Association of Iron Metabolism Abnormalities as Etiopathogenetic Factor in Alteration of Beta Cell Function and Impairment in Generation of Diabetes Mellitus: A Systematic Review

Research Article

Association of Iron Metabolism Abnormalities as Etiopathogenetic Factor in Alteration of Beta Cell Function and Impairment in Generation of Diabetes Mellitus: A Systematic Review

  • Kulvinder Kochar Kaur ID 1*
  • Gautam Allahbadia 2
  • Mandeep Singh 3

*Corresponding Author: Kulvinder Kochar Kaur, Centre for Human Reproduction 721, G.T.B. Nagar, Jalandhar-144001, Punjab, India.

Citation: Kulvinder K Kaur, Gautam Allahbadia and Mandeep Singh. (2022). Association of Iron Metabolism Abnormalities as Etiopathogenetic Factor in Alteration of Beta Cell Function and Impairment in Generation of Diabetes Mellitus: A Systematic Review. J Clinical Research and Reports, 11(1); DOI:10.31579/2690-1919/241

Copyright: ©2022, Kulvinder Kochar Kaur. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 10 March 2022 | Accepted: 25 March 2022 | Published: 04 April 2022

Keywords: ironmetabolism; β cells function; ROS; DM; Alzheimer’s disease; DNA; IR

Abstract

Iron constitutes an essential element that is implicated innumerous physiological functions. In the context of the pancreatic β cells, they act as components of   the Fe –S cluster proteins, which are a must for the appropriate insulin generation and processing. As far as mitochondria are concerned , in the form of a constituent of the respiratory  chain it aids in the generation   of ATP along with Reactive oxygen species(ROS),that result   in induction    of β cells depolarization   that causes potentiation   of   insulin liberation  that is calcium   based .It is of great importance  that  a marked fiine tuning  gets established  with regards to the iron cellular amounts   to guarantee normal  provision of Iron along  with  avoidance of iron overload. Actually, in  view of the great reaction  with  oxygen in addition to  the generation  of free radicals , iron overload might result in Oxidative injury  of cells that possess  susceptibility  to this situations in view of the normal escalation  of  ROS development besides  lesser  availability of antioxidant enzymes action .Thus here we conducted a systematic review utilizing usual search engine utilizing  the MeSH; iron metabolism; DM; haemochromatosis; thallasemia; Alzheimer’s ;Parkinson’s  disease ; Friedrich’s ataxia; Iron homeostasis; Iron binding protein; transferrin  bound iron(TBI); non TBINTBI); Divalentmetal transporter I(DMT1); ferroportin; islet amyloid polypeptide; zinc transporter  ZIP 14; Chaperone  proteins- poly CR binding proteins(PCBPs); mitoferrin(Mfrn); Fe-S   clusters - enzyme CDKAL1; hepcidin; hephaestin; frataxin ;  labile iron  pool (LIP); ABCT7; PDX1;MafA; PHD; MAMs; Miner  1;gestational DM; ferroptosis; ferroportin; iron overload &treatment ;toxicity in brain, GIT; from 1980 till 2022 till date. We found a total of 4500 articles out of which we selected  135 articles for this review. No meta-analysis was done. Main aim of this review was to get a better insight in mode of iron homeostasis in β cells, with mode of changed in this event in their damage. How abnormal iron storage/chaperon proteins might cause diabetes.

Introduction

Iron has a main part in numerous cellular functions like oxygen transportation along with exchange, constituting the metal part that possesses the capacity of development of Reactive oxygen species (ROS) which has the ability of injuring the DNA, phospholipids along with proteins. Hence it holds considerable significance with regards to cells in addition to organisms for the sustenance of homeostasis which sees to it that provision of Iron besides accrual of escalated Iron. Indeed, numerous disease events states are resultant of abnormal tackling of iron. Aberrations of   iron homeostasis has been the properties of abnormal tackling of iron. This has been the observation in haemochromatosis, anemia, atherosclerosis along with diseases that implicate the central nervous system (CNS) like Alzheimer’s disease as well as Parkinson’s diseases, Huntington’s, Friedrich’s ataxia in addition to eating disorders like pica [1-5].

Escalation of proof has suggested an etiological part of iron in type2 diabetes mellitus (T2DM). Iron is necessary for insulin liberation [6], however, its collection is of significance in   the causation of pancreatic islets inflammation, besides being believed to be a biomarker of risk of diabetes along with mortality [7].

The association   amongst  iron   along   with diabetes was initially picked up in case of patients of haemochromatosis in addition to β thallasemia [8,9], where   abundance of   iron was implicated    in  failure of β cells as well as insulin resistance (IR) was emphasized.

Additionally, in T2DM patients’ escalation of amounts of ferritin [10], that is a biomarker    of enhancement of body iron   stores    as well as   reduction  of hepcidin amounts, that is the hepatic hormone implicated in systemic iron homeostasis have been the observation in blood, that emphasizes   the systemic changes in iron metabolism [11].

Inspite of the collection of proof, the   insight in the context of molecular modes   that are correlated with   escalation of    iron as well as   diabetes is absent. Moreover, whereas   its  homeostasis might have influence     on separate organs, the islets  of Langerhans appear to have specific proneness   to   iron. The collection   of   ROS taking place in the, existence of enhancement of   iron possesses the capacity of resulting in Oxidative    injury   of the  pancreatic β cells. The robustness of vulnerability towards   Oxidative stress (OS) of these cells is secondary to enhancement of   metabolic   action [12,13], in addition to escalated generation of ROS in combination with the lowered defense modes   against Oxidative    insults. Actually, β cells   possess the properties of reduction in   expression  of super oxide dismutase (SOD), catalase (CAT), as well as     glutathione peroxidase (GPx) [12,14]. With the knowledge    of  escalation of failure of β cells  in the generation along   with propagation   of   diabetes here our Objective   is to detail   the progression   with regards to tackling of  iron along  with  iron  cross talking    proteins in   β cells  physiology in addition to pathology. A greater  insight  of  iron  metabolism  along  with  homeostasis  in  these particular  cells might aid in the  generation  of innovative treatments  for the   management  of  diabetes mellitus .Earlier we had reviewed lot of articles with regards to etiopathogenesis  that was inclusive of gut microbiota, hypothalamic gliosis, macrophage polarization alterations, genetic predisposition, obesity, epigenetic alterations in obesity  and treatment Diabetes mellitus[(DM)(both type1&type2)] [15-34]besides lot of novel modes of treatment. Here we attempt to correlate another etiological factor with the influence of iron metabolism.

Methods

Here we conducted a systematic review utilizing search engine PubMed, google scholar ;web of science ; embase;  Cochrane  review  library  utilizing the MeSH terms  like the generation of DM, namely iron metabolism; DM; haemochromatosis  i; β thallasemia; Alzheimer’s  disease; Parkinson’s  diseases; Friedrich’s ataxia; Iron homeostasis; Iron binding protein; transferrin bound    iron(TBI); non transferrin  bound iron(NTBI); iron regulatory proteins (IRPs); Divalent   metal transporter I(DMT1); ferroportin; islet amyloid  polypeptide; zinc transporter   ZIP 14; Chaperone  proteins- poly CR binding proteins(PCBPs); mitochondrial   iron  transporters    mitoferrin (Mfrn); Fe-S   clusters - enzyme CDKAL1; electron transport     proteins; hepcidin; hephaestin; frataxin;  labile iron  pool (LIP); ABCT7; PDX1; MafA; prolyl and asparaginyl hydroxylase (PHD); Mitochondria  correlated ER (endoplasmic reticulum)  membranes (MAMs); Miner  1; gestational DM; ferroptosis; ferroportin; iron overload & treatment; toxicity in brain, GIT; from 1980 till 2022 till date.

Results

We found a total of 4500 articles out of which we selected 135 articles for this review. No meta-analysis was done.

2. Homeostasis of Iron in β cells 

In view of its chemical feature in addition to probable deleterious actions, cells have generated a complicated system in the  context of tackling Iron: transportation of the ion by both carriers in addition to receptor subsequent to binding across the membranes, enzymes along with buffering proteins regulate the redox status along with free amounts, besides iron binding   proteins, as per the ion amount. There is existence of   numerous of these proteins in the pancreatic β cells, despite us not getting insight with regards to certain particular actors of this applicable event till date (figure 1) [revin 35].

Figure 1: Courtesy ref no-35-Overview of iron homeostasis in beta-cells. (a) Iron uptake in beta-cells is mediated by endocytosis of the transferrin-transferrin receptor complex and its release from endosomes by the divalent metal ion transporter DMT1. As non-transferrin-bound iron (NTBI), it can also be imported by the zinc transporter ZIP14 transporter. Being toxic as a free ion, Fe2+ is then readily distributed for storage, bound to ferritin or for utilisation by chaperoning proteins as PCBPs and lipocalin. Iron efflux is mediated by ferroportin, a process regulated by hepcidin and hephaestin. LIP: labile iron pool. (b) Within the cell, the major site of utilisation is the mitochondria, where the ion is transported via DMT1 and mitoferrin (Mfrn1, Mfrn2) and inserted into heme and Fe/S cluster prosthetic groups. Mitochondria iron efflux is probably mediated by the ATP-binding cassette (ABC) transporter ABCB7. (c) Beta-cells, together with insulin, release IAPP and hepcidin, involved in a possible modulation of iron metabolism by an autocrine mechanism, via regulation of ferroportin.

2.1 Influx of Iron via the plasma membrane

Iron uptake in β cells occur by 2 separate systems i) a receptor modulated transportation for the transferrin bound  iron (TBI) as well as a  non transferrin bound iron (NTBI) shift. The initial  mode is dependent on the crosstalk of (TBI  with the particular cell surface transferrin receptor 1 (TfRI) [6,36]. This complex   subsequently gets  internalized  in the endocytic partition with the Divalent metal transporter I (DMT1 or SLC11A2) as well as  the metalloreductase six transmembrane  epithelial antigen of the prostate (STEAP3) [37].

The vesicles subsequent  to internalization  undergo  fusion  with the lysosomal chambers along with  the acidic environment causes stimulation of the conformational alterations of Tf-Fe –complex  in addition to  the  liberation of Fe 3+, that aids in the reduction of ferrous form through STEAP3. Expulsion of this Fe 3+ occurs in  the cytoplasm via DMT1, that makes use of the H+ gradient that gets generated by the vacuolar H+ -ATPase (v- ATPase) in the form  of the pushing force [38].

More recently,  a NTBI uptake has further been the observation in the human beta cell  line βlox5 [39].The precise chemical entity of plasma   NTBI   is not clear however  it is thought  to be  existent  basically in  ferric citrate along with   other low molecular  weight species [40]. In certain pathological situations, higher molecular  weight  NTBI   plasma fractions   has been the observation, that  pointed   that   probably  binding   of    Fe 2+  as well as Fe 3+ to the proteins [41] in addition to the presence of separate  NTBI pools, that is based   on the iron overload situations [42]. NTBI might get found in the  blood of patients  in possession of  iron overload situations on saturation  of transferrin  amounts [43], despite its existence has  been the observation  when saturation of transferrin amounts  is not total [44]. Intriguingly in patients with diabetes NTBI existence is there at the saturation   of transferrin under 60% [45]. In  case  of primary human islets of langerhans, modulation  of NTBI occurs by  the zinc transporter ZIP 14 (SLC39A14) that resides   in the plasma  membrane  of the β cells at a place where  iron overload is limited. Chronically  high glucose amounts  over24h results  in   up regulation   of the expression of the  transporter  hence corroboration  of the  functional  significance  of  ZIP 14 as well as   pointed  the   probable sequelae  of iron   homeostasis [45]. Nevertheless, si RNA modulated ZIP 14  knocks down decided just by 50percentage decrease of NTBI uptake, pointed towards the implication   of other transport systems. A part of L or T kind calcium channels appears not probable in view of absence   of  iron overload in murine β cells that display their expression [46].

2.2 Efflux of Iron via the plasma membrane

How Iron   leaves the β cells   remains in controversy; ferroportin/Ireg 1(FPN1, SLC40A1)thus far remains the only  exporter  for iron believed to exist  in our  knowledge[47], as well as   islets demonstrate   markedly low immunoreactivity with regards to this transporter  [48] despite  expression of hephaestin by them. This specific protein   is implicated for the stabilization of the ferroportin, besides induction of its internalization [49], hence pointed to a positive feedback mode for Iron control at the time of   glucose stimulated insulin secretion (GSIS) that gets modulated by ferroportin regulation [50].

An alternative probable ferroportin modulator   is the islet amyloid polypeptide (IAPP) [51], that gets liberated   along with insulin playing a part in glucose homeostasis [52], besides in regulation of food   consumption [53]. Despite, its part in Iron homeostasis   in β cells has not got proved, it might point to correspondent role in neurons, where amyloid polypeptide (APP result in    stabilization of ferroportin at the plasma membrane in addition to cause induction of liberation of Iron  via ferroxidase action [54-56], hence  avoidance of   iron overload besides Oxidative stress (OS).

2.3 Proteins that are Iron binding 

With a good   regulation of Iron homeostasis, cells prevent enhancement of  deteriorating free iron. On gaining entry in the cells, they   generate  a cytoplasmic    labile iron pool (LIP)which gets concealed by ferritin, that is the only cytosolic iron    storage protein. Expression of H as well as L chains, both occurs in β cells, besides modulation  at the translational    level by  iron overload; once there is escalation of iron, escalation of ferritin generation in addition to storage of ferritin occurs [57]. Via cloistering of this element, ferritin    has a significant part   in detoxification of iron, besides working in the form of iron reserve protein. Despite, the    existence of a cytoplasmic LIP that comprises of iron that can be chelated has got observed earlier, there have been botheration with regards to iron    on internalization in the cells gets transported to ferritin through direct protein- protein crosstalk in a hydrophobic milieu, as   LIP   does not appear   to possess the properties of an intermediate iron pool [58]. Chaperone proteins, like poly CR binding proteins (PCBPs) [59], get implicated in this   event.   All the 4  PCBP isoforms whose knowledge we possess have the capacity of binding as well as transportation to cytosolic ferritin [57], however displaying     various capacities   of iron chaperone. Like just PCBP2   possesses the capacity of    binding  with the carrier systems like DMT1 as well as FPN1, in an iron-based method [60]. PCBP1 as well as PCBP2 both possess the capacity of transportation of iron to ferritin, with only PCBP1   being foundational in ferritinophagy, that constitutes   a recycling event [61], where iron- ferritin complex gets engulfed by the nuclear receptor coactivator4(NCOA4) as well as is   given direction towards the autophagosome [62].

Both PCBP1   as well as PCBP2 expression   in pancreatic β cells   have been demonstrated, however their particular part   in iron   tackling  as well as if they are further implicated in transportation of iron to intracellular organelles as well as FeF proteins has not been proved in this cell kind.

2.4 Exchange of iron   with organelles 

Despite the observation of iron   with practically each   intracellular organelle, it is the mitochondria that is believed to be the major storage house with regards to iron cellular metabolism.

Actually, they represent the main station where iron storage in addition to utilization of  iron occurs. Key generation of heme as well as iron-sulphur (Fe-S) clusters of electron transport  proteins occurs amongst them.

The  iron exchange with   mitochondria is believed to be modulated via DMT1 as well as the   traditional   mitochondrial iron transporters mitoferrin (Mfrn)1 as well as 2 [63], as the one that is thought to be the 2nd greater particular with respect to non- erythroid cells [64]. Besides that, lipocalin (LCN) protein 2 is further implicated in this event of chaperone protein [6,65]. The continued  expression of   DMT1 has been the observation in case of HK293 that is the transporter existent at the outer cellular mitochondrial membrane (OMM) [65] in addition to implicated in, Fe 2+ as well as Mn2+ uptake [67]. Mfrn1 as well as 2 make sure that iron gets shifted across the inner mitochondrial membrane, where utilization of iron takes place for heme generation in addition to Fe-S clusters bio generation or gets isolated   by the  mitochondrial ferritin (MTFT).

The generation   of   Fe-S  clusters  needs frataxin   i.e. an iron mitochondrial chaperone whose  expression   occurs   in   islets  along with  β cells, besides  getting induced  under , hyperglycemic situations[68].  Friedrich’s ataxia(FRDA) is a neurological  disorder   involving neurodegeneration that occurs  secondary to frataxin deficiency in persons afflicted by this disease, in which non neurological  sequelae like  diabetes  or glucose  intolerance occurs as well  with the incidence, of 8-32%[69].Thus these patients,  have a  manifestation of iron overload in addition to β cells apoptosis, which further corroborates the association with impairment of Iron homeostasis along with diabetes.   

Iron gets exited from the mitochondrial matrix, the ATP-binding cassette (ABC) transporter gene ABCT7 is thought to cause Iron efflux as Fe-S clusters. This posit is dependent on the action of yeast orthologue Atm1 [70], which possesses the capacity of transportation of glutathione harmonized Fe-S  clusters   that connects the mitochondrial as well as cytosolic Fe-S cluster congregating systems [71]. More recently, Pearson et al. [72], corroborated this substance particular relation, emphasizes the part of Mg-ATP in this event of transportation [72]. Furthermore, an extra mode for Iron efflux from the mitochondrial matrix might be the exportation of heme by particular transporters [73].

Moreover, Iron can get supplied to the mitochondria via direct connection with the other organelles. In the generating erythroid cells for which effectiveness of iron supply to mitochondria for aid in heme generation, direct iron supply from  endosomes   to mitochondria for a mode described ( ‘’as kiss as well as run’’) mode [74], where shift of the cation gets modulated has been detailed via the voltage dependent anion channel (VDAC1) or DMT1[67].  In view of the applicable part  that gets   played by [67] iron in insulin liberation, akin modes of iron supply to the β cells can be believed to  be  existent, with the knowledge that akin event having been detailed in the epithelial cell [75].

Regions where   mitochondria   as well as  lysosomes  come  in  close proximity  that is not associated with  mitophagy or breakdown of mitochondrial vesicles by   lysosomes have further been detailed by    the aid of high resolution microscopy   [76].Validating  the functional importance  of these   intricate  contacts  with regards to iron transport in  case of  erythroid progenitors  ,where administration of lysosomal- transferrin    to mitochondria gets modulated   by the TfR2 isoforms ,if there is  TfR2deficient   state reduction  of mitochondrial size along   with heme generation  results [77]. Moreover, in cases of fibroblast   from patients afflicted by  neurodegeneration with brain iron   accrual, aberrations of mitochondrial function, besides reduction in proteolytic action of lysosomes  have been seen [78], that pointed that another mode of intracellular iron trafficking that is dependent on the  crosstalk amongst mitochondria as well as a lysosome.

Mitochondria correlated ER (endoplasmic reticulum) membranes (MAMs) might further be implicated   in the Iron homeostasis    of the cell. If Cisd2  is   deficient (CDGSH  iron-sulphur domain2) an  Fe-S protein that  resides on    MAMs results  in mitochondrial  impairment, besides  impairment, of Ca2+   homeostasis causing  an insulin sensitivity reduction in   case of  adipocytes [79]. Intriguingly in yeast deletion of protein complex ERMES (endoplasmic reticulum mitochondria encounter structure) that bridges 2 organelles, decides an   Iron deficiency   reaction   in Iron   depleted situations as well a, that results in escalation of iron   in the cell [80]. Moreover, vacuolar protein   sorting 13 (protein (VSP13p) dominants mutants rescue the ERMES mutants, that results in repression of Iron deficiency reaction. Till now Identification of no   transporters   with regards to iron transportation to endoplasmic reticulum (ER) have got proved. The 2 Fe-2S protein iron-sulphur domain2 (Miner 1) that resides in ER other cell types besides has importance in ER intactness [81] might be implicated in this function [82].

2.5 Regulatory proteins for Iron metabolism 

Since both iron deficit in addition to iron overload might be deleterious, in β cells, iron genes   regulation   occurs post transcriptionally controlled by iron regulatory proteins (IRPs), that is dependent on how much   iron   is available [83]. They are RNA binding proteins, which via binding  to IRE  sequences    that are  existent   on the mRNAs of  iron  tackling proteins,   manipulate their  translation. Specifically   in situations of Iron deficiency, IRP binding occurs with TfR1, DMT1 besides ferittin mRNA along with facilitates their translation, hence resulting in escalation of iron absorption along   with its storage [83]. Simultaneously IRP results in repression of FPN1 translation, hence reduction in cellular iron liberation [84]. IRP 1 as well as IRP 2 both get expressed in β cells, with IRP 2 knockdown mice   generate  type2 diabetes mellitus (T2DM) in view of aberrant iron metabolism [85].

3.1 Requirements of iron with regards to normal β cells function

Expression of greater amounts  of iron in addition to  storage   proteins gets displayed  by β cells besides demonstrate, escalation of iron metabolism in contrast to alpha as well as   delta cells . The  reason  being iron   acts as a cofactor  of various enzymes besides being  a necessary  constituent of Fe-S cluster proteins that are implicated  in important functions that  vary from i)insulin liberation  to ii)β cells proliferation, as well as   differentiation (figure 2).

Figure 2: Courtesy ref no-35-Iron is relevant for beta-cell function and preservation. Beta-cell iron homeostasis is under the control of the iron regulatory proteins (IRPs). Fe-S-cluster proteins are necessary for the correct processing and synthesis of insulin. The Fe-S cluster enzyme CDKAL1 is responsible for the adenosine methylthiolation in the tRNA for lysine, a modification required for the pro-insulin translational fidelity in pancreatic beta-cells. CDKAL1 is under the control of IRP2 (1). Iron is also essential for the metabolic coupling of insulin release: obligatory steps of the tricarboxylic acid (TCA) cycle are mediated by iron-dependent enzymes, and Fe-S cluster proteins are part of the respiratory chain complexes, allowing the synthesis of ATP (2). As a co-factor of the prolyl and asparaginyl hydroxylase (PHD), iron controls the degradation of hypoxia-inducible factor HIF-1α factor, influencing beta-cell response to hypoxia (3). Iron is also necessary to control inflammation, as PHD hydroxylates and inactivates the inhibitor of κB kinase (IKKb), an important upstream regulator of nuclear factor (NF)-kB (NF-kB) pathway, the major pro-inflammatory pathway in beta-cells (4)

In agreement with this probability, mouse that have iron   deletion reveal abnormal glucose stimulated insulin secretion, besides upregulation of transferrin surface expression in situations of glucose absence [86].

Insulin generation as well as liberation are significantly   based  on iron. Pro insulin translational allegiance  in pancreatic β cells needs the action of the Fe-S cluster enzyme CDKAL1. This enzyme is implicated  for the adenosine methylthiolation in  the  t RNA  for lysine ,a  modification that  is the requirement for sustenance  of the correctness of the codon recapitulation at the time of protein translation. On impairment of CDKAL1 function resulting  in codon   incorrect  reading   in addition to  dysregulation  of Proinsulin getting  processed as well as   liberation[85]. Intriguingly, mice with absence of IRP2 protein get the generation of T2DM secondary to subsequent  iron deficiency, hence resulting in reduction of function of CDKAL1 [85].

Furthermore, iron requirement is there for the effectiveness of coupling of glucose   metabolism along with insulin liberation. A crucial step for this mode is the glucose oxidation in the tricarboxylic acid (TCA) cycle for the generation of reducing equivalent, whose utilization by the respiratory chain   results in the   generation of    the proton gradient   that causes stimulation   of ATP generation. The escalation of   the ATP: ADP ratio as a result   causes the closure of the ATP-sensitive-K+ channel (K ATP)- depolarization of the plasma membrane; the resulting  opening of voltage-gated Ca2+ channels (CaV causing insulin liberation). Iron is implicated in the   TCA cycle as the succinate dehydrogenase as well as   aconitase that are   implicated in the catalysis of the mandatory steps in the cycle are both iron based  enzymes. ii)Furthermore, direct regulation   of ATP generation   is caused by iron, since Fe-S   cluster protein is part of complex I, II, III as well as   IV of the mitochondrial respiratory chain.  In agreement   with this probability in case of Ins-1 E β cell-line, silencing of ZIP 14 resulting in reduction   of iron transportation into cells in addition to down regulation of numerous metal binding proteins, like the cytoplasmic iron detecting protein aconitase 1(ACO1) as well as ribosomal mitochondrial proteins, impacting  the Oxidative phosphorylation along   with liberation of insulin [45].

ii)Moreover indirect regulation of iron with regards to modulation of liberation of insulin occurs via the generation of ROS. Numerous steps in the insulin liberation possess sensitivity   to the redox balance, like the depolarization of the plasma membrane; that gets initiated by the   closure of the ATP-sensitive-K+ channel gets corroborated by the stimulation of the  nonspecific  cation channels (NSCC) [87]. Moreover, at the time of granule fusion the activity of voltage-gated Ca2+ channels (CaV) get   magnified  by the liberation of calcium from the ER, via a ROS based activation of the ryanodine   receptor 2 [33,88].

iii)Furthermore, pancreatic β cells physiology   gets   controlled by iron, like proliferation, differentiation as well as    survival. In the form of a cofactor of the HIF prolyl as well as asparaginyl hydroxylase (PHD), iron regulates the hypoxia inducible factor 1 alpha (HIF 1-α) breakdown besides participation in the β cells reaction to low   oxygen situations [89]. During normoxia, PHD   causes  hydroxylation of  HIF 1-α, hence resulted in  its  breakdown; whereas at the time of hypoxia or iron  absence, PHD become inactive  with HIF 1-α translocating  to the nucleus  as well as   causing regulation  of numerous  genes   transcription that are implicated in  the control  of the anaerobic glycolytic  pathway. Consequently the  modification of cellular  metabolism occurs, with the cells moving from a  proliferation phase towards a     resting phase .In validation  of this  part  absence   of  iron in view of lysosomal impairment, resulted in   the stimulation  of  the   HIF 1-α signaling with a resultant proliferation becoming  dysfunctional [90].

iv)Via its association with HIF 1-α, iron   might further impact the control of β cells working that gets modulated  through the circadian   clock mode. The metabolism of glucose in addition to insulin liberation are controlled by this mode in the β cells [91], along with interference with these circadian     modes is implicated in the generation of T2DM in rodents along with humans [92,93]. Actually, a reciprocal crosstalk amongst the  clock genes  away the HIF 1-α transcriptional programming appears clear ,having the knowledge  that HIF 1-α possesses the capacity of binding the promoter area of the clock genes in addition to  regulation of their  transcription, at the minimum  chances in  skeletal muscle cells [94], as well as on the other hand HIF 1-α by itself represents a direct target for  transcription by the orthologue  of Clock  gene,  NPAS2,in Hepatocellular carcinoma(HCC)[95]. Moreover, various iron associated genes as well as PHD get  regulated at transcription   level by the clock genes [96], which pointed that a circadian control of iron homeostasis is existent, which possesses the probability of being significant in the regulation of tissue particular metabolic reprogramming, that is dependent on oxygen as well as   fuel existence. Intriguingly, alterations in Clock, NPAS2, as well as   a Baml1 expression have been seen amongst newborns as well as adult rat islets, as acquiring circadian regulation of insulin liberation aids immature islets, possessing the properties of amino acid stimulated insulin bio generation as well as liberation, for attainment of the mature capacity of insulin liberation  as a reaction to escalation of  glucose   amounts [97].

An appropriate consumption is further essential in β cells for regulation of inflammation in the form of  iron based PHD hydroxylates, besides inactivation of the inhibitor of κB kinase (IKKb), that is an upstream significant controller of the nuclear factor κB(NFκB) pathway, that is the biggest proinflammatory pathway in β cells [98].

More recently, the results have pointed that probably there is implication of iron in β cell differentiation. Actually,  TfR1, amounts, transferrin  bound  iron uptake as well as ferritin transcripts get upregulated in early post-natal weeks     of the β cell maturation [86].This finding  pointed that               an escalated need  of iron  precisely at the time of   metabolic  shifting  from aerobic glycolysis  to Oxidative  phosphorylation,   that is essential  for β cell maturation[99].As documented earlier ,various  iron based  proteins are  needed for the maintenance of action of the  totally mature  β cells that are functional  .

The biophysical properties  of the extracellular milieu   might impact the  cell differentiation  as well as    survival of human  islets of Langerhans  along with β cells as  demonstrated by Galli, et al [100].Their observation was that the extracellular matrix[ECM), nanotopography, through a mechanotransduction pathway ,that implicates  a mechanosensitive integrins with reorganization of the actin  cytoskeleton along  with alterations in nuclear  architectonic, that stimulates  a particular transcriptional program that is essential  for  the metabolic   adjustments of the cell towards the  new surroundings. This reaction gets modulated by modifications of the mitochondrial action as well as    dynamics besides implicated in the inter action of mitochondria with other organelles like lysosomes as well as ER, where iron gets exchanged [74,80] that further posits a probable part   of iron with regards to this signaling.

3.2 β cells impairment occurs secondary   to iron overload   

A normal   iron amount is   needed for appropriate β cells function, however its escalation results in toxicity based   on generation of ROS in addition to enhancement of stimulation    of the Oxidative pathways (figure 3).

Figure 3: Courtesy ref no-35-Iron-mediated toxic effects in beta-cells. Iron-mediated beta-cell toxicity is mainly due to reactive oxygen species (ROS) accumulation through Fenton’s reaction. ROS excess determines DNA, lipid and protein oxidation that causes mitochondrial damage, leading to insulin release and apoptosis (1). ROS also influence the activity of the pancreatic and duodenal homeobox 1 (PDX1) and V-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), critical transcription factors for the control of insulin gene [removed]2). Iron can induce beta-cell loss also through ferroptosis, a non-apoptotic cell death mechanism characterized by lipid ROS accumulation due to glutathione (GSH) depletion and consequent glutathione peroxidase-4 (GPX4) inhibition (3).

Hereditary haemochromatosis (HH) models have demonstrated, that iron accrual influences greater β cells in contrast to α cells or δ cells [101], possibly in view of the reduction of the ROS detoxification in   this cell subkind.

Variety of modes have been posited mechanistically as a reason for iron toxicity; i) directly subsequent to  intracellular   iron overload, since  in the form  of a  positively charged ion    on gaining entry to mitochondria it can result   in depolarization of  the organelle membrane potential that has     an  impact on the electron transport chain (ETC), along  with  the energy liberation for insulin secretion [102]. Iron accrual  can   result in the development of ROS directly as well as   indirectly. The active iron state (Fe 2+) results in  oxidation of lipids in a Fenton’s like reaction with resultant ROS modulated DNA as well as  protein oxidation, reduction in insulin generation  as well as   liberation, besides apoptosis as seen in the homeostatic iron  regulator (Hfe) knockout  mouse model  of HH[103]. Noticeably other robust iron overload  models that impact hepcidin expression like Hamps as well as Hjv  knockout along with  the hepcidin resistant model that possesses  p.C326S mutation  in ferroportin, despite manifesting pancreatic iron collection, do not display liver disease or endocrine abnormalities, possibly  in view of higher Oxidative  stress damage  of mouse models[104].  The pancreatic    as well as duodenal   homeobox1(PDX1), in addition to V-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog (Maf A), are 2 key transcription factors implicated in the regulation of insulin gene expression are the targets for ROS [105], along with reduction of hepcidin expression in the MIN6 cells with resultant hampering   of insulin generation   through iron overload along with reduction of PDX1 expression [106].

Furthermore, reduction of    the  β cells   oxidant defenses takes place by iron overload via the hampering of the enzymes implicated in detoxification of ROS, like the, Mn2+ uptake as well as Mn2+   based  SOD action [107].

Ii}An alternative mode of iron overload influence might be on the β cell  function, besides survival through amylin. Misfolding along  with accrual of Human islet  amyloid polypeptide(HIAPP)- in the ECM as well as within β cells observation  occurred  studies in the  postmortem pancreas of subjects afflicted   by DM [108],where this polypeptide   demonstrated   cytotoxic  action that was secondary to the disturbance  of the cell membrane, disconcerted   ion  homeostasis ,ER stress , mitochondrial injury  along with  impairment in addition to Oxidative  stress[rev in109].Interestingly  iron has been demonstrated to result  in  escalation of amylin amyloidal  beta sheet generation, that causes  stimulation of the precipitation  of amyloid  aggregates [110]. Moreover, in the form of amylin, generation of a Heme Aβ and Heme- HIAPP  complexes which might cause resultant generation of   H2O2 through Oxidative stress [111,112], hence facilitation of β cells failure.

iii)More modes by which iron aids   in the impairment of β cells failing along with demise is Ferroptosis which represents a nonapoptotic form of cell demise that occurs secondary to   iron accrual.  Initial observation of Ferroptosis was seen in   cancer cells that had received treatment with glutamate/cystine exchanger (Xc) inhibitor elastin [113]. The properties of this are lipid ROS collection   in view of hampering of glutathione peroxidase (GPx), by glutathione (GSH)deletion. Glucolipotoxic situations in mouse have been documented to cause escalation of β cell Iron import along with cytosolic ROS generation [114]. Moreover, pharmacologic  hampering of GPx4 generation has  been demonstrated to cause  glucose modulated   β cell impairment in vitro[115],where substances  that cause induction of ferroptosis have been documented to interfere  with the in vitro   viability of human    pancreatic islets along  with their  [116], function with the  antidiabetic,  quercetin has been demonstrated   more recently   to cause reduction  in  the ferroptotic  injury  in the pancreatic β cells of  T2DM mouse models [117]. In the 1st instance  Davalli et al. [118], could yield proof  that escalation of  extracellular amounts  of glutamate might imply     an  insult for the  β cells . Interestingly, the action   of glutamate was   not modulated by the stimulation of ionotropic receptors, however, by  glutamate stimulated Oxidative stress that was   correlated with the changes the glutamate/cystine exchanger (Xc)  action, GSH) deletion in addition to  enhancement    of lipid peroxidation, a mode that is akin to ferroptosis [118].

More recently, fratraxin    has further been attributed to be a controller    of ferroptosis. In case of human fibrosarcoma HHT-1080 cells [119], repression   of  fratraxin   expression causes acceleration of erastin stimulated   cell   demise, escalation of iron collection, lipid peroxidation along with mitochondrial injury processes that could get reversed by overexpression of fratraxin or pharmacological hampering of ferroptosis. As per  proof  with regards to this stimulation of a  ferroptotic pathway of  cell  demise got derived  from  FRDA models ,like primary patient- obtained  fibroblasts murine fibroblasts that  possess  FRDA correlated mutations along  with fratraxin knockin/knockout murine fibroblasts[120]. 

Recently, it has been corroborated   that failing of   β cell in case of T2DM might be correlated with cell dedifferentiation even [121]. Epigenetic modifications or alterations in transcription factor action as well as /or associated difference in RNA or protein amounts   might decide the depletion of β cells gene expression or the upregulation the genes that do not get expressed in the natural course in the mature β cells like the   ones that get expressed in the islet’s progenitors or the other islets cell kinds [121]. Intriguingly,  the Jumonji C-domain(JMJD6) possessing Histone arginine demethylase, that represents  an epigenetic   controlling enzyme which is iron based[122], besides in   Hepatocellular carcinoma   specimens  a shifting of expression from TfR2 to TfR1 as well as  overexpression  have  been correlated with tumor dedifferentiation, in addition to prognostically is poor [[141],that suggests the probability   that  dedifferentiation might be further associated with  changes in the iron metabolism.

4. Implication of Impairment of Iron homeostasis in Diabetes 

There has been corroboration   that a direct association is existent amongst Impairment of Iron metabolism as well as diabetic situations.  Earlier emphasizing on the escalation of ferritin in subjects with T2DM can be the observation [19], in addition to subjects with Metabolic Syndrome [123]. Escalation of the    incidence  of type2 diabetes mellitus (T2DM) (varying from 20-60%) has been visualized among patients with primary or secondary     iron overload caused by Hereditary haemochromatosis (HH) or   thallasemia in view of pancreatic β cells Impairment along with IR [124]. Furthermore, patients  impacted by aceruloplasminemia, that represents  an auosomal recessive condition      in  possession   of  the properties  of absence of ceruloplasmin ferroxidase  generation with  accrual  of iron  in the brain along with   liver, demonstrate  diabetes mellitus generation as  well[125], in addition to persons afflicted  by  Friedrich’s ataxia  ,that is the neurodegenerative condition that occurs secondary   to the deficit of the mitochondrial   iron chaperone fratraxin  [69].

Minimal iron overload    also  that is    under the amounts   that is classical of haemochromatosis or other iron storage abnormalities, has been  correlated with the escalation of risk of generation of Gestational Diabetes mellitus [126,127], besides that of non-alcoholic fatty liver disease INAFLD) in the existence of Metabolic Syndrome [128].

Obesity, metabolic stress along with   T2DM possess the properties of changed iron homeostasis; leptin deficiency in  genetically obese (ob/ob) mice where generation   of both Obesity along with T2DM   occurs, demonstrate escalation of iron   absorption along with   getting retained [129]. Hyperglycemia   has been illustrated to   cause enhancement   of DMT1 expression   in microvillus membrane along with escalation of    intestinal iron   uptake in case of streptozocin (STZ), - induced diabetic mice   along with brush border residing DMT1 have been the observation in intestinal    biopsies in humans with T2DM [130]. Shu et al [106], documented a glucotoxicity- induced reduction in hepcidin expression, which resulted in failing of β cells by causing up regulation of TfR1 along with DMT1 that was   followed by subsequent iron   overload [106]. Frataxin which is the iron chaperone protein reduction has been the observation in islets from T2DM donors along with in the humanized model of frataxin deficiency FDRAYG8R, that results in iron overload in the mitochondria along with β cell Impairment [68].

In agreement  with this an etiological  part  of iron   in   diabetes mellitus, it has been documented that dietary  restriction causes enhancement  of   β cells function,   along with   glucose tolerance in (ob/ob) mice [125], along with  phlebotomy has  been demonstrated   to result  in   enhancement  of insulin sensitivity, insulin  liberation along with glucose control in T2DM [132], despite clinical  results that have been collected thus far are not conclusive with regards to this approach on  iron letting or deletion [133].

Summary

β cells   possess requirement of iron   for their appropriate    function. In view of that they have possession   of numerous proteins that are implicated   in the tackling of this ion, like the importers of iron, TfR1 along with DMT1 along with the   iron  storage proteins ferritin. The insight we do not possess, in the context of why alterations   of proteins occur at the time of hyperglycemia, obesity, along with T2DM thus causing   iron    accrual   that via ROS generation, results in   Impairment of insulin generation, liberation along with   apoptosis   that aids in the generation of T2DM along with propagation. Intriguingly, certain drugs that have been  posited   for the therapy   of   diabetes mellitus  demonstrate a definite  action on  iron  homeostasis  in  the  β cells .Like   in  the KIKO  mouse model    of FRDA, Exenatide  that is an incretin   mimetic has been  recently corroborated to result   in  enhancement of  glucose homeostasis by causing escalation of  insulin  liberation along with result  in  reduction of  Oxidative  stress    via the induction of frataxin  along with    Fe-S  cluster protein   expression [134].Akin to that thiazolidenediones  avoid  mitochondrial iron collection   [135] that further emphasizes     on  the association among   iron   homeostasis  regulation  in addition to   conservation   of   β cells  function.

Conclusions & future Directions

Of the most  significant   factors  that are  implicated  in the  etiopathogenesis     that influence pancreatic β cells  function along  with survival    is Oxidative   stress, with  iron working as  a catalyst in  the generation   of ROS by the  Fenton’s  reaction  that  might  be  a pointer   to  be a modulator of this event  .The  association      among  iron control  impairment, in addition to failing of  β cells  has been proved with   any  aberrations in  iron  storage  along with  chaperone proteins has got   correlated with diabetes   generation  or in  case  of diabetic  situation .The query that requires clarification  is if β cell  sensitivity  towards  iron overload     is secondary  to low  antioxidant ability of these cells or this in ability  might result  in enhancement   of iron  accrual  in hyperglycemic  situation  along with /or  hyperlipidemic situation. Getting further insight with this future exploration might aid in   defining the iron regulation dependent anti diabetic strategies with the Objective of β cells preservation. Furthermore, in situations where anticipate this   iron overload     with any abnormalities of iron storage protein or   chaperone proteins one can attempt avoidance of generation   of T2DM like in FRDA having the knowledge of escalation of IAPP etc.

References

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