452

Agnieszka ZAporA-Kurel1

Marta rydZewsKA1

Maciej Małyszko1

Natalia Anna drobeK1

Adriana ZAjKowsKA1

jolanta Małyszko1,2

12nd department of Nephrology, Medical university of bialystokHead:dr hab. med. Tomasz Hryszko

2department of Nephrology, dialysis and Internal Medicine, warsaw Medical university, poland Head:prof. dr hab. med. joanna Matuszkiewicz-Rowińska

Additional key words:irondiabeteshepcidininflammation

Dodatkowe słowa kluczowe: żelazocukrzycahepcydynastan zapalny

Address for correspondence: Jolanta MałyszkoKatedra i Klinika Nefrologii, dializoterapii i Chorób Wewnętrznychwarszawski uniwersytet Medyczny ul. banacha 1a, 02-097 warszawa, polska tel. +48 225 992 658e-mail: jolmal@poczta.onet.pl

Conflict of interest not declared

received: 13.04.2018Accepted: 21.09.2018

review pApers

Iron metabolism in diabetes

Metabolizm żelaza w cukrzycy

A. Zapora-Kurel et al.

Iron is an essential element nec-essary for every human cell. It has a dual capacity to both donate and accept electrons, and to reversibly bind to ligands such as oxygen and nitrogen. Iron plays a vital role in the transport and storage of oxygen, in oxidative metabolism and in cellu-lar growth and proliferation. There are several proteins participating in iron metabolism, including hepcidin, which is regulated by hypoxia, iron status and inflammation. Diabetes can be also considered as a disorder of inflammatory nature. The bidirec-tional link between iron metabolism and glucose homeostasis has been described. Several pathways of iron metabolism are altered depending on systemic glucose levels, whereas insulin action and secretion are af-fected by changes in relative iron excess. Increased hepcidin concen-tration and negatively changed iron metabolism is common in diabetes mellitus due to its progression and chronicity, especially in patients with poorly controlled diabetes. Insulin cause a stimulation of iron uptake by fat cells, redistribution of transferrin receptors from an intracellular mem-brane compartment to the cell sur-face. Oxidative stress play a core role in both iron and insulin metabolism. In the review associations between iron and diabetes are presented.

Żelazo jest niezbędnym elemen-tem do życia komórek. Ma ono nie-zwykłą własność zarówno oddawa-nia jak i przyjmowania elektronów oraz odwracalnego wiązania z takimi ligandami jak tlen czy azot. Żelazo odgrywa istotną rolę w transporcie i gromadzeniu tlenu, metabolizmie oksydacyjnym, wzroście komórek i ich proliferacji. Szereg białek bierze udział w metabolizmie żelaza, w tym hepcydyna, której ekspresja i stęże-nie jest regulowane przez hipoksję, zasoby żelaza i stan zapalny. Cukrzy-ca jest także uważana za przewlekły stan zapalny. Opisywano dwukierun-kowe związki cukrzycy i żelaza. Wiele dróg biorących udział w metabolizmie żelaza jest zmienionych w środowi-sku hiperglikemii, ponadto działanie insuliny i jej wydzielanie jest zabu-rzone w warunkach nadmiaru żelaza. Stężenie hepcydyny jest zwiększone w cukrzycy, koreluje z progresją cho-roby i jej powikłaniami, szczególnie w sytacji złej kontroli choroby. Insu-lina powoduje pobudzenie wychwytu żelaza poprzez komórki tłuszczowe, redystrybucję receptorów transferyny z części wewnątrzkomórkowej błony na zewnątrz. Stres oksydacyjny od-grywa kluczową rolę zarówno w meta-bolizmie insuliny jak i żelaza. W pracy omówiono związek żelaza i cukrzycy.

one of most important microelements is iron, which contributes to variety of meta-bolic and physiological pathways. owing to its 2 oxidation states ferrous iron (Fe2+), ferric iron (Fe3+) and cycle between those 2 forms, iron gained its catalytic ability. It can quickly act in one-electron oxidation-reduction reactions [1,2] because of its unique ability, iron has a vital role in en-ergy production, oxygen transport and vari-ous enzymatic reactions. Furthermore this element has a role as enzyme cofactor, including dopamine hydroxylase or trypto-phane hydroxylase and it is indispensable for proper proceeding processes in mito-chondria [3]. As haemoglobin component, iron is taking part in transport of oxygen, which is a life-basal process. Although it is very useful, in excess it can be very harm-ful, because of its ability to catalyse forma-tion of oxygen radicals.

Maintenance of iron balance in human body has a dynamic course, yet in adults

this cycle is almost closed. one of the characteristic features is lack of physio-logical pathway of removing iron from the body apart from menstrual loss of blood in women in reproductive age [4]. daily iron requirement for is more than 20-30 mg. Normally only 1-2 mg dietary iron is absorbed through intestines, which corre-sponds to lost iron through skin, bleeding, urinary and gastrointestinal tract [5]. Most of plasma iron is from macrophages, which phagocytes damaged or old erythrocytes and recycles iron from them. Average adult contains 3-5 g of iron in the body [6] with more than 2/3 of it is present in haemo-globin in both developing precursors and mature erythrocytes [7]. plasma contains about 2% of systemic iron [8]. Around 20% as a intracellular storage iron in macropha-ges and hepatocytes, where it is bound by ferritin (Fr) [9]. Fr when it is needed can bound 4500 atoms of iron, prevent toxic influence of elevated plasma iron [9]. The

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remaining body iron is in myoglobin and various proteins and enzymes [6]. roughly ~3 mg of iron (less than 0.1% of body iron) circulates in plasma carrying by transfer-rin (Tf), which is also the best indicator of iron transport [6]. In result proteins bound almost all iron in the body. As there is no pathway to excrete iron, so its intake is regulated by intestinal absorption [10,11]. Iron from diet is absorbed in the duodenum and the upper portions of jejunum. The cells located in the upper part of villi called apical enterocytes are responsible for iron transport from duodenal lumen to the blo-od. enterocytes are bipolar cells with api-cal and basal-lateral membranes equipped with sets of proteins that participate in both iron uptake from food and its release to the bloodstream. Absorption of iron ions requ-ires their transfer through two contralateral parts of cellular membrane. This process requires not only the participation of mem-branous transporters but also the activity of enzymes which change oxidation level of the transported iron ions. enterocytes located on the surface that faces intestinal lumen contain proteins dMT1, divalent me-tal transporter 1), [12] and ferroreductase,--duodenal cytochrome b -dcytb [13] The basal-lateral surface is connected to the vessel lumen and contains transporter, - ferroportin (Fpn) [13] and ferroxidase,- he-phaestin (Heph) [14].

The ferric iron which is principal form of dietary iron must be reduced to ferrous iron Fe2+ before absorption by apical entero-cytes membrane. This reaction is catalysed by duodenal cytochrome b (Cybrd1). It is reduced by brush border membrane ferric reductases. After reduction, Fe2+ is trans-ported into enterocytes by proton-coupled divalent metal transporter 1 (dMT1) [15]. This is the main protein involved in process of absorption. Iron can also be absorbed in form of heme. but this type of uptake is not well understood, it might involve a special-ised heme carrier. The process of reduction is done by dcytb. The same protein per-mit for transport iron from endosomes to cytosol in other types of body cells. dcytb uses ascorbinian as a donor of electrones for reduction Fe3+ [16]. In case of iron de-ficiency or increased production of eryth-rocytes, the cells of mucous membrane produce a small amount of ferritin, while most of iron entering the cell is available for transport through basal-lateral membrane. The rest of iron is exported to the blood-stream through ferroportin which is strongly related to hephaestin enzyme. Ferroportin is a large transmembranous protein which can be found in duodenum as well as in the cells of liver, pancreas, kidneys and in Kupffer cells [17]. Hephaestin oxidises Fe2+ to Fe3+ ions in the blood and this form of iron connects to apotransferrin and forms transferrin [14]. Transferrin is major iron delivery protein. Tf binds two atoms of ferric iron [14].

Iron binding by transferrin depends on pH, yet this process is most effective in neutral pH plasma. Transferrin supplies iron to cells by binding on their surface to the transferrin receptor (Tfr) [18]. Next,

transferrin -Tfr complexes are internalised to intracellular vesicles. In a low pH intra-vesicular environment iron is released from transferrin molecule, reduced to Fe2+ by reductases and transported by endosomal membrane to cytosol by means of dMT1 receptor [19]. processes of association or dissociation depends of pH (the most ef-fective binding in pH around 7.4 [18]. The process of iron transportation to cells un-dergo with receptor mediated endocytosis by transferrin receptor 1 (Tfr1). Tfr1 is located in many cell types, but the highest expression was found in erythroid cells, neoplastic cells and placental syncytiotro-phoblasts [6]. Transferrin-Tfr complex is closing into endosomes and absorbing. In-side endosome pH is around 5.5, which en-ables for releasing iron from proteins. For transport from endosome to cytosole by dMT1, free ferric iron needs to be reduced to ferrous iron with sTeAp3 reductase. In-side target cells iron can be storage with Fr mentioned above. binding to Fr is on iron oxidation state (Fr is binding Fe3+ ox-idized by ceruloplasmin). Inside the cells, iron may be stored in the form bound to fer-ritin which is the major iron-storing protein in the body. The process of binding iron with ferritin depends on the change in iron oxidation level (from Fe2+ to Fe3+),which involves ceruloplasmin [19,20]. Iron ab-sorbed from diet is the only exogenous source of this microelement, yet is not the only source in general. Iron deficiency is balanced mainly with the iron regained from dead red blood cells. dying red blood cells are removed by reticuloendothelial macrophages which metabolise haemo-globin and haem, and release iron into the bloodstream. Through analogy to intestinal enterocytes, macrophages produce Fe 2+ from cellular membrane through FpN in the process connected by re-oxidation of Fe 2+ to Fe 3+ through ceruloplasimin, and next Fe 3+ charge to transferrin [21]. Ferroportin is strictly connected with hepcidin – anoth-er protein responsible for regulation of iron absorption and storage. when plasma iron saturation is increased, hepcidin released from liver incorporate to ferroportin, which causes its internalization and degradation [6]. The level of hepcidin is increasing not only by iron, but it could be induced by in-flammation. This phenomenon is present in pathophysiology of anemia in diabetes and chronic kidney disease.

The amount of iron absorbed from diet constitutes only about 10% of iron regained from old erythrocytes. regulation of iron absorption is aimed at both collecting a su-itable amount necessary for proper course of erythropoiesis and avoiding the absorp-tion of iron excess from food. The control of the amount of absorbed iron involves systemic and regional factors localised in duodenal enterocytes. The main systemic factor is hepcidin [22,23] while regulato-ry proteins in enterocytes include HIF-2α [10,24], ferritin [11] as well as Irp1 and Irp2 [25,26]. These regulatory factors un-dergo numerous interactions, which is why regulation of iron absorption seems to be a highly complex process [27-29].

Iron and diabetes Hyperglycaemia accompanying diabe-

tes exerts direct impact on the progress of inflammatory condition caused by in-creased expression of proinflammatory cy-tokines such as IL-6, TNFα and NFκB. Therefore, diabetes can be also consid-ered as a disorder of inflammatory nature. According to studies, the longer disease duration and/or loss of control over glycae-mia, the stronger inflammation [30,31]. The bidirectional link between iron metabolism and glucose homeostasis is described to a great extent. several pathways of iron metabolism are altered depending on sys-temic glucose levels, whereas insulin ac-tion and secretion are affected by changes in relative iron excess [32]. Furthermore, iron impacts on glucose metabolism even in the absence of meaningful iron overload [33]. Impaired iron metabolism in the form of iron overload in the body causes pro-gressive and sometimes irreversible dam-age to the organs, which in turn may lead to the development of numerous systemic diseases including diabetes (dM) [34-37]. The relationship between iron and dM was first noticed in clinical observations of pa-tients with pathologic iron overload such as hereditary hemochromatosis (HH) and ta-lasemia beta [38]. diabetes commonly ac-companies these disorders as a sequel of iron overload, which is why hemochroma-tosis was primarily referred to as ‘diabetes bronze’ [37]. since patients suffering from hemochromatosis have been described to have strongly increased prevalence of T2d, iron overload is suspected to play a role in its pathogenesis [39-43]. It has been observed that even in seemingly healthy populations, increased iron intake with diet and iron concentration in the body expressed by ferritin in the serum corre-lates with increased risk of developing type 2 diabetes and other insulin resistant con-ditions [44-51]. Furthermore, excessive iron overload in the body has toxic effect on the liver and causes insulin-resistance. In case of increased hepcidin level and de-creased ferroportin concentration, iron is accumulated in adipocytes. This leads to reduced production of adiponectin which is responsible for sensitivity to insulin and thus increased insulin-resistance occurs [52]. The impact of iron excess on diabetes development is confirmed by the fact that reduction of iron concentration through phlebotomy or iron chelation improves gly-caemia control [53-55]. It has been demon-strated, that frequent blood donation in healthy volunteers leads to a decrease in iron storage, reduces postprandial hyperin-sulinaemia [56], increases sensitivity to in-sulin [57] and constitutes a protective fac-tor of type 2 diabetes development [58]. The mechanisms through which iron con-tributes to diabetes pathogenesis have not been fully understood so far, yet seem to be multifactoral and may vary depending on the cause of iron overload and iron dis-tribution in tissues [34]. According to sub-sequent studies, body iron stores, ex-pressed as serum ferritin concentration, are positively associated with the higher

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risk to develop impaired glucose metabo-lism (IGM, ’prediabetes’), T2d [40,41], and gestational diabetes [59,60]. Huth et al. [61] published the study showing that ferri-tin results adjusted for numerous possible confounders and the estimated strength of the association is very similar between indi-viduals with T2d and IGM and stronger in newly diagnosed than in known diabetic cases. It may also suggest that increased body iron (expressed as ferritin levels) might be a factor in the early T2d patho-genesis [61]. It is worth to note, that ferritin is an acute-phase reactant, it can be ele-vated independently of iron level in the case of chronic inflammation, liver disease or insulin resistance, which are also associ-ated with type 2 diabetes [43,62]. on the other hand, type 2 diabetes is a disorder characterised by chronic inflammation [32]. The doubt whether high iron expressed as high ferritin causes diabetes or diabetes causes high ferritin. It was concluded that the independent markers of inflammatory stress (such as Crp) did not account for the association of ferritin with diabetes [34,35]. other studies have also evidenced that the diabetes risk related to high iron is

not accounted for by HH or inflammation but rather is associated with dietary iron overload [36,45]. except for ferritin, there is limited evidence for additional biomarkers of iron metabolism and their association with T2dM. However, the investigations of them might help explain the role of iron in the pathophysiology of diabetes, because they are regulated differently and might act through independent pathways. Transfer-rin, the main iron transport protein has been much less investigated. It is known that transferrin is synthesized growingly if body iron stores are decreased, and thus transferrin is inversely correlated with ferri-tin. recent study has reported strong posi-tive associations between higher transfer-rin concentrations and both IGM and T2dM. Moreover, these results were inde-pendent of all other investigated risk fac-tors [61]. Two other studies with smaller cohorts reported association of increased transferrin levels with higher fasting insulin, 2-h glucose, and HoMA-Ir. These reports also described a higher risk to develop inci-dent hyperglycemia and T2dM with higher baseline transferrin concentrations [36,47]. These results were consistent with obser-

vation of increased transferrin levels al-ready seen in IGM individuals from study by C. Huth. et al. [61]. blood testing of the soluble transferrin receptor (sTfr) is inves-tigation also used in detection of iron defi-ciency, which is demonstrated by increased levels. Transferrin serum concentration is consistent to the total iron binding capacity. In case of decreased body iron stores, its levels increase and vice versa. Transferrin saturation (TsAT), percentage of the total iron binding capacity, is also a useful indi-cator of iron status in the body. The result shows iron overload and by contrast de-creased TsAT indicates iron deficiency. C. Huth et al. [61] in their meta-analysis of relative risks (rr) estimates reported a significantly higher risk of T2d if the TsAT is ≥50% (the normal range - 20%-50%) what also may demonstrate iron overload [61]. In contrast, their meta-analysis of TsAT mean differences had lower levels in type 2 diabetic subjects [46]. These incon-sistent findings should be clarified future studies. Comparing to ferritin and transfer-rin which may be elevated in inflammatory states, sTfr is insensitive to inflammation. However, recent studies investigating as-

Table 1Proteins taking part in regulation of iron metabolism (modified according to 2).Białka biorące udział w metabolizmie żelaza (zmodyfikowane wg 2).

protein Abbreviation Function in iron metabolismTransferrin Tf Iron transfer in plasma

Transferrin receptor 1 TfR1 Internalization of holo-Tf

Ferritin Ft Iron storage in cells

Divalent metal transporter 1 DMT 1 Epithelial/endosomal transport of ferrous iron

Duodenal cytochrome b Dcytb Apical membrane iron reductase (enterocytes)

Haptoglobin HP Hemoglobin binding and endocytosis with CD163

Lipocalin 2 Lcn 2 Uptake iron in kidney

Ferroportin FPN1 Transport of ferrous iron

Hephaestin HEPH Membrane-bound ferroxidase

Ceruloplasmin CP Ferroxidase (plasma)

Hepcidin HEPC Inhibition of ferroportin- mediated iron outflow

Bone morphogeneticprotein 6 BMP 6

Adjustment of hepcidinexpression in response to

hepatic iron

Transferrin receptor 2 TfR2 Adjustment of hepcidinexpression by plasma iron

Iron regulatoryprotein 1 IRP1 Posttranscriptional adjustment of mRNAs

Iron regulatoryprotein 2 IRP2

Posttranscriptionaladjustment of

mRNAs

Table iiMain proteins and storage of Iron. (modified according to 17).Białka biorące udział w magazynowaniu żelaza (zmodyfikowane wg 17).

iron [g] iron storage [%]Total 3.5–4.5 100

Haemoglobin 2.18-2.76 62.0-66.0

Ferritin and haemosiderin 0.5-1.0 19.0-25.0

Myoglobin 0.15-0.18 4.5-5.0

Transferrin 0.005-0.007 0.14-0.17

Cytochromes and other enzymes 0.03 0.7

A. Zapora-Kurel et al.

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sociation between sTfr and risk of T2dM were controversial, because we may ob-serve strong heterogeneity between the described study results [47-51]. Hepatic extraction and metabolism of insulin are reduced with increasing iron stores lead-ing to peripheral hyperinsulinemia via both decreased insulin extraction and impaired insulin signaling and many studies con-firmed that during diabetes type 2 iron load is increased [51,63]. It is known that iron metabolism is regulated in liver by hepcidin [64,65] which is synthesized in response to iron overload and it controls the efflux of iron from duodenal entero-cytes and macrophages [65,66]. previous studies have shown that inflated cytokines manifest crucial function in hepcidin pro-duction. Additionally, Il-6 acts directly on hepatocytes to stimulate hepcidin produc-tion [67]. Moreover, clinical studies have demonstrated higher hepcidin concentra-tion in patients with diabetes, which corre-lated with Il-6 and ferritin concentrations [63,68,69]. Increased hepcidin concentra-tion and negatively changed iron metabo-lism is common in diabetes mellitus due to its progression and chronicity, especially in patients with poorly controlled diabetes [61]. Insulin causes a stimulation of iron up-take by fat cells, caused redistribution of transferrin receptors from an intracellular membrane compartment to the cell surface [70]. Transferrin receptors have been shown to work with insulin-responsive glu-cose transporters and insulin-like growth factor II receptors in the microsomal mem-branes of adipocytes, which suggest that regulation of iron ingestion by insulin oc-curs parallel with its effects on glucose transport [61]. Additionally, oxidative stress play a core role in both iron and insulin me-tabolism. To clarify, oxidative stress induc-es both insulin resistance (by decreasing internalization of insulin) and increased fer-ritin synthesis [71].

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