the role of iron in diabetes and its complications

The Role of Iron in Diabetes and ItsComplicationsSUNDARARAMAN SWAMINATHAN, MD

1

VIVIAN A. FONSECA, MD2

MUHAMMAD G. ALAM, MD, MPH1

SUDHIR V. SHAH, MD1

The central importance of iron in thepathophysiology of disease is de-rived from the ease with which iron

is reversibly oxidized and reduced. Thisproperty, while essential for its metabolicfunctions, makes iron potentially hazard-ous because of its ability to participate inthe generation of powerful oxidant spe-cies such as hydroxyl radical (1). Oxygennormally accepts four electrons and isconverted directly to water. However,partial reduction of oxygen can and doesoccur in biological systems. Thus, the se-quential reduction of oxygen along theunivalent pathway leads to the generationof superoxide anion, hydrogen peroxide,hydroxyl radical, and water (1,2). Super-oxide and hydrogen peroxide appear tobe the primary generated species. Thesespecies may then play a role in the gener-ation of additional and more reactive ox-idants, including the highly reactivehydroxyl radical (or a related highly oxi-dizing species) in which iron salts play acatalytic role in a reaction. This reaction iscommonly referred to as the metal cata-lyzed Haber-Weiss reaction (1):

Fe3� � O 2�� ➝ Fe2� � O2

Fe2� � H2O2 ➝ Fe3� � �OH � OH-

O 2�� H2O2 ➝ O2 � �OH � OH-

Because iron participates in the formationof reactive oxygen species, organisms takegreat care in the handling of iron. Indeed,iron sequestration in transport and stor-age proteins may contribute to antioxi-

dant defenses. It is now well establishedthat oxidants can cause the release of cat-alytic iron (1); thus, a vicious cycle is ini-tiated that leads to the formation of morereactive oxygen species.

In this review, we discuss the role tis-sue iron and elevated body iron storesplay in causing type 2 diabetes and thepathogenesis of its important complica-tions, particularly diabetic nephropathyand cardiovascular disease (CVD). In ad-dition, we emphasize that iron overload isnot a prerequisite for iron to mediate ei-ther diabetes or its complications. Impor-tant in its pathophysiology is theavailability of so-called catalytic iron oriron that is available to participate in freeradical reactions.

THE ROLE OF IRON IN THEINDUCTION OF DIABETESEvidence that systemic iron overloadcould contribute to abnormal glucose me-tabolism was first derived from the obser-vation that the frequency of diabetes isincreased in classic hereditary hemochro-matosis (HH). However, with the discov-ery of novel genetic disorders of ironmetabolism, it is obvious that iron over-load, irrespective of the cause or the geneinvolved, results in an increased inci-dence of type 2 diabetes. The role of ironin the pathogenesis of diabetes is sug-gested by 1) an increased incidence oftype 2 diabetes in diverse causes of ironoverload and 2) reversal or improvementin diabetes (glycemic control) with a re-duction in iron load achieved using eitherphlebotomy or iron chelation therapy.

Recently, a link has been established be-tween increased dietary iron intake, par-ticularly eating red meat and increasedbody iron stores, and the development ofdiabetes. A causative link with iron over-load is suggested by of the improvementin insulin sensitivity and insulin secretionwith frequent blood donation and de-creased iron stores (3,4).

Although the exact mechanism ofiron-induced diabetes is uncertain, it islikely, as discussed below, to be mediatedby three key mechanisms: 1) insulin defi-ciency, 2) insulin resistance, and 3) he-patic dysfunction. An understanding ofthe pathogenic pathways of iron-induceddiabetes is derived mainly from studies onanimal models of hemochromatosis.

In a mouse model of hemochromato-sis, iron excess and oxidative stress medi-ate apoptosis of pancreatic islets with aresultant decrease in insulin secretory ca-pacity (5). Pancreatic islets have an ex-treme susceptibility to oxidative damage,perhaps because of the nearly exclusivereliance on mitochondrial metabolism ofglucose for glucose-induced insulin se-cretion and low expression of the anti-oxidant defense system (6). A high ex-pression of divalent metal transporter ad-ditionally predisposes them for moreaccumulation of iron than other cells (7)and potentiates the danger from iron-catalyzed oxidative stress.

In studies on thalassemic patients, in-sulin resistance is significantly increased(8,9). In human studies, McClain et al.(10) recently demonstrated a high preva-lence of abnormal glucose homeostasis inindividuals with hemochromatosis andexamined possible mechanisms for thishigh prevalence. Using glucose tolerancetests, they demonstrated not only that in-sulin secretion is impaired but also thatthere is insulin resistance. The mecha-nisms for insulin resistance include thepossibility of iron overload causing resis-tance directly or through hepatic dys-function (11). In a study of patients withunexplained hepatic iron overload, mostwere found to be insulin resistant, whichsuggests a common etiologic link amonghepatic iron, hepatic dysfunction, and in-sulin resistance (12) (Fig. 1).

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From the 1Division of Nephrology, University of Arkansas for Medical Sciences, Little Rock, Arkansas; andthe 2Division of Endocrinology, Tulane University School of Medicine, New Orleans, Louisiana.

Address correspondence and reprint requests to Sundararaman Swaminathan, MD, University ofArkansas for Medical Sciences, 4301 West Markham St., Slot 501, Little Rock, AR 72205. E-mail:[email protected].

Received for publication 28 December 2006 and accepted in revised form 29 March 2007.Published ahead of print at http://care.diabetesjournals.org on 11 April 2007. DOI: 10.2337/dc06-2625.Abbreviations: CVD, cardiovascular disease; HCV, hepatitis C; HH, hereditory hemochromatosis; NTBI,

non–transferrin-bound iron.A table elsewhere in this issue shows conventional and Systeme International (SI) units and conversion

factors for many substances.© 2007 by the American Diabetes Association.

R e v i e w s / C o m m e n t a r i e s / A D A S t a t e m e n t sR E V I E W A R T I C L E

1926 DIABETES CARE, VOLUME 30, NUMBER 7, JULY 2007

Epidemiology of type 2 diabetes inknown iron overload conditionsGenetic iron overload syndromes anddiabetes. Over 80% of cases of HH (type1) result from a mutation in the gene en-coding the hereditary hemochromatosisprotein (HFE) (13) (Table 1). These mu-tations lead to an accumulation of iron inseveral tissues and present as a classic syn-drome of hypogonadism, diabetes, liverdisease, cardiomyopathy, and arthritis. Intype 1 hereditary hemochromatosis, up to60% of the affected patients develop dia-betes (14,15). Diabetes appears to be aresult of both insulin deficiency and resis-tance. Evidence for this is derived fromstudies in HH patients whose body ironstores were reduced with phlebotomyand/or iron chelation therapy, which re-sulted in improved glycemic control and30–40% of patients achieving elimina-tion of oral hypoglycemic therapy or asubstantial reduction in dosage (15,16).

A similar increase in the incidence oftype 2 diabetes is observed in other ge-netic iron overload syndromes that in-volve iron transport. For example, in

autosomal dominant hemochromatosissyndrome involving the iron transporterferropontin, diabetes is present in up to25% of patients (17). In juvenile hemo-chromatosis involving hemojuvelin mu-tations, 25% of patients were glucoseintolerant (18). An increased incidence ofdiabetes is also seen in hereditary aceru-loplasminemia, a condition where thelack of synthesis of apoceruloplasmin af-fects the distribution of tissue iron andleads to a progressive accumulation ofiron (19). The levels of malondialdehydeand 4-hydroxynonenals, which are indi-cators of lipid peroxidation, are signifi-cantly elevated in the frontal lobe andputamen and suggest a pathogenic rolefor iron-mediated oxidative stress in end-organ manifestations of this syndrome(20).

Several recent reports focused on spe-cific mutations such as C282Y, and its as-sociations with diabetes extend theseobservations and suggest that even mod-erate elevations of body iron stores out-s ide the se t t ing o f hered i t a ryhemochromatosis can be associated withdiabetes. The C282Y mutation particu-larly has been shown to be associated withelevated ferritin and transferrin saturationvalues (13). This genotype is found in pa-tients with diverse endocrine problemsincluding diabetes despite the absence ofovert hereditary hemochromatosis (21).Acton et al. (22) evaluated the associa-tions of diabetes with serum ferritin,transferrin saturation, and hereditaryhemochromatosis mutations in theHemochromatosis and Iron OverloadScreening (HEIRS) Study. Serum ferritinconcentrations were associated with dia-

betes at levels below those typically asso-ciated with hemochromatosis and ironoverload. Fumeron et al. (23), in a pro-spective study, also reported a positive as-sociation between transferrin and ferritinwith the onset of abnormalities and glu-cose metabolism. They argue that theirresults support a causative role of disor-dered iron metabolism in the onset of in-sulin resistance in type 2 diabetes.Transfusional iron overload and diabe-tes. Transfusional iron overload is themost common cause of acquired ironoverload and is typically seen in transfu-sion-dependent chronic hemolytic ane-mia such as �-thalassemia. Impairedglucose tolerance is often detected in thesecond decade of life. In a study of 80transfusion-dependent �-thalassemic pa-tients, diabetes was reported in 19.5% ofpatients and impaired glucose tolerancein 8.5% of patients. The risk factors forimpaired glucose tolerance and type 2 di-abetes found in that study were high se-rum ferritin and hepatitis C (HCV)infection (24). Insulin deficiency due toiron deposition in the interstitial pancre-atic cells, with resultant excess collagendeposition and defective microcirculation(25) and insulin resistance (26), are thelikely mechanisms for type 2 diabetes.Treatment with intravenous or oral chela-tion improves glucose tolerance in up toone-third of these patients, suggesting acausal role for iron (27,28). Preliminaryevidence also suggests a direct role foriron-derived free radicals in mediatingend-organ damage of diabetes in transfu-sional iron overload (29). In this study,patients with higher degrees of lipid per-oxidation had an accelerated onset of di-abetic nephropathy.African iron overload and diabetes.Dietary iron overload is well described inSouth African tribal populations. It is as-cribed to cooking food in African three-legged iron pots and eating acidic cereal,which increases iron absorption. How-ever, a genetic predisposition has alsobeen considered. Clinically, it behaveslike hereditary hemochromatosis, andtype 2 diabetes is a well known late man-ifestation (30). Similarly, autopsy studiesof African Americans suggest that patho-logic iron overload that cannot be linkedto specific gene mutations occurs in 1% ofthese patients. This data has been con-firmed in National Health and NutritionExamination Survey (NHANES) II and IIIstudies, where 0.9% of African Americanshad markedly elevated transferrin satura-tions and 14% had intermediate eleva-

Figure 1—Pathogenic pathways for iron in induction of diabetes.

Table 1—Iron overload states and diabetes

Genetic iron overloadHH (C282Y and H63D mutations)Ferropontin diseaseHemojuvelin mutationHereditary aceruloplasminemia

Mitochondrial iron overloadFriedreich’s ataxia (frataxin mutation)

Transfusional iron overloadHepatic iron overload

HCVPorphyria cutanea tarda

Swaminathan and Associates

DIABETES CARE, VOLUME 30, NUMBER 7, JULY 2007 1927

tions of transferrin saturation (31). Pilotdata from the Jackson Heart Study showsa positive correlation between serum fer-ritin and fasting blood glucose and A1C(r � 0.15), though no correlation hasbeen found between transferrin satura-tion and glycemic status (32). Because ofthese inconsistencies and absence of spe-cific data on iron chelation or phlebotomyto reverse diabetes or improve glycemiccontrol, it is difficult to draw firm conclu-sions on the link between iron overloadand diabetes in African Americans.HCV, porphyria cutanea tarda, and di-abetes. Recent studies have describednot only a significantly increased risk fordiabetes in patients with HCV infection(33,34) but also its associated conditionssuch as porphyria cutanea tarda. In por-phyria cutanea tarda, a cutaneous condi-tion associated with increased ironoverload, up to 87% of patients were glu-cose intolerant (35). Further, HCV canadversely affect progression of kidney dis-ease in patients with biopsy-proven dia-betic nephropathy (36). HCV infection iswell known to be associated with an ac-cumulation of iron in the liver paren-chyma. Many patients with chronic HCVinfection often have elevated serum iron,transferrin saturation, and ferritin levels,and a few have severe hepatic iron over-load (37,38). This might suggest that ironoverload has a role in the pathogenic linkbetween HCV and accelerated end-organdamage in diabetes.Type 2 diabetes in mitochondrial ironoverload. Friedreich’s ataxia, an inher-ited neurodegenerative disease with atrinucleotide (GAA) hyperexpansionwithin the first intron of the Friedreich’sataxia gene (FRDA), is a classic disorderassociated with mitochondrial iron accu-mulation. FRDA encodes for a proteincalled frataxin, which has a specific asso-ciation with the mitochondrial innermembrane and is involved in the forma-tion of Fe-S clusters. Friedreich’s ataxia isassociated with a high incidence of type 2diabetes (39), suggesting a possible rela-tion between mitochondrial iron accumu-lation leading to mitochondrial DNAdamage and type 2 diabetes. Disruptionof the frataxin gene in pancreatic �-cellscauses diabetes following cellular growtharrest and apoptosis, paralleled by an in-crease in reactive oxygen species in islets(40). In turn, this leads to progressivedamage to both mitochondrial and nu-clear DNA (41). Noted occurrence of di-abetes in other disorders of mitochondrialDNA, such as Wolfram Syndrome (42),

thiamine-dependent megaloblastic ane-mia (43), and specific disorders with mi-tochondrial mutation (tRNA) (44),support this conclusion. Absence of asimilar association of type 2 diabetes withother disorders of mitochondrial ironoverload, such as Hallervorden-Spatz dis-ease, might be due to an organ-localizednature of iron overload in these condi-tions (45).

The role of iron in diabetes withoutovert iron overloadA relationship between high iron intakeand high body iron stores outside the set-ting of genetic iron overload and type 2diabetes is well recognized (46). LomaLinda University’s Adventist Health Studywas the first to report the association be-tween meat intake and type 2 diabetesrisk (47) that has since been consistentlyobserved by several other studies (48,49).Numerous studies have confirmed thatthis association is related to the high hemecontent of meat and increased dietaryheme intake (3,50–52). Similarly, highbody iron stores have been linked to in-sulin resistance (53,54), metabolic syn-drome (53,55–57), and gestationaldiabetes (58,59). Recently, Jiang et al.(60) carried out a nested case-controlstudy within the Nurses’ Health Study co-hort. Among cases of incident diabetes,the mean concentration of serum ferritinwas significantly higher compared withcontrol subjects, and the mean ratio oftransferrin receptors to ferritin was signif-icantly lower. This relationship withmarkers of body iron stores persisted aftercorrection for various other risk factorsfor diabetes, including markers of obesityand inflammation.

Jehn et al. (61) argue that the modestelevations in ferritin levels observed in di-abetes may be a consequence or markerrather than the cause of impending insu-lin resistance and that elevated ferritinmay not reflect elevated body iron storesor an intracellular labile iron pool thatparticipates in oxidant injury. However,the common presence (59–92% of pa-tients) of non–transferrin-bound iron(NTBI), a form of iron most susceptible toredox activity, in excess amounts in type 2diabetes with a strong gradient for sever-ity (62), and the preliminary evidencethat reduction in body iron stores withbloodletting in type 2 diabetes results inimprovement in glycemic control and in-sulin resistance (56,63), suggests a patho-genic role of iron in type 2 diabetes.

Blood donation and diabetesAs discussed, iron overload is common inpatients outside the setting of known ironoverload syndromes. Insulin resistancehas been described in such patients(11,64), and iron-chelating agents andblood donations have been shown to de-crease the development of diabetes insuch patients (65,66). Interestingly, evenin apparently healthy individuals, blooddonation resulting in decreased ironstores has been associated with a low in-cidence of diabetes (66). Recent random-ized studies (56) have demonstrated thatiron stores influence insulin action, andfollowing bloodletting over a 4-monthperiod, insulin sensitivity improved. Fi-nally, a low-iron diet improves cardiovas-cular risk profiles (67). Fernandez et al.(68) investigated the relationship be-tween iron stores and insulin sensitivity in181 men. Men who donated blood morethan two times over a 5-year period werematched with nondonors. Blood dona-tion was associated with increased insulinsensitivity and decreased iron stores. Ad-ditional and intriguing support to this as-sociation also comes from a study onpatients with iron deficiency who exhibita decreased incidence of diabetes.

THE ROLE OF IRON INCOMPLICATIONS OFDIABETESThe importance of protein glycation iswell known in the pathogenesis of dia-betic vascular complications. Transitionmetals also play a role in protein glycationinduced by hyperglycemia. It has beenshown that glycated proteins have a sub-stantial affinity for the transition metals,and the bound metal retains redox activ-ity and participates in catalytic oxidation(69). Thus, should similar glycochelatesform in vivo, reactions mediated by thechelates could be involved in the vascularcomplications of diabetes (70). Desferox-amine causes a modest reduction in A1C.Also, in in vivo conditions, treatment withdesferoxamine has been shown tomodestly reduce A1C levels in patientswith non–insulin-dependent diabetes(71) and diabetic rats (72). In this section,we review additional clinical and epide-miological studies and pathogenic mech-anisms that link iron to complications ofdiabetes.

The role of iron in diabeticnephropathyEvidence linking iron to diabetic ne-phropathy includes 1) animal and epide-

Iron and diabetes


miological studies, 2) studies in which anincreased amount of iron has been shownin the kidneys of both animals (73,74)and humans (75) with kidney disease, 3)evidence for increased urinary iron in pa-tients with diabetic nephropathy, and 4)the prevention of progression either by aniron-deficient diet or agents that bind andremove iron (chelators) (76–78).

Animal studies provide considerableevidence for the role of iron and oxidantsin diabetic nephropathy (79–84). Oxida-tive stress from factors such as hypergly-cemia, advanced glycation end products,and hyperlipidemia further contribute tothe availability of intracellular iron thatcan generate and viciously worsen oxida-tive stress and renal damage. Iron contentin the kidney has been shown to be in-creased in an animal model of diabetes(84), and urinary iron excretion is in-creased early in the course of diabetic re-nal disease in humans (83,85). There isconsiderable evidence that, once renal in-sufficiency develops, regardless of etiol-ogy, it tends to progress over time. Thishas been interpreted to indicate somecommon pathways for progression of kid-ney disease. Thus, lessons learned fromother models of progression are likely tobe relevant to diabetic nephropathy. Inproteinuric models of kidney disease,iron accumulates within proximal tubulelysosomes. Nankivell et al. evaluated ironaccumulation in kidney biopsies of pa-tients with chronic kidney disease andproteinuria by energy-dispersive analysis.Compared with normal kidneys, iron ac-cumulates in proximal tubular lysosomesin chronic kidney disease kidneys, and itsaccumulation correlates with the degreeof proteinuria (73,75). Most importantly,the pathogenic role of iron in progressionis indicated by the observation that pro-gression can be prevented either by aniron-deficient diet or chelators (76–78).More specifically, in diabetes, a recentrandomized trial involving 191 patientswith diabetes, proteinuria, and a de-creased glomerular filtration rate showedthat a low-iron–available, carbohydrate-restricted, polyphenol-enriched dietcompared with a standard protein-restricted diet had a renoprotective effect(67).

The role of iron in endothelial andvascular diseaseThe possibility that iron status has a rolein CVD was postulated by J.L. Sullivan in1981 (70). The man-woman ratio for me-dian serum ferritin levels for ages 18–45

years is 3.8, which is similar to the in-creased risk for heart disease, with the re-duced risk against heart disease in womenending with the onset of menopause. Ep-idemiologic studies in overt iron overloadstates such as transfusional iron overloadand hemochromatosis have shown thatthe incidence of cardiac disease is in-creased (64) and that treatment with ironchelation improves cardiovascular out-come (27,86,87). Similarly, several stud-ies have demonstrated a direct associationbetween increased iron intake, body ironstores, and cardiovascular risk in the gen-eral population. Increased intake of hemeiron is associated with increased cardio-vascular events (88–91), and increasedbody iron stores are associated with myo-cardial infarction in a prospective epide-miological study (92). Additionally,varieties of cardiovascular risk factors areassociated with iron overload and com-monly cluster in the metabolic syndrome.Ramakrishnan et al. (91) have demon-strated this close relationship betweeniron stores and cardiovascular risk factorsin women of reproductive age in the U.S.The association was seen with total cho-lesterol, triglycerides, diastolic bloodpressure, and glucose, factors that oftencluster in individual patients. Additionalevidence of the role of iron can also bederived from studies on surrogate mark-ers such as carotid atherosclerosis findinga positive association with iron stores(93). However, several other studies ar-gue against an association between in-creased iron intake and body iron storesand cardiovascular risk (94 –99). Onepossible reason for these conflicting datais the lack of precision of markers thatwere used to indicate iron load. In most ofthese studies, serum ferritin has beenused as an indicator of iron load; how-ever, serum ferritin also increases with avariety of inflammatory and stressful con-ditions. Similarly, other markers indica-tive of iron status in the body such astransferrin saturation are not reflective oftotal body iron stores or the presence ofreactive forms of iron in blood. In fact,NTBI may be present in the serum evenwhen transferrin is not fully saturated(62,100).

Pathologic mechanisms for iron inpromoting vascular disease can be de-rived from cell culture studies, animalmodels, and human functional studies(vascular reactivity). In cell culture mod-els, the addition of NTBI to human endo-thelial cell cultures increases surfaceexpression of adhesion molecules

(101,102) and also increases monocyteadherence to the endothelium. These ab-normalities can be corrected by the addi-tion of iron chelators such as desferoxamineand dipirydyl. Such an addition decreasesexpression of adhesion molecules andmonocyte adherence (101–103). In humanstudies of end-stage renal disease patients,intravenous iron therapy has been shown toincrease vascular and systemic oxidativestress (104–106), promote atherosclerosis(106), and increase the risk of arterialthrombosis (105). Further, intravenousiron has been shown to cause impairedflow-mediated dilatation in the brachial ar-tery, a surrogate for endothelial dysfunction(107). Conversely, improvement in vascu-lar reactivity after phlebotomy in patientswith high-ferritin type 2 diabetes furthersupports these observations (108). Addi-tionally, several recent studies on cardiovas-cular evaluation and outcome in high-frequency blood donors demonstrateimprovement in surrogate markers of vas-cular health such as decreased oxidativestress and enhanced vascular reactivitywhen compared with low-frequency do-nors (107). However, conflicting data existsregarding the relationship between de-creased iron stores from frequent blood do-nation and hard end points such as adecrease in cardiovascular events and mor-tality (66,109).

Plasma NTBI measures reactive formsof iron that result in increased oxidativestress and cell injury. A recent prospectivestudy on the association of NTBI with car-diovascular events in postmenopausalwomen, the first of its kind, disappoint-ingly showed no excess of CVD or acutemyocardial infarction in patients with ahighest tertile of NTBI compared withthose with a lowest tertile of NTBI (110).The reason for negative results in thisstudy might reside in the limitations ofthe study itself, including short follow-up, low event rates, and age of the popu-lation studied (49–70 years). Also, theNTBI assay method used yielded negativeNTBI values in some patients and skepti-cism has been cast on this method before(111). Future studies using a reliable andprecise NTBI measurement method totest its association with cardiovascularevents will be very informative. Alterna-tively, better methods of measuring ex-cess free/catalytic iron need to bedeveloped and validated.

The beneficial effect of iron chelatorson endothelial dysfunction suggests therole of iron in vascular disease. Impairedendothelial function as a result of in-



creased NAD(P)H oxidase-dependent ox-idant generation was restored bydesferoxamine (112). Furthermore, des-feroxamine has been shown to prevent di-abetes-induced endothelial dysfunction(113) and deficits in endoneural nutritiveblood flow in streptozotocin-induced di-abetic rats (113,114). Additionally,dexrazoxane, a chelating agent, has beenshown to prevent homocysteine-inducedendothelial dysfunction in healthysubjects.

Desferoxamine continues to be themost common iron chelator in use, but ithas several limitations, including the needfor parenteral administration, side effects,and cost. The availability of safe and ef-fective oral iron chelators such as de-feriprone and deferasirox has madetreatment of iron overload states morepractical. These drugs are widely availableoutside the U.S. but have not yet beenapproved by the Food and Drug Admin-istration. Yet another potential advantageof oral iron chelators is their ability topenetrate the cell membrane and chelateintracellular iron species (115). Random-ized clinical trials of these agents areneeded to determine their effectivenessin treating/preventing diabetes and itscomplications.

CONCLUSIONSIn summary, there is suggestive evidencethat iron plays a pathogenic role in diabe-tes and its complications such as microan-giopathy and atherosclerosis. Reliableand sensitive methods need to be devel-oped to precisely measure the free/catalytic iron that participates in oxidativeinjury. Iron chelation therapy maypresent a novel way to interrupt the cycleof catalytic iron–induced oxidative stressand tissue injury and consequent releaseof catalytic iron in diabetes and to preventdiabetes-related complications.

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