.B.Watkins III.

c 2003Wiley Periodicals,Inc.numerous complications affecting the vascular system, kidney,retina,lens,peripheral nerves,an

d skin ar

e common and are extremely costly in terms o

f longevity and quality of life.

Increased oxidative stress is a widely accepted par-ticipant in the development and progression of diabetes and its complications[6–8].Diabetes is usually accom-panied by increased production of free radicals[7–10] or impaired antioxidant defenses[11–13].Mechanisms by which increased oxidative stress is involved in the diabetic complications are partly known,including ac-tivation of transcription factors,advanced glycated end products(AGEs),and protein kinase C.This review fo-cuses on recent experimental studies of diabetes and drug interventions done within the context of in vivo assay systems.There are also myriad in vitro experi-ments and clinical studies which deserve a review of their own.

OVERVIEW OF FREE RADICALS

AND DIABETIC COMPLICATIONS

Excessively high levels of free radicals cause dam-age to cellular proteins,membrane lipids and nucleic acids,and eventually cell death.Various mechanisms have been suggested to contribute to the formation of these reactive oxygen-free radicals.Glucose oxidation is believed to be the main source of free radicals.In its enediol form,glucose is oxidized in a transition-metal-dependent reaction to an enediol radical anion that is converted into reactive ketoaldehydes and to super-oxide anion radicals.The superoxide anion radicals undergo dismutation to hydrogen peroxide,which if not degraded by catalase or glutathione peroxidase, and in the presence of transition metals,can lead to production of extremely reactive hydroxyl radicals [14,15].Superoxide anion radicals can also react with nitric oxide to form reactive peroxynitrite radicals [11,16].Hyperglycemia is also found to promote lipid peroxidation of low density lipoprotein(LDL)by a superoxide-dependent pathway resulting in the generation of free radicals[17,18].Another important

Volume17,Number1,2003OXIDATIVE STRESS IN DIABETES25

source of free radicals in diabetes is the interaction of glucose with proteins leading to the formation of an Amadori product and then advanced glycation endproducts(AGEs)[19,20].These AGEs,via their receptors(RAGEs),inactivate enzymes and alter their structures and functions[21],promote free radical formation[7,8],and quench and block antiproliferative effects of nitric oxide[22,23].By increasing intracellular oxidative stress,AGEs activate the transcription factor NF-?B,thus promoting up-regulation of various NF-?B controlled target genes[24].NF-?B enhances production of nitric oxide,which is believed to be a mediator of islet beta cell damage.

Considerable evidence also implicates activation of the sorbitol pathway by glucose as a component in the pathogenesis of diabetic complications,for exam-ple,in lens cataract formation or peripheral neuropathy [25–27].Efforts to understand cataract formation have provoked various hypotheses.In the aldose reductase osmotic hypothesis,accumulation of polyols initiates lenticular osmotic changes.In addition,oxidative stress is linked to decreased glutathione levels and depletion of NADPH levels[28,29].Alternatively,increased sor-bitol dehydrogenase activity is associated with altered NAD+levels[30],which results in protein modi?cation by nonenzymatic glycosylation of lens proteins[31,32].

Mechanisms linking the changes in diabetic neu-ropathy and induced sorbitol pathway are not well delineated.One possible mechanism,metabolic im-balances in the neural tissues,has been implicated in impaired neurotrophism[33–35],neurotransmission changes[36–38],Schwann cell injury[39,40],and ax-onopathy[41,42].

OVERVIEW OF ANTIOXIDANTS

While on the one hand hyperglycemia engen-ders free radicals,on the other hand it also impairs the endogenous antioxidant defense system in many ways during diabetes[12].Antioxidant defense mech-anisms involve both enzymatic and nonenzymatic https://www.wendangku.net/doc/bc10574268.html,mon antioxidants include the vitamins A,C,and E,glutathione,and the enzymes superox-ide dismutase,catalase,glutathione peroxidase,and glutathione reductase.Other antioxidants include?-lipoic acid,mixed carotenoids,coenzyme Q10,several bio?avonoids,antioxidant minerals(copper,zinc,man-ganese,and selenium),and the cofactors(folic acid,vi-tamins B1,B2,B6,B12).They work in synergy with each other and against different types of free radicals.Vi-tamin E suppresses the propagation of lipid peroxida-tion;vitamin C,with vitamin E,inhibits hydroperoxide formation;metal complexing agents,such as peni-cillamine,bind transition metals involved in some reactions in lipid peroxidation[43]and inhibit Fenton-and Haber-Weiss-type reactions;vitamins A and E scav-enge free radicals[8,11,44–47].

Extensive studies of pharmacological interventions based on biological antioxidants have been carried out since the last review by Oberley[48].Discrepancies in observed biomarkers for oxidative stress continue to be seen in the present review,especially in the activi-ties of SOD,catalase,and glutathione peroxidase in ex-perimentally diabetic animals.Decreased levels of glu-tathione and elevated concentrations of thiobarbituric acid reactants are consistently observed in diabetes.In addition,changes in nitric oxide and glycated proteins are also seen in diabetes.The effects of antioxidants on these biomarkers for oxidative stress are summarized here after.

BIOMARKERS OF OXIDATIVE STRESS:

IN VIVO DIABETES STUDIES

Lipid Peroxidation

Hydroperoxides have toxic effects on cells both di-rectly and through degradation to highly toxic hydroxyl radicals.They may also react with transition metals like iron or copper to form stable aldehydes such as malon-dialdehydes that will damage cell membranes.Peroxyl radicals can remove hydrogen from lipids,producing hydroperoxides that further propagate the free-radical pathway[11].

Induction of diabetes in rats with streptozotocin (STZ)or alloxan uniformly results in an increase in thio-barbituric acid reactive substances(TBARS)(Table1), an indirect evidence of intensi?ed free-radical pro-duction.Preventing the formation of hydroxyl radi-cals would be an ef?cient means to reduce hydroxyl-induced damage,and several compounds have been tested as antioxidants in diabetic animals with varying success.For example,the increase in TBARS associated with diabetes is prevented by treatment with nicoti-namide[61],boldine[62],melatonin[45,49,63],aspirin [74],L-arginine or sodium nitroprusside[67],probucol [51],?-lipoic acid[71,77],aminoguanidine[69],capto-pril,enalapril[65],or nitecapone[66],if this treatment is given before or immediately after the diabetogen.

Even after diabetes is established,the buildup of TBARS may be reversed by treatment with combined vitamins C,E,and?-carotene[78],melatonin[58], gem?brozil[53],probucol[52,80],and vitamin E[80]. Dietary supplementation with?-lipoic acid,evening primrose oil or sun?ower oil lowers plasma lipids and hemostatic risk factors[81].

These normalization effects are seen in kidney [58,59,62,65,66,78],liver[58–62,64,74],heart[51–53,77], brain[49],intestine[58],lung[60],pancreas[45,61,62],

MARITIM,SANDERS,AND WATKINS Volume 17,Number 1,2003

TABLE 1.Effect of Diabetogen and Diabetogen Plus Antioxidant on the Concentration of Thiobarbituric Acid Reactive Sub-stances (TBARS)

Diabetogen

Animal Kidney

Liver

Heart

Brain Other

Pierre ?che et al.(1993)[49]

Melatonin,100–450mg/kg,i.p.ALX

40mg/kg,i.v.Mice ?N

Thompson and McNeill (1993)[50]

Vanadyl SO 4,1–1.25mg/mL in water STZ

Wistar rats ???

Kaul et al.(1995)[51]

Probucol,10mg/kg,i.p.on day 1after STZ for 4weeks STZ

65mg/kg,i.v.SD rats

?But not N Kaul et al.(1996)[52]

Probucol 10mg/kg,i.p.weeks 5–8after STZ

STZ

65mg/kg,i.v.SD rats

?But not N Ozansoy et al.(2000)[53]

Gem ?brozil 100mg/kg,p.o.

weeks12–14of induced diabetes STZ

45mg/kg,i.p.Wistar rats

?(Aorta)N

?(Plasma)N

Rauscher et al.(2001)[54]

Coenzyme Q 1010mg/kg,i.p.weeks 5–6post STZ

STZ

100mg/kg,i.p.SD rats

?Rauscher et al.(2001)[55]

Isoeugenol 10mg/kg,i.p.weeks 5–6post STZ

STZ

100mg/kg,i.p.SD rats

Rauscher et al.(2000)[56]

PNU-104067F or PNU-74389G

10mg/kg,i.p.weeks 5–6post STZ STZ

100mg/kg,i.p.SD rats

Rauscher et al.(2000)[57]

Piperine 10mg/kg,i.p.weeks 5–6post STZ

STZ

100mg/kg,i.p.SD rats

Maritim et al.(1999)[58]

Melatonin 10mg/kg,i.p.on days 30–34post STZ

STZ

50mg/kg,i.v.SD rats

?N ?N ?(Intestine)N

Aragno et al.(1999)[59]

DHEA 4mg/kg orally for 3weeks STZ

50mg/kg Wistar rats ?N

?N ?N

Cinar et al.(1999)[60]

Vitamin E supplement 1000mg/kg chow for 12weeks STZ

50mg/kg Wistar rats

?N ?(Lung)N

Melo et al.(2000)[61]

Nicotinamide 500mg/kg diet for 1–4weeks prior to STZ STZ

40mg/kg,i.v.Wistar rats

?(Pancreas)N

Jang et al.(2000)[62]

Boldine 100mg/kg/day in water for 8weeks immediately after STZ STZ

80mg/kg,i.p.SD rats

?(Pancreas)N Montilla et al.(1998)[63]

Melatonin 100and 200?g/kg,i.p.-3days to 8weeks of STZ

STZ

60mg/kg,i.p.Wistar rats

?(Plasma,RBCs)N

El-Missiry and El-Gindy (2000)[64]

Oil of Eruca sativa seeds 0.06mL/kg orally

ALX

100mg/kg Wistar rats

Kedziora-Kornatowski et al.(2000)[65]

Captopril 2mg/kg or enalapril

1mg/kg in water for 6and 12weeks STZ

65mg/kg,i.p.Wistar rats

?N Lal et al.(2000)[66]

Nitecapone 30mg/kg aq.soln.2×day or via gavage 25?g/mL STZ

70mg/kg,i.p.SD rats

Mohan and Das (1998)[67]

L -arginine 50mg in 0.5mL NaCl pre-and simultaneous with ALX ALX

75mg/kg/day *5days

Wistar rats

?(Plasma)N Sodium nitroprusside 2–10?g pre-and simultaneous with ALX N

El-Khatib et al.(2001)[68]

Aminoguanidine 100mg/kg,i.p.for 14days

STZ

65mg/kg,i.p.

Wistar rats

?(Plasma)N

Continued

Volume17,Number1,2003OXIDATIVE STRESS IN DIABETES27

TABLE1.Continued

Diabetogen Animal Kidney Liver Heart Brain Other Desferrioxamine50mg/kg,i.p.

for14days

Abdel-Wahab and Abd-Allah(2000)[45] Melatonin5mg/kg orally,

-3and15days after STZ injection STZ

60mg/kg/day,i.p.

days

mice?(Pancreas)

Melatonin+desferrioxamine

250mg/kg,p.o.,-3and15days

after STZ

Kedsiora-Kornatowski et al.(1998)[69] Aminoguanidine1g/L in water

for6and12weeks STZ

65mg/kg,

i.p.

Wistar rats?(RBC)

Obrosova et al.(1999)[70]STZ

55mg/kg,

i.p.

SD rats?(Precataract

lens)

Taurine5%in feed for3weeks N

Obrosova et al.(2000)[71]

?-Lipoic acid100mg/kg,i.p.

for6weeks starting48h after STZ STZ

55mg/kg,

i.p.

Wistar rats?(Retina)

van Dam et al.(2001)[72]

?-Lipoic acid(different doses)STZ

i.p.

Wistar rats?(Plasma)

Sailaja Devi and Das(2000)[73] Melatonin200?g/rat,p.o.with ALX+7weeks ALX

75mg/kg,

i.p.

Wistar rats?

?(Plasma)

Caballero et al.(2000)[74] Aspirin0.16%w/w in diet,30min after STZ injection STZ

200mg/kg,

i.p.

CF1mice?

Sanders et al.(2001)[75] Quercetin10mg/kg/day,i.p.weeks 5–6post STZ STZ

100mg/kg,

i.p.

SD rats?

Obrosova et al.(1999)[76]

SDI-157100mg/kg in water48h to3weeks after STZ STZ

55mg/kg,

i.p.

Wistar rats?(Nerve)

Kocak et al.(2000)[77]

?-Lipoic acid50mg/kg/day,i.p. for6weeks STZ

55mg/kg,

i.p.

Wistar rats?

Mekinova et al.(1995)[78] Vitamins C,E,and?-carotene p.o. 8days after STZ+8weeks STZ

45mg/kg,

i.v.

Wistar rats?

Altavilla et al.(2001)[79] Raxofelast15mg/kg/day,i.p. for3,6,12days Diabetic mice

C57BL/

Ksdb+/db+

?(Wound

dienes)

Diabetogens alloxan(ALX)or streptozotocin(STZ),administered to mice or Wistar or Sprague-Dawley(SD)rats,produced increases(?)or decreases(?)from normal levels of TBARS as indicated in the top line for each study.Dose and route of diabetogen administration is indicated in the second line of column2,and the asterisk in line3indicates diabetogen treatment continued for the speci?ed number of days.Treatment with antioxidant chemicals produced no effect(?),further increase(??),or normal levels(N)of TBARS at the speci?ed time,as indicated in lower line(s)of each study.

plasma[53,63,67,68,72],red blood cells[63,69],lens[70], and retina[71].In addition,increased lipid peroxida-tion in genetically diabetic C57BL/Ksdb+/db+mice, as measured by conjugated dienes at wound sites,re-turns to normal levels after raxofelast treatment[79].

In contrast,both basal and iron-stimulated TBARS levels are signi?cantly elevated in livers of rats treated with vanadyl sulfate compared to untreated STZ-induced diabetic rats,highlighting the impor-tance of using multiple indicators of peroxidative change[50].Similarly,quercetin[75]and the sorbitol dehydrogenase inhibitor SDI-157[76]exacerbate the increased TBARS concentrations in livers[75]and nerves[76]of untreated diabetic rats.On the other hand treatment with coenzyme Q10[54],piperine[57], isoeugenol[55],or experimental antioxidants PNU-104067F or PNU-74389G[56],results in no change in lipid peroxidation in liver,kidney,heart,and brain of diabetic rats.

Glutathione Levels

Reduced glutathione is a major intracellular redox buffer that may approach concentrations up to10mM [82].Glutathione functions as a direct free-radical scavenger,as a cosubstrate for glutathione peroxidase

28MARITIM,SANDERS,AND WATKINS Volume17,Number1,2003

activity,and as a cofactor for many enzymes,and forms

conjugates in endo-and xenobiotic reactions[83,84].

Table2summarizes recent studies of the effects

of various antioxidants on glutathione concentrations.

Glutathione concentration is found to be decreased in

the liver[50,54–59,61,64,75],kidney[59],pancreas[45],

plasma[63,67],red blood cells[63],nerve[76],and pre-

cataractous lens[70]of chemically induced diabetic an-

imals.However,there is also some contradictory evi-

dence of increased glutathione concentration in diabetic

rat kidney[78]and lens[85].

Levels of glutathione are reported to be normal-

ized by vanadyl[50],dehydroepiandrosterone(DHEA)

[59],oil of Eruca sativa seeds[64],nicotinamide[61], L-arginine or nitroprusside[67],melatonin[63],and melatonin plus desferrioxamine[45]when these an-

tioxidants are given prior to or at the same time as

the diabetogen.However,antioxidants that fail to re-

verse the effects of established diabetes on glutathione

levels include coenzyme Q10[54],quercetin[75],piper-

ine[57],isoeugenol[55],PNU-104067F or PNU-74389G

[56],DHEA[59],melatonin[58],and taurine[70].

The increase in renal glutathione levels in diabetic

Wistar rats is normalized by simultaneous treatment

with vitamin C,vitamin E,and?-carotene[78].Sand

rats modeling both type I and type II diabetes had in-

creased levels of glutathione in lens,which were nor-

malized by treatment with?-lipoic acid[85].

Glutathione Peroxidase and Glutathione

Reductase

Glutathione peroxidase and reductase are two en-

zymes that are found in the cytoplasm,mitochondria,

and nucleus.Glutathione peroxidase metabolizes hy-

drogen peroxide to water by using reduced glutathione

as a hydrogen donor[86,87].Glutathione disul?de is

recycled back to glutathione by glutathione reductase,

using the cofactor NADPH generated by glucose6-

phosphate dehydrogenase.Investigations into the ef-

fects of various drugs on these two enzymes in the tis-

sues of diabetic animals are summarized in Table3.

There is not total agreement about the effects of

diabetes on the activities of these enzymes.However,

glutathione peroxidase activity is seen to be elevated in

liver[54–57,59,75],kidney[54,55,57,59,65,75,78],aorta

[77],pancreas[62],blood[67–69],and red blood cells

[73],whereas decreased activity was seen in heart

[51,52]and retina[71].

Diabetes-induced alterations in glutathione perox-

idase activity are reversed by treatment with probu-

col[51,52],DHEA[59],combined vitamins C,E,

and?-carotene[78],quercetin(in liver and brain,

though not in kidney or heart)[75],coenzyme Q10and

isoeugenol(only in liver)[54,55],piperine(in kidney)[57],boldine[62],aminoguanidine[68],desferioxamine [68],L-arginine and nitrooprusside[67],captopril and enalapril[69],melatonin[73],and?-lipoic acid[77].Al-tered enzyme activity in diabetic animals is not restored to normal levels by?-lipoic acid in retina[71],boldine in kidney[62],quercetin[75]or coenzyme Q10[54]in heart and kidney,or piperine in heart and liver[57].It is in-teresting to note that all these studies instituted antiox-idant treatment after diabetes was well established,as opposed to prior to or simultaneously with the diabeto-gen.Aminoguanidine treatment attenuates erythrocyte glutathione peroxidase activity,exceeding control val-ues after both6and12weeks of induced diabetes [69].

Activity of glutathione reductase,which regen-erates cellular glutathione,is reduced in retina[71] and plasma[67]but increased in heart[54,55,57,75] of diabetic animals.None of these effects is reversed by treatment with antioxidants,including?-lipoic acid,quercetin,piperine,isoeugenol,coenzyme Q10,L-arginine,or nitroprusside.

Catalase

Catalase,located in peroxisomes,decomposes hy-drogen peroxide to water and oxygen[88].Docu-mented changes in catalase activity in chemically in-duced diabetic animals are given in Table4.For exam-ple,catalase activity is consistently found to be elevated in heart[51,52,54,55,57,75,89]and aorta[53,77],as well as brain[59]of diabetic rats.In contrast to decreased re-nal[58,65,78],hepatic[54,58,75]and red blood cell[69] catalase activity,catalase activity in liver[59,74]and kidney[59]of diabetic animals is increased.

These alterations of catalase activity due to dia-betes are normalized by treatment with captopril[65], aminoguanidine[69],melatonin(in liver)[58],acetyl-salicylic acid[74],DHEA[59],probucol[51,52],?-lipoic acid[77],and stobadine[89],all of which were ad-ministered before or at the same time as the diabeto-gen.By contrast,treatment of established diabetes of4 weeks or more does not reverse or normalize diabetic effects.For example,no reversals are seen after treat-ment with melatonin[58],quercetin[75],coenzyme Q10 [54],piperine[57],isoeugenol[55],gem?brozil[53],or combined vitamin C,vitamin E,and?-carotene[78].Fi-nally,effects of diabetes on cardiac catalase activity are exacerbated by treatment with quercetin[75]or coen-zyme Q10[54].

Superoxide Dismutase(SOD)

Isoforms of SOD are variously located within the cell.CuZn-SOD is found in both the cytoplasm and the

Volume17,Number1,2003OXIDATIVE STRESS IN DIABETES29

TABLE2.Effect of Diabetogen and Diabetogen Plus Antioxidant on the Concentration of Reduced Glutathione(GSH)

Diabetogen Animal Kidney Liver Heart Brain Other

Thompson and McNeill(1993)[50] Vanadyl SO41–1.25mg/mL in water

STZ Wistar rats?

Rauscher et al.(2001)[54] Coenzyme Q1010mg/kg,i.p.weeks 5–6post STZ STZ

100mg/kg,

i.p.

SD rats?

Rauscher et al.(2001)[55] Isoeugenol10mg/kg,i.p.weeks 5–6post STZ STZ

100mg/kg,

i.p.

SD rats?

Rauscher et al.(2000)[57] Piperine10mg/kg,i.p.weeks 5–6post STZ STZ

100mg/kg,

i.p.

SD rats?

Rauscher et al.(2000)[56] PNU-104067F or PNU-74389G 10mg/kg,i.p.weeks

5–6post STZ STZ

100mg/kg,

i.p.

SD rats?

Sanders et al.(2001)[75] Quercetin10mg/kg/day,i.p.weeks 5–6post STZ STZ

100mg/kg,

i.p.

SD rats?

Aragno et al.(1999)[59]

DHEA4mg/kg orally for3weeks STZ

mg/kg

Wistar rats?

El-Missiry and El-Gindy(2000)[64] Oil of Eruca sativa seeds0.06mL/kg orally ALX

100

mg/kg

Wistar rats?

Maritim et al.(1999)[58] Melatonin10mg/kg,i.p.on days 30–34post STZ STZ

50mg/kg,

i.v.

SD rats??????

(Intestines)

Mohan and Das(1998)[67]

L-arginine50mg in0.5mL NaCl pre-and simultaneously with ALX

Na nitroprusside2–10?g pre-and simultaneously with ALX ALX

75mg/kg/day

days

Wistar rats?(Plasma)

Montilla et al.(1998)[63] Melatonin100and200?g/kg,i.p. -3days to8weeks of STZ STZ

60mg/kg,

i.p.

Wistar rats?(RBC,

Plasma)

Abdel-Wahab and Abd-Allah(2000)[45] Melatonin5mg/kg orally,-3and15 days after STZ injection STZ

60mg/kg/day i.p.

days

mice?(Pancreas)

Melatonin+desferrioxamine

250mg/kg,p.o.,-3and15days

after STZ

Melo et al.(2000)[61] Nicotinamide500mg/kg diet for4weeks prior STZ injection STZ

40mg/kg,

i.v.

Wistar rats?

Obrosova et al.(1999)[76]

SDI-157100mg/kg in water48h to3weeks after STZ STZ

55mg/kg,

i.p.

Wistar rats?(Nerve)

Obrosova et al.(1999)[70] Taurine1%in diet for3weeks Taurine5%in diet for3weeks STZ

55mg/kg,

i.p.

SD rats?(Precataract

lens)

Mekinova et al.(1995)[78] Vitamins C,E,and?-carotene p.o. in weeks2–8after STZ STZ

45mg/kg,

i.v.

Wistar rats?

Borenshtein et al.(2001)[85]

?-Lipoic acid,?-linolenic acid i.p.Sand rats

(Type I and ll

DM)

?Lens

Diabetogens alloxan(ALX)or streptozotocin(STZ),administered to mice or Wistar and/or Sprague-Dawley(SD)rats,produced increases(?)or decreases(?) from normal concentrations of GSH as indicated in top line for each study.Dose and route of diabetogen administration is indicated in the second line of column2, and the asterisk in line3indicates diabetogen treatment continued for the speci?ed number of days.Treatment with antioxidant chemicals produced no effect(?) or normal levels(N)of GSH at the speci?ed time,as indicated in lower line(s)of each study.

MARITIM,SANDERS,AND WATKINS Volume 17,Number 1,2003

TABLE 3.Effect of Diabetogen and Diabetogen Plus Antioxidant on the Activity of Glutathione Peroxidase

Diabetogen

Animal Kidney

Liver

Heart Brain

Other

Kaul et al.(1995,1996)[51,52]

Probucol 10mg/kg,i.p.,on day 1after STZ +4weeks

STZ

65mg/kg,i.v.

SD rats

?But not N Probucol 10mg/kg,i.p.,weeks 5–8post STZ

Aragno et al.(1999)[59]

DHEA 4mg/kg orally for 3weeks STZ

50mg/kg Wistar rats ?N

Obrosova et al.(2000)[71]

?-Lipoic acid 100mg/kg,i.p.,starting 48h after STZ injection STZ

55mg/kg,i.p.Wistar rats

?(Retina)

Mekinova et al.(1995)[78]

Vitamins C,E,and ?-carotene p.o.weeks 2–8after STZ

STZ

45mg/kg,i.v.Wistar rats

Sanders et al.(2001)[75]

Quercetin 10mg/kg/day,i.p.weeks 5–6post STZ

STZ

100mg/kg,i.p.SD rats

??N ?

?Rauscher et al.(2001)[54]

Coenzyme Q 1010mg/kg,i.p.weeks 5–6post STZ

STZ

100mg/kg,i.p.SD rats

Rauscher et al.(2000)[57]

Piperine 10mg/kg,i.p.weeks 5–6post STZ

STZ

100mg/kg,i.p.SD rats

?N ?

???Rauscher et al.(2001)[55]

Isoeugenol 10mg/kg,i.p.weeks 5–6post STZ

STZ

100mg/kg,i.p.SD rats

??N

????Rauscher et al.(2000)[56]

PNU-104067F or PNU-74389G

10mg/kg,i.p.weeks 5–6post STZ STZ

100mg/kg,i.p.SD rats

???

Jang et al.(2000)[62]

Boldine 100mg/kg/day in water for 8weeks immediately after STZ STZ

80mg/kg,i.p.SD rats

?(Pancreas)N El-Khatib et al.(2001)[68]

Aminoguanidine 100mg/kg,i.p.for 14days

STZ

65mg/kg,i.p.

Wistar rats

?(Blood)N Desferrioxamine 50mg/kg,i.p.for 14days

Mohan and Das (1998)[67]

L -arginine 50mg in 0.5mL NaCl pre-and simultaneous with ALX ALX

75mg/kg/day *5days

Wistar rats

?(Plasma)N Sodium nitroprusside 2–10?g pre-and simultaneous with ALX

Kedziova-Kornatowska et al.(1998)[69]

Aminoguanidine 1g/L in water for 6and 12weeks

STZ

65mg/kg ,i.p.Wistar rats

?(RBCs)N (12weeks)

Kedziova-Kornatowska et al.(2000)[65]

Captopril 2mg/kg or enalapril

1mg/kg in water for 6and 12weeks STZ

65mg/kg,i.p.Wistar rats

Maritim et al.(1999)[58]

Melatonin 10mg/kg,i.p.on days 30–34post STZ

STZ

50mg/kg,i.v.SD rats

?(Spleen)

Sailaja Devi and Das (2000)[73]

Melatonin 200?g/rat p.o.with ALX +7weeks

ALX

75mg/kg,i.p.Wistar rats

?(Plasma)N

Kocak et al.(2000)[77]

?-Lipoic acid 50mg/kg/day i.p.for 6weeks

STZ

55mg/kg,i.p.Wistar rats

?(Aorta)N

Ozansoy et al.(2000)[53]

Gem ?brozil 100mg/kg p.o.weeks 12–14of induced diabetes

STZ

45mg/kg,i.p.

Wistar rats

?(Aorta)?

Diabetogens alloxan (ALX)or streptozotocin (STZ),administered to Wistar or Sprague-Dawley (SD)rats,produced increases (?)or decreases (?)from normal activities of glutathione peroxidase as indicated in the top line for each study.Dose and route of diabetogen administration is indicated in the second line of column 2,and the asterisk in line 3indicates diabetogen treatment continued for the speci ?ed number of days.Treatment with antioxidant chemicals produced no effect (?

),increase (?),decrease (?),or normal activities (N)of glutathione peroxidase at the speci ?ed time,as indicated on the lower line(s)for each study.

Volume17,Number1,2003OXIDATIVE STRESS IN DIABETES31

TABLE4.Effect of Diabetogen and Diabetogen Plus Antioxidant on the Activity of Superoxide Dismutase

Diabetogen Animal Kidney Liver Heart Brain Other

Kaul et al.(1995)[51]

Probucol10mg/kg,i.p.for4weeks STZ

65mg/kg,

i.v.

SD rats?

Kaul et al.(1996)[52]

Probucol10mg/kg,i.p.weeks5–8 after STZ STZ

65mg/kg,

i.v.

SD rats?

Mohan and Das(1998)[67]

L-arginine50mg in0.5mL NaCl pre-and simultaneous with ALX Sodium nitroprusside2–10?g

pre-and simultaneous with ALX ALX

75mg/kg/day

days

Wistar rats?(Plasma)

Kedziora-Kornatowski et al.(1998)[69] Aminoguanidine(1g/L in water,6and 12weeks)

Aminoguanidine(1g/L in water,6and 12weeks)STZ

65mg/kg,

i.p.

Wistar rats?(RBC)

Kedziora-Kornatowski et al.(2000)[65] Captopril(2mg/kg in water,6and12 weeks)

Enalapril(1mg/kg in water,6and12 weeks)STZ

65mg/kg

i.p.Wistar

rats

Maritim et al.(1999)[58] Melatonin10mg/kg,i.p.days30–34 post STZ STZ

50mg/kg,

i.v.

SD rats????

Obrosova et al.(2000)[71]

?-Lipoic acid(100mg/kg/day) 6weeks starting48h post STZ STZ

55mg/kg,

i.p.

Wistar rats?(Retina)

Aragno et al.(1999)[59]

DHEA4mg/kg orally for3weeks STZ

mg/kg

Wistar rats?

Sailaja Devi and Das(2000)[73] Melatonin200?g/rat p.o.with ALX +7weeks ALX

75mg/kg,

i.p.

Wistar rats?(Plasma)

Rauscher et al.(2001)[54] Coenzyme Q1010mg/kg,i.p.in weeks 5and6post STZ STZ

100mg/kg,

i.p.

SD rats?

Rauscher et al.(2000)[57] Piperine10mg/kg,i.p.in weeks 5and6post STZ STZ

100mg/kg,

i.p.

SD rats?

Jang et al.(2000)[62]

Boldine100mg/kg/day in water for8weeks immediately after STZ STZ

80mg/kg,

i.p.

SD rats?

??(Pancreas)

Lal et al.(2000)[66]

Nitecapone30mg/kg aq.soln.2×day or via gavage25?g/mL STZ

70mg/kg,

i.p.

SD rats?

El-Khatib et al.(2001)[68] Aminoguanidine100mg/kg,i.p. for14days Desferrioxamine50mg/kg,i.p. for14days STZ

65mg/kg,

i.p.

Wistar rats?(RBC)

Ozansoy et al.(2000)[53]

Gem?brozil100mg/kg p.o.weeks 12–14of induced diabetes STZ

45mg/kg,

i.p.

Wistar rats?(Aorta)

Mekinova et al.(1995)[78] Vitamin C,E,and?-carotene p.o. weeks2–8after STZ STZ

45mg/kg,

i.v.

Wistar rats?

Kocak et al.(2000)[77]

?-Lipoic acid50mg/kg/day i.p. for6weeks STZ

55mg/kg,

i.p.

Wistar rats?(Aorta)

Stefek et al.(2000)[89] Stobadine0.05%w/w for32days

STZ Wistar rats?

Diabetogens alloxan(ALX)or streptozotocin(STZ),administered to Wistar or Sprague-Dawley(SD)rats,produced increases(?)or decreases(?)from normal activity of superoxide dismutase as indicated in the top line for each study.Dose and route of diabetogen administration is indicated in the second line of column2, and the asterisk in line3indicates diabetogen treatment continued for the speci?ed number of days.Treatment with antioxidant chemicals produced no effect(?), increased(?),or normal activities(N)of superoxide dismutase at the speci?ed time,as indicated in the lower line(s)of each study.

MARITIM,SANDERS,AND WATKINS Volume 17,Number 1,2003

nucleus.Mn-SOD is con ?ned to the mitochondria,but can be released into extracellular space [90].SOD con-verts superoxide anion radicals produced in the body to hydrogen peroxide,thereby reducing the likelihood of superoxide anion interacting with nitric oxide to form reactive peroxynitrite.Changes in SOD activity in the tissues of chemically induced diabetic animals are sur-veyed and summarized in Table 5.

The effect of diabetes on the activity of SOD is er-ratic,with no discernable pattern based on gender or species of animal,or duration of diabetes,or tissue stud-ied.Renal activity,for example,is within normal levels at 3[59]and 6weeks [58]after STZ,lower than nor-mal at 6weeks [54,75]post-STZ,but also elevated after 6or 12weeks of diabetes [65].In liver,SOD activity is depressed by the third [59]or fourth week [58]of TABLE 5.Effect of Diabetogen and Diabetogen Plus Antioxidant on the Activity of Catalase

Diabetogen

Animal Kidney

Liver

Heart

Brain

Other Kedziova-Kornatowska et al.(1998)[69]Aminoguanidine (1g/L in water)for 6and 12weeks post STZ

STZ

65mg,

i.p.Wistar rats

N-(RBC)

Kedziova-Kornatowska et al.(2000)[65]Captopril 2mg/kg in water 6and 12weeks post STZ

STZ

65mg,

i.p.

Wistar rats

?N Enalapril 1mg/kg in water 6and 12weeks post STZ

Maritim et al.(1999)[58]

Melatonin 10mg/kg,i.p.days 30–34post STZ

STZ

50mg/kg,

i.v.SD rats

Sanders et al.(2001)[75]

Quercetin 10mg/kg/day,i.p.weeks 5and 6post STZ

STZ

100mg/kg,

i.p.SD rats

????Rauscher et al.(2001)[54]

Coenzyme Q 1010mg/kg,i.p.weeks 5and 6post STZ

STZ

100mg/kg,

i.p.SD rats

????

Mekinova et al.(1995)[78]

Vitamin C,E,and ?-carotene p.o.weeks 2–8after STZ

STZ

45mg/kg,

i.v.Wistar rats

Caballero et al.(2000)[74]

Acetylsalicylic acid 0.16%w/w in diet for 7and 45days post STZ STZ

200mg,

i.p.CF1mice

N (15d)

Aragno et al.(1999)[59]

DHEA 4mg/kg orally for 3weeks STZ

mg/kg Wistar rats ?N

Kaul et al.(1995,1996)[51,52]

Probucol 10mg/kg,i.p.on day 1thru 4weeks after STZ

STZ

65mg,

i.v.

SD rats

?N Probucol given weeks 5–8post STZ N

Ozansoy et al.(2000)[53]

Gem ?brozil 100mg/kg p.o.weeks 12–14of induced diabetes STZ

45mg/kg,

i.p.Wistar rats

?(Aorta)

Kocak et al.(2000)[77]

?-Lipoic acid 50mg/kg,i.p.for 6weeks STZ

55mg,

i.p.Wistar rats ?

N (Aorta)Stefek et al.(2000)[89]

Stobadine 0.05%w/w for 32days

STZ

Wistar rats

Diabetogens alloxan (ALX)or streptozotocin (STZ),administered to Wistar or Sprague-Dawley (SD)rats,produced increases (?)or decreases (?)from normal levels of catalase activity as indicated in the top line for each study.Dose and route of diabetogen administration is indicated in the second line of column 2.Treatment with antioxidant chemicals produced no effect (?

),further increase (??),or normal activities (N)of catalase at the speci ?ed time,as indicated in the lower line(s)of each study.

diabetes,but is either normal [78]or elevated [62]8weeks after STZ.Kaul et al.[51,52]found cardiac SOD activity decreased after 4or 8weeks of diabetes,but Stefek et al.[89]reported elevated cardiac activity at 32weeks,and activity in aorta seems to be unaffected by diabetes [53,77].Likewise,activity may be elevated [68,73]or decreased [69]in red blood cells,decreased in retina [71]and plasma [67],and increased in pancreas [62].

Alterations of SOD activity in diabetic animals are normalized by probucol [51,52],captopril [69],DHEA [59],?-lipoic acid [71],melatonin [73],boldine [62],nitecapone [66],and stobadine [89],all of which were administered prior to or concomitant with the diabeto-gen.When treatment is initiated in animals with well-established diabetes,coenzyme Q 10[54]and piperine

Volume17,Number1,2003OXIDATIVE STRESS IN DIABETES33

[57]normalize renal activity,but no reversal of dia-betic effects is seen with melatonin[58],aminogua-nidine or desferrioxamine[68],or gem?brozil[53]. Treatment with vitamin C,vitamin E,and?-carotene for8weeks elevates hepatic SOD activity in diabetic rats,which is normal without treatment[78].

Vitamins

Vitamins A,C,and E are diet-derived and detox-ify free radicals directly.They also interact in recycling processes to generate reduced forms of the vitamins.?-Tocopherol is reconstituted when ascorbic acid recycles the tocopherol radical;dihydroascorbic acid,which is generated,is recycled by glutathione.These vitamins also foster toxicity by producing prooxidants under some conditions.Vitamin E,a component of the total peroxyl radical-trapping antioxidant system[91],reacts directly with peroxyl and superoxide radicals and sin-glet oxygen and protects membranes from lipid per-oxidation.The de?ciency of vitamin E is concurrent with increased peroxides and aldehydes in many tis-sues.There have been con?icting reports about vitamin E levels in diabetic animals and human subjects.Plasma and/or tissue levels of vitamin E are reported to be un-altered[92],increased[93],or decreased[60,94,95]by diabetes.Discrepancies among studies in terms of pre-ventive or deleterious effects of vitamin E on diabetes-induced vascular aberrations may arise from the variety of examined blood vessels or the administered dose of vitamin E.

Nitrite Concentration

Increasing evidence suggests that oxidative stress and changes in nitric oxide formation or action play major roles in the onset of diabetic complications.Ni-tric oxide synthase oxidizes arginine to citrulline in the presence of biopterin,NADPH,and oxygen.Generally, nitric oxide at physiological levels produces many ben-e?ts to the vascular system.However,increased oxida-tive stress and subsequent activation of the transcrip-tion factor NF-?B have been linked to the development of late diabetic complications.NF-?B enhances nitric oxide production,which is believed to be a mediator of islet beta-cell damage.Nitric oxide may react with su-peroxide anion radical to form reactive peroxyl nitrite radicals.

A number of studies are continuing to examine the role of nitric oxide in diabetes mellitus.For ex-ample,subnormal hepatic nitric oxide concentrations in STZ-diabetic rats are restored after melatonin treat-ment to levels signi?cantly higher than normal[58]. And,although elevated levels of nitric oxide levels in kidneys of3week diabetic rats are further enhanced by S-methyl-L-thiocitrulline treatment,administration of losartan along with S-L-thiocitrulline for3–5weeks nor-malizes the nitric oxide levels implying that angiotensin II is an important modulator of nitric oxide pathway in diabetes[96].

On the other hand,nitric oxide levels in plasma are decreased in alloxan-diabetic rats,an effect that can be abrogated by prior and simultaneous administration of L-arginine,a precursor of nitric oxide[67].When N-monomethyl-L-arginine,a speci?c inhibitor of nitric ox-ide synthase,is given along with alloxan,the bene?cial actions of L-arginine in diabetes are blocked.However, when sodium nitroprusside and L-arginine are admin-istered simultaneously with alloxan for5days,nitric oxide production remains at control levels.These re-sults suggest that both L-arginine and sodium nitro-prusside,with the capacity to enhance nitric oxide lev-els in alloxan-diabetic animals,can prevent alloxan-induced islet beta-cell damage and the development of diabetes as well as restore the antioxidant status.

Finally,retinal nitric oxide levels are increased in alloxan-diabetes and experimental galactosemia in rats [97].Aminoguanidine supplementation signi?cantly inhibits retinal nitric oxide concentrations and normal-izes the hyperglycemia-induced increases in retinal ox-idative stress without lowering the blood hexose levels of these animals.

Nonenzymatic Glycosylated Proteins

and Hyperglycemia

Diabetic hyperglycemia results in an increase in free-radical production by a mechanism involving glu-cose oxidation followed by protein glycation and oxida-tive degeneration[98].Glycation(nonenzymatic glyco-sylation)involves the condensation of glucose with the ε-amino group of lysine,the?-amino group of an N-terminal amino acid or the amines of nucleic acids[99]. The?rst reaction is the formation of an unstable Schiff base,which reaches a steady state within hours[100] and is reversible.Rearrangement of the Schiff base into an Amadori product reaches a steady state in approxi-mately28days and is also reversible.When molecules have slow turnover rates,these Amadori products un-dergo multiple dehydration reactions and rearrange-ments to irreversibly form AGEs[101].AGEs are be-lieved to be involved in the genesis of many of the irre-versible complications of diabetes,including expanded extracellular matrix,cellular hypertrophy,hyperplasia, and vascular complications[102,103].

Markers used for estimating the degree of pro-tein glycation in diabetes include fructosamine and glycated hemoglobin levels.Nonenzymatic glycation may also alter the structure and function of antioxidant

34MARITIM,SANDERS,AND WATKINS Volume17,Number1,2003

enzymes such that they are unable to detoxify free rad-icals,exacerbating oxidative stress in diabetes.For ex-ample,high glucose levels,leading to glycation and high levels of glycated proteins,modulate the activity of nitric oxide synthase directly or indirectly(through protein kinase C)[104].

Normoglycemia is a desired effect of any drug used either singly or in combination in the treatment of diabetes,but apart from insulin,only a limited num-ber of drugs including melatonin,probucol,vitamins C and E plus?-carotene,and?-lipoic acid[51,52,63,77,78] reduce high blood glucose levels in diabetes.The ma-jority of antioxidants do not reverse diabetes-induced hyperglycemia,and these agents must be given as ad-juvants to insulin therapy.

Elevated glycosylated hemoglobin and fruc-tosamine concentrations in diabetic Wistar rats are restored to normal levels after treatment with?-carotene(50mg/kg)for a period of40days[105].STZ-induced diabetic Sprague-Dawley rats demonstrate hy-perglycemia,high levels of glycated hemoglobin A1c and AGEs,as well as impaired acetylcholine-induced relaxations of the vascular segments.However,treat-ment with acarbose immediately after STZ,supple-mented with low dose insulin(1unit/day),restores both blood glucose and glycated hemoglobin A1c to normal levels,but not the AGE content.Addition of 100U/mL SOD normalizes the impaired vascular relax-ation,suggesting an important role of superoxide radi-cals in diabetes-induced endothelial dysfunction[106].

Increased nonenzymatic glycation and AGEs are also postulated to contribute to cataract formation.Ad-ministration of aldose reductase inhibitors(0.06%tol-restat or polnalrestat,0.0125%AL-1576for8weeks) in the diet of STZ-induced diabetic rats results in re-duced sorbitol levels,inhibition of cataract formation, lowered concentrations of glycosylated lens proteins, and slightly reduced lenticular AGE levels compared to untreated diabetic rats after45and87days of dia-betes[107].

Treatment of diabetes in male CF1mice with acetyl-salicylic acid(0.16%w/w in diet starting30min after STZ injection)blocks the accumulation of lipoperoxide aldehydes,reduces hyperglycemia,and prevents the inactivation of heme enzymes,?-aminolevulinic dehy-drase,and porphobilinogen deaminase[74].This inhi-bition of protein glycosylation through acetylation of free amino groups and lowering of blood glucose by acetylsalicylic acid may prevent some of the complica-tions of diabetes.

STZ-diabetes induces a10-fold increase in?-glutamyl transferase activity in rat liver[108–110],re-sulting in decreased biliary excretion of glutathione and other chemicals[111].Although regulation of ?-glutamyl transferase activity has been shown to be independent of message or expression[108],alterations in kinetic and other physical characteristics of the en-zyme in diabetic rats implicate glycation as a mech-anism of regulation[112].A decrease in glutathione excretion into bile in diabetics may have important con-sequences such as impairing the capacity of the intes-tine to detoxify dietary lipid peroxides or carcinogens. On the other hand,increased reclamation of glutathione may bene?t the liver by increasing its ability to detoxify reactive prooxidants within the liver.

CONCLUSIONS

STZ-or alloxan-induced diabetes in rats repre-sent well-established animal models of type1insulin-dependent,diabetes mellitus.Increased production of high levels of oxygen free radicals has been linked to glucose oxidation and nonenzymatic glycation of pro-teins which contribute to the development of diabetic complications.Protective effects of exogenously ad-ministered antioxidants have been extensively studied in animal models within recent years,thus providing some insight into the relationship between free radi-cals,diabetes,and its complications.In vitro and clini-cal studies may provide additional useful ways to probe the interconnections of oxidant stress and diabetes,and there is a need to continue to explore the mechanisms by which increased oxidative stress accelerates the de-velopment of complications in diabetes. REFERENCES

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