|Year : 2016 | Volume
| Issue : 1 | Page : 11-16
Role of iron in diabetes mellitus and its complications
Mohamed A Shaaban1, Alaa Eldeen A Dawod1, Mohammed A Nasr2
1 Department of Internal Medicine, Faculty of Medicine, Menoufyia University, Menoufyia, Egypt
2 Kafr Elshiekh Liver Centre, Kafr Elshiekh, Egypt
|Date of Submission||23-Nov-2014|
|Date of Acceptance||18-Jan-2015|
|Date of Web Publication||18-Mar-2016|
Mohammed A Nasr
MBBCh, Sidi Salim, 33713 Kfr Elshiek
Source of Support: None, Conflict of Interest: None
Iron is one of the essential minerals that is required for a variety of molecules to maintain their normal structures and functions. Although it is essential, iron can also be toxic in excess amounts. Oxidative stress is one of the major causative factors for diabetes and diabetic complications. Increasing evidence has indicated that iron overload not only increases risks for insulin resistance and diabetes but also causes cardiovascular diseases in nondiabetic and diabetic individuals.
The aim of this study was to investigate the role of iron in diabetes mellitus and its complications.
Data sources: Data were collected from medical text books, medical journals, medical websites that had updated research with keywords (iron and diabetes mellitus) in the title of the paper.
Study selection: Systematic reviews that addressed diabetes mellitus and studies that addressed the role of iron in the pathogenesis of diabetes and diabetic complications were selected for study.
Data extraction: A special search was carried out at midline with keywords (iron and diabetes mellitus) in the title of papers and extraction was made, including assessment of quality and validity of papers that met with the prior criteria that describe the role of iron in the pathogenesis of diabetes and diabetic complications.
Data synthesis: Each study was reviewed independently and the obtained data were rebuilt in new language according to the need of the researcher and arranged in topics through the article.
Recent findings: Iron overload not only increases risks for insulin resistance and diabetes but also accelerates diabetic complications.
Oxidative stress is one of the major causative factors for diabetes and diabetic complications. Increasing evidence has indicated that iron overload not only increases risks for insulin resistance and diabetes but also causes cardiovascular diseases in nondiabetic and diabetic individuals.
Keywords: Diabetes mellitus, iron, type 2
|How to cite this article:|
Shaaban MA, Dawod AA, Nasr MA. Role of iron in diabetes mellitus and its complications. Menoufia Med J 2016;29:11-6
| Introduction|| |
Oxidative stress is one of the major causative factors for diabetes and diabetic complications. Increasing evidence has indicated that iron overload not only increases risks for insulin resistance and diabetes but also causes cardiovascular diseases in nondiabetic and diabetic individuals. Temporal iron deficiency was found to sensitize insulin action, but chronic iron deficiency with anemia can accelerate the development of cardiovascular diseases in nondiabetic and diabetic individuals .
It has long been recognized that iron overload can increase the risk for diabetes, particularly in iron-overload states such as hemochromatosis and recurrent transfusions in diseases such as thalassemia. Furthermore, a large body of epidemiological evidence suggests that an increase in dietary iron (such as heme, mainly from meat and meat products) is associated with an increased risk for diabetes .
In contrast, iron deficiency may lower the risk for diabetes. Indeed, it has been suggested that recurrent phlebotomy may protect against diabetes .
| Objective|| |
The aim of this study was to investigate the role of iron in diabetes mellitus and its complications.
| Materials and methods|| |
The guidance published by the Centre for Reviews and Dissemination was used to assess the methodology and outcomes of the studies. This review was reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. An institutional review board and ethics committee approved this study.
A systematic search of several bibliographical databases was performed, to identify relevant reports in any language. These included MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, TRIP database, Clinical Trials Registry, ISI Web of Knowledge, and Web of Science. Articles electronically published ahead of print were included. The search was performed in the electronic databases from the start of the database up to 2012.
All studies were independently assessed for inclusion. They were included if they fulfiled the following criteria:
Participants: diabetic and nondiabetic patients.
Interventions: predictors of iron states in the development of diabetes and diabetic complications.
Outcomes: iron overload impairs insulin action and accelerates diabetic complications.
If the studies did not fulfill the above criteria, they were excluded. Articles in non-English languages were translated. The article title and abstracts were initially screened; thereafter, the selected articles were read in full and further assessed for eligibility. All references from the eligible articles were reviewed to identify additional studies.
Study quality assessment included the following: whether or not ethical approval was gained, prospective design, eligibility criteria specified, appropriate controls used, adequate follow-up achieved, and defined outcome measures such as iron overload impairs insulin action and accelerates diabetic complications.
The quality of all studies was assessed. Important factors included prospective study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, specified outcome measures, and adequate follow-up. It was expected that confounding factors would be reported and controlled for and appropriate data analysis made, in addition to an explanation of missing data.
Because of heterogeneity in postoperative follow-up periods and outcome measures reported, it was not possible to pool the data and perform meta-analysis. Comparisons were made using a structured review.
| Results|| |
Iron seems to negatively impact insulin action even in healthy people and not just in classic pathologic conditions associated with iron overload (hemochromatosis and hemosiderosis). Iron overload not only increases risks for insulin resistance and diabetes but also causes cardiovascular diseases in nondiabetic and diabetic individuals. Temporal iron deficiency was found to sensitize insulin action, but chronic iron deficiency with anemia can accelerate the development of cardiovascular diseases in nondiabetic and diabetic individuals. Therefore, in the treatment of iron deficiency anemia in diabetic patients, we must be careful not to make overcorrection or undercorrection, and treatment should be guided by serum ferritin and iron profile. An increase in dietary iron (such as heme, mainly from meat and meat products) is associated with an increased risk for diabetes. Iron-chelating agents and blood donation can prevent the development of diabetes in transfusional iron overload. In apparently healthy people, frequent blood donation leading to decreasing iron stores has been demonstrated to be a protective factor for the development of diabetes mellitus. Frequent blood donations, leading to decreased iron stores, have been demonstrated to reduce postprandial hyperinsulinemia in healthy volunteers to improve insulin sensitivity and to constitute a protective factor for the development of type 2 diabetes. Studies in overt iron-overload states such as transfusional overload and hemochromatosis have shown that the incidence of cardiac disease is increased in diabetic patients and that treatment with iron chelation improves cardiovascular outcome.
| Discussion|| |
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the B cells of the pancreas, with consequent insulin deficiency, to abnormalities that result in resistance to insulin action. The basis of the abnormalities in carbohydrate, fat, and protein metabolism in diabetes is the deficient action of insulin on target tissues. Deficient insulin action results from inadequate insulin secretion and/or diminished tissue response to insulin at one or more points in the complex pathways of hormone action. Symptoms of marked hyperglycemia include polyuria, polydipsia, weight loss, sometimes with polyphagia, and blurred vision. Impairment of growth and susceptibility to certain infections may also accompany chronic hyperglycemia .
Diabetes can be classified into four clinical categories :
(1) Type 1 diabetes (due to B-cell destruction, usually leading to absolute insulin deficiency).
(2) Type 2 diabetes (due to progressive insulin secretory defect on the background of insulin resistance).
(3) Other specific types of diabetes due to other causes - for example, genetic defects in B-cell function, genetic defects in insulin action, diseases of the exocrine pancreas (such as cystic fibrosis), and drug-induced or chemical-induced (such as in the treatment of HIV or after organ transplantation).
(4) Gestational diabetes mellitus (diabetes diagnosed during pregnancy that is not clearly overt diabetes).
Type 1 diabetic patients often present with acute symptoms of diabetes and markedly elevated blood glucose levels, and some cases are diagnosed with life-threatening ketoacidosis. The incidence and prevalence of type 1 diabetes is increasing . Several studies suggest that measuring islet autoantibodies in relatives of those with type 1 diabetes may identify individuals who are at risk for developing type 1 diabetes. Such testing, coupled with education on diabetes symptoms and close follow-up in an observational clinical study, may enable earlier identification of type 1 diabetes onset .
Complications of diabetes mellitus
Diabetic patients are at high risk to develop multiple complications, which may be acute or chronic. Acute life-threatening consequences of uncontrolled diabetes are hyperglycemia with ketoacidosis, or the nonketotic hyperosmolar syndrome. In contrast, hypoglycemia is the leading limiting factor in the glycemic management of type 1 and insulin-treated type 2 diabetes . Long-term complications of diabetes include retinopathy with potential loss of vision and nephropathy leading to renal failure . In some studies, the overall prevalence rate of albuminuria was considerably high (47.01%) among 234 type 2 diabetic patients. Therefore, regular screening for microalbuminuria is recommended for all diabetic patients, as early treatment is critical for reducing cardiovascular risks and slowing the progression to late stages of diabetic nephropathy (overt proteinuria and end-stage renal disease) . Complications include peripheral neuropathy, with risk of foot ulcers, amputations, and Charcot joints, and autonomic neuropathy, causing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dysfunction. Patients with diabetes have an increased incidence of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular disease. Hypertension and abnormalities of lipoprotein metabolism are often found in individuals with diabetes . Advanced glycation end products (AGEs) cause vascular stiffening by forming cross-links through the collagen molecule, or by interaction with their cellular transductional receptor , which, in role, worsen the cardiovascular complications.
Iron is an essential metal for hemoglobin synthesis of erythrocytes, oxidation-reduction reactions, and cellular proliferation, whereas excess iron accumulation causes organ dysfunction through the production of reactive oxygen species. The total amount of body iron is ∼3-4 g, two-thirds of which is composed of red blood cell iron and recycled iron by red blood cell destruction, and the remainder is stored in ferritin/hemosiderin, whereas only 1-2 mg of iron is absorbed in the intestinal tract and circulated in the blood. Body iron metabolism is a semiclosed system and is critically regulated by several factors, including the newly identified peptide hepcidin. In the circulation, iron is usually bound to transferrin, and most of the transferrin-bound iron is utilized for bone marrow erythropoiesis .
Mechanisms of iron toxicity
The central importance of iron in the pathophysiology of disease is derived from the ease with which iron is reversibly oxidized and reduced. This property, although essential for its metabolic functions, makes iron potentially hazardous because of its ability to participate in the generation of powerful oxidant species such as hydroxyl radical .
Iron and diabetes mellitus
Evidence that systemic iron overload could contribute to abnormal glucose metabolism was first derived from the observation that the frequency of diabetes is increased in classic hereditary hemochromatosis (HH). However, with the discovery of novel genetic disorders of iron metabolism, it is obvious that iron overload, irrespective of the cause or the gene involved, results in an increased incidence of type 2 diabetes. The role of iron in the pathogenesis of diabetes is suggested by an increased incidence of type 2 diabetes in diverse causes of iron overload and reversal or improvement in diabetes (glycemic control), with a reduction in iron load achieved using either phlebotomy or iron chelation therapy .
A link has been established between increased dietary iron intake, particularly eating red meat and increased body iron stores, and the development of diabetes. A causative link with iron overload is suggested by improvement in insulin sensitivity and insulin secretion, with frequent blood donation and decreased iron stores .
Ferritin in type 2 diabetes mellitus
Multiple factors appear to be involved in the pathogenesis of type 2 diabetes mellitus. One of these factors may be iron overload. Plasma ferritin concentration is positively correlated with insulin resistance and with the risk of acquiring type 2 diabetes mellitus .
Higher concentrations of ferritin consequently had higher HbA1c, glucose, and insulin concentrations. There was a positive association between type 2 diabetes and high plasma ferritin concentrations .
Another explanation of increased serum ferritin in type 2 diabetes is that excess levels of iron can increase cellular oxidative stress and can damage tissues because iron is a potent pro-oxidant. This may lead to insulin resistance and abnormal glucose metabolism, elevating risk for type 2 diabetes .
In fact, the higher the ferritin concentrations, the higher is the incidence of type 2 diabetes, according to epidemiologic studies .
Genetic iron overload syndromes and diabetes
Over 80% of cases of HH (type 1) result from a mutation in the gene encoding the hereditary hemochromatosis protein (HFE) . These mutations lead to an accumulation of iron in several tissues and present as a classic syndrome of hypogonadism, diabetes, liver disease, cardiomyopathy, and arthritis. In type 1 HH, up to 60% of the affected patients developed diabetes .
Diabetes appears to be a result of both insulin deficiency and resistance. Evidence for this is derived from studies in HH patients whose body iron stores were reduced with phlebotomy and/or iron chelation therapy, which resulted in improved glycemic control and 30-40% of patients achieving elimination of oral hypoglycemic therapy or a substantial reduction in dosage .
Transfusional iron overload and diabetes
Transfusional iron overload is the most common cause of acquired iron overload and is typically seen in transfusion-dependent chronic hemolytic anemia such as α-thalassemia. Impaired glucose tolerance is often detected during the second decade of life. In a study of 80 transfusion-dependent α-thalassemic patients, diabetes was reported in 19.5% of patients and impaired glucose tolerance in 8.5% of patients. The risk factors for impaired glucose tolerance and type 2 diabetes found in that study were high serum ferritin and hepatitis C virus infection .
Blood donation and diabetes
Iron overload is common in patients outside the setting of known iron overload syndromes. Insulin resistance has been described in such patients, and iron-chelating agents and blood donations have been shown to decrease the development of diabetes in such patients .
Role of iron in complications of diabetes
The importance of protein glycation is well known in the pathogenesis of diabetic vascular complications. Transition metals also play a role in protein glycation induced by hyperglycemia. It has been shown that glycated proteins have a substantial affinity for the transition metals, and the bound metal retains redox activity and participates in catalytic oxidation. Desferoxamine causes a modest reduction in HbA1c. Moreover, under in-vivo conditions, treatment with desferoxamine has been shown to modestly reduce A1C levels in patients with noninsulin-dependent diabetes and diabetic rats .
Iron-induced damage might also modulate the development of chronic diabetes complications. Iron depletion has been demonstrated to be beneficial in coronary artery responses, endothelial dysfunction, insulin secretion, insulin action, and metabolic control in type 2 diabetes .
Role of iron in diabetic nephropathy
Evidence linking iron to diabetic nephropathy includes the following: animal and epidemiological studies in which an increased amount of iron has been shown in the kidneys of both animals and humans with kidney disease; increased urinary iron in patients with diabetic nephropathy; and the prevention of progression either by an iron-deficient diet or agents that bind and remove iron (chelators) . Oxidative stress from factors such as hyperglycemia, AGEs, and hyperlipidemia further contribute to the availability of intracellular iron that can generate and viciously worsen oxidative stress and renal damage.
Role of iron in endothelial and vascular disease
The possibility that iron status has a role in cardiovascular disease (CVD) was postulated by Sullivan in 1981. The man-woman ratio for median serum ferritin levels for ages 18-45 years is 3.8, which is similar to the increased risk for heart disease, with the reduced risk against heart disease in women ending with the onset of menopause. Epidemiologic studies in overt iron-overload states such as transfusional iron overload and hemochromatosis have shown that the incidence of cardiac disease is increased and that treatment with iron chelation improves cardiovascular outcome . Similarly, several studies have demonstrated a direct association between increased iron intake, body iron stores, and cardiovascular risk in the general population. Increased intake of heme iron is associated with increased cardiovascular events, and increased body iron stores are associated with myocardial infarction in a prospective epidemiological study . In addition, varieties of cardiovascular risk factors are associated with iron overload and commonly cluster in the metabolic syndrome. Several studies have demonstrated this close relationship between iron stores and cardiovascular risk factors in women of reproductive age in the USA. The association was seen with total cholesterol, triglycerides, diastolic blood pressure, and glucose, factors that often cluster in individual patients. Additional evidence of the role of iron can also be derived from studies on surrogate markers such as carotid atherosclerosis finding a positive association with iron stores .
Role of iron in diabetic neuropathy
In recent years, there has been increasing interest in brain iron metabolism during normal aging, particularly as excessive iron deposition has been found in neurological disorders. Oxidative stress and inflammatory factors may play a pivotal role in this relationship . However, there is no direct evidence on whether abnormal iron metabolism is related to diabetic neuropathy, but iron overload-induced neurotoxicity might be associated with oxidative stress .
Although numerous factors contribute to diabetic peripheral neuropathy, including insulin-induced resistance to neuronal trophic support decreased (Na/K)-ATP-ase activity, and Schwann cell dysfunction, increased oxidative stress and mitochondrial dysfunction seem intimately associated with nerve dysfunction and diminished regenerative capacity. Oxidative stress and apoptosis have been found to play crucial roles in diabetic peripheral neuropathy . Under hyperglycemia, large amounts of reactive oxygen species are produced by the mitochondrial respiratory chain, and neuronal apoptosis is increased .
Role of iron in diabetic retinopathy
Oxidative stress is considered to be one of the crucial contributors to the pathogenesis of diabetic retinopathy, and it is highly inter-related with other biochemical imbalances (i.e. increase in the polyol, hexosamine, and AGE pathways), which lead to structural and functional changes such as accelerated loss of capillary cells in the retinal microvasculature, increased vascular permeability, and increased vascular endothelial growth factor formation . In the human retina, iron levels increase with age in both men and women. However, women have significantly more retinal iron compared with men at all ages, despite having a higher incidence of anemia, which suggests tissue-specific mechanisms of iron regulation .
Abnormalities in local iron homeostasis have been implicated in several degenerative diseases, including Parkinson's, Alzheimer's, and age-related macular degeneration, in which it has been hypothesized that oxidative stress contributes to cell death . In addition, iron participates in other ocular diseases such as glaucoma and cataract .
Increased intraocular levels of iron cause oxidative damage to photoreceptors, with greater damage to cones than to rods . In addition, it has been shown that iron chelation protects the retinal pigment epithelial cells against cell death induced by oxidative stress .
| Conclusion|| |
Iron seems to impact negatively on insulin action even in healthy people and not just in classic pathologic conditions associated with iron overload (hemochromatosis and hemosiderosis). Oxidative stress is one of the major causative factors for diabetes and diabetic complications. Increasing evidence has indicated that iron overload not only increases risks for insulin resistance and diabetes but also causes cardiovascular diseases in nondiabetic and diabetic individuals.
| Acknowledgements|| |
Conflicts of interest
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