Diabetes Care Volume 38, November 2015 2169

Jose´ Manuel Fernandez-Real,´ 1,2 Mechanisms Linking Donald McClain,3,4 and Melania Manco5 and Toward the Onset and Progression of Type 2 Diabetes Care 2015;38:2169–2176 | DOI: 10.2337/dc14-3082

OBJECTIVE The bidirectional relationship between iron metabolism and glucose homeostasis is increasingly recognized. Several pathways of iron metabolism are modified according to systemic glucose levels, whereas action and secretion are influenced by changes in relative iron excess. We aimed to update the possible influence of iron on insulin action and secretion and vice versa.

RESEARCH DESIGN AND METHODS The mechanisms that link iron metabolism and glucose homeostasis in the main b

insulin-sensitive tissues and insulin-producing -cells were revised according to REVIEW their possible influence on the development of type 2 diabetes (T2D).

RESULTS The mechanisms leading to dysmetabolic hyperferritinemia and hepatic overload syndrome were diverse, including diet-induced alterations in iron absorption, modulation of gluconeogenesis, heme-mediated disruption of circadian glucose rhythm, impaired secretion and action, and reduced availability. Glucose metabolism in seems to be affected by both iron deficiency and excess through interaction with differentiation, tissue hyperplasia and hypertrophy, release of adipokines, lipid synthesis, and lipolysis. Reduced 1University Hospital of Girona "DrJosepTrueta," heme synthesis and dysregulated iron uptake or export could also be contributing Department of Diabetes, Endocrinology and Nu- factors affecting glucose metabolism in the senescent muscle, whereas exercise is trition, Institut d’Investigacio´ Biomedica` de Gi- known to affect iron and glucose status. Finally, iron also seems to modulate rona (IdIBGi), Girona, Spain 2 ı b CIBER Fisiopatolog´a de la Obesidad y Nutricion,´ -cells and insulin secretion, although this has been scarcely studied. Girona, Spain 3Departments of Biochemistry and Internal Med- CONCLUSIONS icine, University of Utah, Salt Lake City, UT Iron is increasingly recognized to influence glucose metabolism at multiple levels. 4Veterans Administration Research Service, Salt Body iron stores should be considered as a potential target for therapy in subjects Lake City VAHCS, Salt Lake City, UT 5Bambino Gesu` Children’s Hospital and Research with T2D or those at risk for developing T2D. Further research is warranted. Institute, Research Unit for Multifactorial Dis- ease, Rome, Italy Iron levels help to modulate the clinical manifestations of numerous systemic dis- Corresponding author: Jose´ Manuel Fernandez-´ Real, [email protected]. eases. The importance of adequate amounts of iron for health and well-being in humans is well known. Iron is involved in binding and transporting oxygen and Received 29 December 2014 and accepted 21 August 2015. regulating growth and differentiation, as well as electron transport, DNA syn- © 2015 by the American Diabetes Association. thesis, and many important metabolic processes (1). Readers may use this article as long as the work is From a clinical standpoint, assessing serum concentrations is a useful properly cited, the use is educational and not for measure of iron storage. Ferritin is also an acute-phase reactant and, as such, is profit, and the work is not altered. 2170 Glucose and Iron Metabolism Diabetes Care Volume 38, November 2015

expected to increase under conditions iron concentration in patients with between iron and T2D has been re- of low-grade inflammation. Inflamma- HHis,onaverage,200–250 mmol/g). viewed and updated in several articles tory cytokines influence iron storage in Serum levels of ferritin and , (14,15). At least four systematic re- various cell types, but different studies and transferrin saturation, are severely views and meta-analyses confirm the have shown that the link between ele- elevated. associationofironandincreasedT2D vated iron and metabolic abnormalities Interest in the topic has been growing risk (16). is independent of inflammation (2). in the almost two decades since the link The initial investigations of glucose Given its clinical relevance, it is surpris- between and serum metabolism in patients with HH helped ing that the source of human serum fer- ferritin was noticed in 1999. Some insulin- in understanding the interplay between ritin remains to be defined (whether it resistant patients present mild abnor- glucose and iron metabolism. Major dif- is derived from damaged cells or actively malities of iron metabolism. In general ferences in terms of pathogenesis, liver secreted by a regulated mechanism). In they are obese; have diabetes, with stig- histopathology, clinical sequelae, and mice, serum ferritin seems to be derived mata of the metabolic syndrome (MetS) potential therapeutic approaches be- mainly from through a and/or nonalcoholic fatty liver disease tween inherited and dysmetabolic- nonclassical secretory pathway (3). A (NAFLD); and have no major genetic based syndromes clearly soluble form of the extracellular trans- mutations among identifiable genetic came to light soon after, with recogni- ferrin receptor (TfR) can be detected in hemochromatosis-related defects. HH tion of the role of hepcidin in such in- serum (serum TfR [sTfR]) as a result of genetic defects involve the hepcidin terplay. The iron regulatory feedback the externalization of TfR during the en- itself (HAMP) or the hepcidin of hepcidin is lost in inherited forms docytic cycle. sTfR concentration is regulators (such as HFE, TfR2, hemojuve- that present inadequate or defective closely related to cellular iron demands lin, and -1 [FPN1]) (8). hepcidin production (hepcidin-deficient and is a marker of erythropoiesis; hence, The term for this disease was “insu- model), whereas it is perfectly pre- the higher the ferritin level, the lower lin resistance–hepatic iron overload served in dysmetabolic-based condi- the sTfR concentration. syndrome” (9). tions (excess hepcidin model). This A full picture of iron metabolism is Acquired abnormalities of iron me- would explain most of the difference available in several excellent reviews tabolism range from mild/modest to se- between phenotypes. (4–6). Here we update the mechanisms vere dysmetabolic hyperferritinemia The foremost lesson from the investi- linking iron metabolism to glucose ho- (DHF; with normal to mildly elevated gation of patients with HH was that iron meostasis and the possible influence of transferrin saturation and no intrahe- overload leads to diabetes by progres- either iron excess or deficiency on the patic iron deposition) to hyperferritinemia sively reducing their b-cell function. Iron development and progression of type 2 with mild to moderate liver iron concen- overload, on the other hand, is not so diabetes (T2D). We mainly focus on hu- tration, generally higher than the normal severe as to induce the rapid man studies, although research in ani- value of 35 but below 100 mmol/g dry of b-cells in dysmetabolic-based iron malmodelsisalsoconsideredwhen weight (dysmetabolic-hepatic iron over- overload syndromes, but it exerts an im- the information available in humans is load syndrome [DIOS]). Iron deposits in portant effect on glucose homeostasis scarce. and cells of the reticulo- by impairing the response to insulin in endothelial system). the liver, muscle, and adipose tissue. INHERITED VERSUS ACQUIRED Indeed, in 1998, iron stores, ex- IRON OVERLOAD SYNDROMES pressed as serum ferritin concentration, IMPACT OF IRON ON INSULIN- The interest of clinical diabetologists in were proposed to be a component of SENSITIVE TISSUES the interplay between iron metabolism the MetS (10,11), and increased preva- Iron and Liver “Cross Talk” Affects and glucose homeostasis dates back to lence of excess iron in the body was ob- Glucose Metabolism Apollinaire Bouchardat, who, in the 19th served in subjects with the syndrome The liver is the major reservoir of iron in century, first described “bronze diabe- (12). Insulin resistance measured using the body. Hepatocytes take up transferrin- tes.” Strikingly, the first description of gold-standard methodologies (euglycemic- bound iron from the bloodstream “insulin resistance” might have been in hyperinsulinemic clamp) was associated through TfR1, expressed on surfaces patients with hereditary hemochroma- with total body iron stores, even in the that face the sinusoids, once iron load tosis (HH). Howard Root observed in presence of normal glucose tolerance exceeds the iron-binding capacity of fer- 1929 an inadequately high need for in- (11). Serum ferritin concentration in ritin (4–6). The liver can maintain iron sulin in different diseases, and he called the apparently healthy general popu- homeostasis within a narrow physio- the phenomenon “insulin resistance” lation was positively correlated with logic range by secreting hepcidin. (7). The title of the article referred to fasting and postload glucose (10). Iron Hepcidin senses a number of physiolog- “bronze diabetes,” the term for hemo- stores have accordingly been associated ical and pathophysiological stimuli that chromatosis at that time (7). with an enhanced risk of developing regulate iron homeostasis, and it re- Iron deposits within hemosiderin in T2D. The first prospective (nested case- sponds by downregulating the ex- different cells, including b-cells, induce control) study demonstrating a positive pression of FPN1 on the apoptosis in patients with HH, leading to association between the ratio of TfRs to basolateral side. Hepcidin induces phos- diabetes while causing the characteris- ferritin and risk of T2D was reported by phorylation, internalization, and degrada- tic skin pigmentation. High amounts of Salonen et al. (13). Many authors have tion of the iron transporter ferroportin iron are found in hepatocytes (the liver since studied this association. The link (FPN). This factor inhibits the duodenal care.diabetesjournals.org Fernandez-Real,´ McClain, and Manco 2171

absorption of the metal (17) and also inhib- its the release of iron from macrophages. Excess iron, once stored in the liver, interferes with glucose metabolism, causing via both de- creased insulin extraction and impaired insulin signaling (18). Hyperinsulinemic status, on the other hand, favors the intrahepatic deposition of iron. Insulin enhances the uptake of extracellular iron, inducing the redistribution of TfRs to the cell surface (19) while downregu- lating hepcidin expression (20). An edi- torial hypothesized that “iron and insulin are synergistic in promoting oxida- tive stress with release of reactive oxy- gen species (ROS) and inflammatory cytokines in the sub-endothelial space” (21). Such cytokines, in turn, promote ferritin synthesis in Kupffer cells and macrophages. The question of why some obese pa- tientsdevelopironexcess,whichcan Figure 1—Postulated mechanisms promoting DIOS. Excess dietary fats favor hepatic iron uptake evolve into DHF or DIOS, and some by enhancing the surface expression of the TfRs and secretion of hepcidin from hepatic and others do not is still controversial, al- adipose tissue. Hepcidin senses gluconeogenesis in conditions of starvation. Dietary iron can affect the circadian rhythm of hepatic gluconeogenesis through the heme-mediated regulation though genetics explain major biochem- of nuclear receptor subfamily 1 group d member 1 (Rev-Erba) and its cosuppressor nuclear ical, histological, and clinical differences receptor corepressor 1. Despite being appropriately released, hepcidin might be less effective between inherited and acquired forms. because of reduced FPN expression in the duodenum and in the liver as a result of the excess of Genetics (mutations in the b-globin and proinflammatory adipocytokines. Copper serves mainly for enterocyte ferroxidase activity. a1-antitrypsin ) (22) and dietary habits may explain some of the pheno- typic variability. Different mechanisms of T2D. Dietary iron seems to affect levels of Ppargc1a and Creb313 mRNAs, have been hypothesized to answer the circadian gluconeogenesis and glucose and administration of mRNAs interfer- question, from alterations in diet or duo- metabolism by influencing the heme- ing against Ppargc1a and Creb313 re- denal iron absorption to dysfunction of mediated regulation of two important duced levels of the hepcidin gene. target molecules involved in iron metab- molecules: the nuclear receptor sub- olism (Fig. 1). Alterations in Duodenal Absorption of Iron family1groupdmember1andits Increased duodenal absorption of iron A High-Fat Diet Changes Iron Metabolism cosuppressor nuclear receptor corepressor is a possibility that has been studied Ruivard et al. (23,24) hypothesized that 1. When heme synthesis was blocked as a potential primary defect causing the natural history of DIOS originates by the administration of aminolevu- DIOS. However, patients with DIOS had from a Western diet that is rich in fats linic acid, variations in dietary iron did significantly less intestinal iron absorp- and iron and is able to stimulate the not affect hepatic glucose production tion (evaluated using stable isotopes) compensatory release of hepcidin from or expression of gluconeogenic than subjects without hepatic siderosis the liver and adipose tissue. Animals (26). or control subjects (23). fed a high-fat diet had increased activity Hepcidin of iron regulatory 1 in the liver Starvation and Persistently Activated Gluconeogenesis Hepcidin is primarily secreted by hepato- and an increase in TfR1 expression (25). Persistently activated gluconeogenesis cytes and, to a minor extent, by The high-fat diet also resulted in the in- is known to occur in patients with obe- and macrophages. a2-Macroglobulin is creased secretion of hepcidin and the sity, insulin resistance, NAFLD, and T2D. the specifichigh-affinity, hepcidin-binding downregulation of FPN1, factors linked Gluconeogenesis provides fuel during molecule that carries hepcidin into the to increased intrahepatic deposition of starvation. Hepcidin has been shown bloodstream. Enlarged adipose tissue iron (25). to serve as a gluconeogenic sensor in overreleases hepcidin (excess hepcidin Dietary Iron and the Circadian Clock starving mice. Starvation induced liver model), and inflammatory molecules, Feeding is one of the factors known to iron deposition by increasing the tran- including interleukin-6, tumor necrosis set the circadian clock in peripheral tis- scription of phosphoenolpyruvate car- factor-a, and leptin, stimulate further pro- sues. The circadian rhythm of the liver is boxykinase 1 while also augmenting duction of hepcidin mRNA. The hepcidin- known to maintain glucose homeosta- the levels of hepcidin and consequently induced downregulation of intestinal sis, and disruption of this rhythm is as- the degradation of FPN1 (27). Starvation iron absorption was physiologically pre- sociated with the onset and progression also was associated with increased served in patients with DIOS (23). They 2172 Glucose and Iron Metabolism Diabetes Care Volume 38, November 2015

overexpress and release hepcidin in to apo-transferrin. Copper is implicated in this regard, MRI is a reliable tool for non- concordance with the increased levels ferroxidase activity to mobi- invasive assessment of the iron concen- of circulating ferritin to counterbalance lize iron from hepatocytes and macro- trationinspecific tissues (liver, brain, intrahepatic iron deposition (28). Hep- phages. As such, copper is also involved in spleen). The MRI techniques used for cidin, however, might be less effective cell surface stability of FPN1 (32). Patients iron assessment are based on the since the expression of FPN1, the phys- with DIOS have low levels of hepatic and changes of relaxation times produced iological target of hepcidin, was re- serum copper in parallel to reduced activ- by local magnetic field inhomogeneities duced in the duodenum and liver of ity of serum ferroxidase ceruloplas- and intrinsic tissue properties. Micro- these patients (29). The reduced ex- min (33), and consequently reduced scopic field gradients induced by para- pression of FPN1 is the consequence iron mobilization in hepatic cells (30). magnetic ferritin-loaded cells produce a of an increased proinflammatory milieu random phase shift of the hydrogen pro- with particularly elevated levels of tu- Enhanced Phagocytosis of Fragile tons, affecting their relaxation. The relax- mor necrosis factor-a (30). Normal or Erythrocytes ation signals of tissues are therefore overexpressed levels of hepcidin result Enhanced phagocytosis of fragile eryth- affected by diffusion-mediated contribu- in retention and redistri- rocytes might favor the development of tions of iron. Transverse relaxation rates bution of iron toward Kupffer cells de- DIOS. It is interesting that aggregates of of the MRI parameter R2* show a strong spite FPN1 downregulation (Fig. 2). Iron erythrocytes were documented in mi- linear correlation with liver iron concen- fl deposition in hepatocytes is usually croscopic areas of in ammation from tration (35). Iron depletion is effective in moderate (31). liver biopsies of patients with NAFLD ameliorating parameters of glucose (34). Excess iron and erythrocytes en- TfR1 metabolism in patients with DHF, as gulfed by Kupffer cells were also re- discussed elsewhere (16). Based on An impaired hepatic expression of TfR1 ported in a rabbit model of familial in patients with DIOS is also a possibility. the available evidence, iron depletion hypercholesterolemia that exhibits stea- should also be tested in patients with TfR1 expression was, however, physio- fi tohepatitis and brosis (34). DIOS and T2D, and MRI is of poten- logically reduced in response to iron ac- Most of the evidence of the associa- cumulation in these patients, showing a tially extreme utility in their follow up tion of hepatic iron overload and im- to evaluate its effectiveness. Although preserved compensatory response to paired glucose homeostasis has been iron overload (30). only liver biopsy visualizes iron-associated collected in patients referred for hepatic liver damage and provides significant Alterations in Copper Metabolism steatosis. Some of them presented with informationonthedegreeofsimple Copper serves a role in hephaestin ferrox- overt T2D. It will, however, be important steatosis, steatohepatitis, and fibrosis, idase activity in duodenal , to investigate the prevalence of hepatic further research on liver iron using MRI where it promotes the loading of iron siderosis among patients with T2D. In is needed.

Iron and Muscle Relationships With Glucose Homeostasis There is some evidence that iron over- load also affects (36), the main effector of insulin action. Skel- etal muscle represents about 40% of body mass and contains 10–15% of body iron, which is mainly located in myoglobin. Muscular contraction, but not insulin, is known to stimulate TfR recruitment from a GLUT4-containing intracellular fraction to the plasma membrane (Fig. 3). Exercise affects iron status, but this is usually under- recognized. When obese subjects were submittedtoadietandexercisepro- gram resulting in weight loss, circulat- ing sTfR significantly decreased, and this decrease was proportional to changes in muscle volume and leg and arm force. Weight loss induced by diet alone did not affect circulating sTfR (37). Figure 2—Iron (Fe) overload in hepcidin-excess vs. hepcidin-deficient disease models. Increased The iron status of skeletal muscle also hepcidin downregulates cellular FPN expression and promotes macrophage retention of excess iron, resulting in iron redistribution toward Kupffer cells, with prevalent sinusoidal distribution changes dramatically with aging. Iron- of iron. Conversely, insulin downregulates hepcidin expression in hepatocytes and adipocytes. induced free radical production seems IL-6, interleukin-6; TNF-a, tumor necrosis factor-a. to be a pivotal factor in the progression care.diabetesjournals.org Fernandez-Real,´ McClain, and Manco 2173

adipogenic capacity. Adipocytes accu- mulate fat during differentiation, and stored iron and the expression of several iron-related genes change at the same time (44). Iron-enriched diets affect adipocyte size, which is significantly reduced, along with decreased adipocyte insulin sensitivity, in murine models. This iron- enriched diet was associated at the same time with visceral adipose tissue hyperplasia and hypertrophy (45). An iron-restricted diet led to the opposite results, with low amounts of circulating free fatty acids and triglycerides (46). The reduction of iron levels by deferox- amine, an iron chelator, inhibited the development of adipocyte hypertrophy in mice and decreased macrophage in- filtration (47). A parallel reduction in oxidative stress and inflammatory cyto- kine production, and improved glucose — fi Figure 3 Effects of insulin on body iron traf cking. Insulin causes increased ferritin synthesis metabolism and insulin signaling, were and redistribution of TfRs to the cell surface, thereby facilitating iron uptake by different tissues and cells. Insulin downregulates hepcidin expression in adipocytes and hepatocytes; stimulates observed in adipose tissue and skeletal expression of FPN, ferritin heavy chains (FTH), and ferritin light chains (FTL); and reduces muscle (47). The importance of iron in expression of transferrin (Tf) in adipocytes. It promotes the release of ROS in hepatocytes. In adipocyte differentiation and insulin ac- myocytes, the muscular contraction stimulates TfR recruitment from a GLUT4-containing in- tion was confirmed by in vitro models: In- tracellular fraction to the plasma membrane. IGF2R, insulin-like growth factor-2 receptor; IL, interleukin; TNF-a, tumor necrosis factor-a. cubation of rat adipocytes with excess iron resulted in decreased insulin- stimulated glucose transport and in- of oxidative injury and dysfunction ob- with the increased AMP-activated pro- creased lipolysis (48), whereas silencing served in senescent skeletal muscle tein kinase activity, was of the iron-related genes transferrin and (38). Declines in heme synthesis and enhanced (42). in murine cell lines resulted in dysregulation of iron uptake or export impaired adipocyte differentiation and pathways have been suggested to con- Iron and Adipose Tissue reduced insulin signaling (49). Immune stitute contributing factors (39). In- Obesity is a crucial component of pe- cells that are resident in adipose tissue creasedironuptakethroughtheiron ripheral insulin resistance. A recent may have a pivotal role since polar- transporter DMT1 and intracellular study revealed that ferritin light chain ized macrophages have increased iron- iron retention as a result of decreased (FTL) mRNA and protein levels, and handling capabilities, promoting local FPN both contribute to iron status ele- FPN transcripts, were significantly in- and systemic insulin resistance, and vation in senescent muscle (38,40). The creased, whereas transferrin mRNA de- contributing significantly to the overall increase of muscle iron content is not creased in adipose tissue from obese metabolic derangement and progression paralleled by increased ferritin expres- subjects in association with insulin ac- toward T2D (50). sion, suggesting an expansion of iron tion (43). Bariatric surgery–induced fi in the nonferritin compartment (40). weight loss resulted in increased trans- The Paradox of Iron De ciency A paradox exists about the relationship Whether these alterations in aging ferrin mRNA and decreased FTL and FPN muscle result in impaired glucose me- in subcutaneous adipose tissue in asso- of iron status with glucose metabolism tabolism should be studied in more ciation with improved insulin action in obese patients and/or patients with depth. (43). Why were these iron-related genes T2D, which is important to keep in mind In vitro studies have shown that re- altered in adipose tissue from obese since ferropenic anemia is prevalent ductions in iron availability induced by subjects? Iron may affect insulin action among these patients. fi iron chelators resulted in increased glu- by modulating the degree of adiposity Old studies found out that iron de - cose utilization owing to the enhanced with different mechanisms. ciency induced increased lipid synthesis expression of GLUT-1 in the muscle cell in white adipose tissue from rats, as well line L6 (41). Paradoxical effects have Iron Affects Adipocyte Differentiation and as hyperglycemia despite enhanced in- been observed in animal models. Iron- Adipose Tissue Hyperplasia and sulin sensitivity (51). An independent rich diets led to elevated AMP-activated Hypertrophy study recently confirmed these findings, protein kinase activity and impaired in- Disruption of iron homeostasis, either in showing enhanced expression of lipo- sulin signaling in skeletal muscle and excess or in defect, results in impaired genic genes and alterations in levels of liver of C57BL/6J male mice. Consistent adipocyte differentiation and decreased plasma lipids in response to dietary iron 2174 Glucose and Iron Metabolism Diabetes Care Volume 38, November 2015

deficiency (52). The precise mechanisms Retinol binding protein-4 (RBP4) is a even though visfatin mRNA is enriched responsible for the relative hyperglyce- fat-derived lipocalin belonging to a fam- in iron-rich tissues (liver, muscle, bone mia associated with ferropenic anemia ily of that bind small hydropho- marrow) (61). remain unclear (53,54). A more pro- bic molecules, such as retinol (RBP4) and nounced increase in fasting blood glu- iron (lipocalin-2, another adipokine Iron and b-Cell Relationships cose was associated with more severe linkedtoironandinsulinresistance An increase in b-cell mass, with increased anemia (53,54). [56]), that constitute appropriate trans- basal and stimulated C-peptide secretion, porters for transferring biologically haz- was suggested in a small number of pa- Iron Status May Influence the Release of ardous molecules between cells in a safe tients with T2D with increased serum fer- Adipokines From Adipose Tissue and controlled manner. RBP4 expres- ritin levels (62). C-peptide secretion Adipose tissue releases a number of sion in adipose tissue was increased in decreased after phlebotomy-induced proinflammatory adipokines that might obesity and insulin resistance in associ- iron depletion, suggesting increased interfere with iron homeostasis. Secre- ationwithironstores,beinghigherin b-cell insulin sensitivity (62). tion of several adipokines may be influ- menthanwomen,inparalleltoin- HH is, conversely, diabetogenic mainly enced by iron levels. Research shows creased serum ferritin in men (58). Ex- because of decreased insulin secretion, that leptin and adiponectin are ac- cess iron led to increased plasma retinol and diabetes usually results when insulin tively involved in iron homeostasis (55). and RBP4, whereas iron depletion re- resistance develops (such as with increas- Bloodletting of patients with impaired sulted in decreased serum RBP4 concen- ing body weight). Patients with HH cannot glucose tolerance and increased ferritin tration (58). respond with increased insulin secretion values led to increased adiponectin and Associations between levels of serum because of the primary impairment of improved glucose tolerance, showing an visfatin, an adipokine secreted preva- b-cells. Insulin-secretory abnormalities interplay between iron status and adi- lently by the visceral adipose tissue, improve with phlebotomy in this context ponectin secretion (55). Serum ferritin and different parameters of iron metab- (63). has also been linked to adipocyte insulin olism (serum prohepcidin and sTfR) Experimental studies have also shown resistance (defined by the product of were observed in obese patients and the importance of iron in b-cell physiol- fasting insulin and nonesterified fatty patients with T2D; these associations ogy. Ob/ob mice administered low-iron acids) and negatively correlated with cir- differed according to obesity and glu- diets exhibited significant increases in culating adiponectin. Mice fed a high-iron cose tolerance status (61). The meaning insulin sensitivity and b-cell function, diet, and cultured adipocytes treated of such associations remains unclear, consistent with the phenotype in mouse with iron, exhibited decreased adi- ponectin mRNA and protein (55). Iron seems to negatively regulate adiponectin transcription via FOXO1-mediated re- pression. Loss of the adipocyte iron ex- port channel, FPN, in mice resulted in adipocyte iron loading, decreased adipo- nectin, and insulin resistance. Body iron overload and increased adipocyte FPN ex- pression in the context of hemochroma- tosis were associated with decreased adipocyte iron, increased adiponectin, and improved glucose tolerance and in- sulin sensitivity (55). We speculated that the sexually di- morphic behavior of some adipokines, not completely explained on the basis of different fat amounts and the influ- ences of sex hormones (56), might relate to iron metabolism as well (56–58). For instance, leptin (57) has, remarkably, been shown to stimulate hepcidin mRNA production in a similar manner — as interleukin-6 (59). In obese children Figure 4 Effects of iron deprivation vs. acquired iron overload on glucose metabolism. Excess iron (solid lines) causes insulin resistance (IR) in hepatic (reduced insulin extraction and in- following a 6-month weight loss pro- appropriate gluconeogenesis) and adipose tissue (reduced adipose tissue mass and cell volume). gram, weight loss was associated with It affects expression of adiponectin, resistin, and leptin, which enhances oxidative stress and lower hepcidin concentrations. The causes the redistribution of TfRs on the cell surface. In the pancreas, it causes increased b-cell fi extent of leptin reduction paralleled mass. Iron de ciency (dashed lines) is associated with enhanced hepatic glucose production as a result of the increased expression of sterol regulatory element binding factor (SREBF1), hepcidin reduction, and this associa- acetyl-CoA carboxylase a (ACACA), and synthase (FASN), as well as higher glucose tion was independent of BMI (60). disappearance. care.diabetesjournals.org Fernandez-Real,´ McClain, and Manco 2175

models of hereditary iron overload. The given the association between elevated 11. Fernandez-Real´ JM, Lopez-Bermejo´ A, effects were not accounted for by iron stores and MetS in people with mild Ricart W. Cross-talk between iron metabolism – changes in weight or feeding behavior. hyperferritinemia (ferritin between 100 and diabetes. Diabetes 2002;51:2348 2354 12. Bozzini C, Girelli D, Olivieri O, et al. Preva- Treatment with iron chelation had a and 300 mg/dL). lence of body iron excess in the metabolic syn- dramatic effect, allowing the ob/ob Further research is needed regard- drome. Diabetes Care 2005;28:2061–2063 mice to maintain normal glucose toler- ing the target serum ferritin concen- 13. Salonen JT, Tuomainen TP, Nyyssonen¨ K, ance for at least 10.5 weeks (46). The trationinpatientswithT2D.The Lakka HM, Punnonen K. Relation between iron effects on overall glucose levels were focus of the research should move to- stores and non-insulin dependent diabetes in men: case-control study. BMJ 1998;317:727 less apparent because of a loss of ward investigation of body iron stores 14. Swaminathan S, Fonseca VA, Alam MG, the beneficial effects of iron on insulin affecting solid measures such as insu- Shah SV. The role of iron in diabetes and its com- sensitivity, although dietary iron re- lin sensitivity, vascular resistance, vis- plications. Diabetes Care 2007;30:1926–1933 striction preserved b-cell function in cosity, and oxidative damage (11). An 15. Simcox JA, McClain DA. Iron and diabetes – ob/ob mice fed a high-fat diet. Benefi- in-depth study of iron metabolism in risk. Cell Metab 2013;17:329 341 16. Fernandez-Real´ JM, Manco M. Effects of cial effects of iron restriction were T2D may uncover unsuspected rela- iron overload on chronic metabolic diseases. minimal in wild-type mice on a control tionships. The search for an ideal iron Lancet Diabetes Endocrinol 2014;2:513–526 diet but were apparent in mice on a status in T2D may result in unexpected 17. Nemeth E, Tuttle MS, Powelson J, et al. high-fat diet (63). benefits. Hepcidin regulates cellular iron efflux by binding In vitro studies have shown that to ferroportin and inducing its internalization. Science 2004;306:2090–2093 H-ferritin mRNA is four- to eightfold 18. Niederau C, Berger M, Stremmel W, et al. higher in rat islets treated with 20 mmol/L Hyperinsulinaemia in non-cirrhotic haemochro- Acknowledgments. The authors acknowledge glucose than in islets treated with the help of Viola Luciano and Rosa Luciano in the matosis: impaired hepatic insulin degradation? – 1 mmol/L glucose. The potential reason elaboration of the figures. This article was edited Diabetologia 1984;26:441 444 19. Davis RJ, Corvera S, Czech MP. Insulin stim- for the increased ferritin in the b-cells is by Paolo Varricchio, MD, Department of Cell Biology and Molecular Medicine, Rutgers School ulates cellular iron uptake and causes the redis- that ferritin exhibits antioxidant proper- tribution of intracellular transferrin receptors to b of Biomedical and Health Sciences, New Jersey ties, and -cells are particularly sensitive Medical School, Newark, NJ. the plasma membrane. J Biol Chem 1986;261: – to oxygen radicals. The large amount of Funding. J.M.F.-R. is partially supported by 8708 8711 ferritin can explain why iron is preferen- CIBERobn (CIBER Pathophysiology of Obesity 20. Wang H, Li H, Jiang X, Shi W, Shen Z, Li M. Hepcidin is directly regulated by insulin and tially retained in b-cells. 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