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Type 2 diabetes mellitus (T2DM) is implicated in development of various comorbidities and complications, including iron deficiency anemia (IDA). However, the exact mechanisms have not been properly documented. This review sought to highlight the interlink between T2DM and the development of iron deficiency anemia.
Methods and analysis
Two independent researchers searched the literature on MEDLINE. About 33 studies were retrieved, however, only 15 were deemed relevant to this review. Data drawn from each study was critically evaluated, and personal viewpoints were made from the results.
Results
According to the evidence summarized in this review, shows T2DM patients have an increased risk of developing IDA. Moreover, suggests that chronic inflammation due to the aberrant activation of pro-inflammatory cytokines (interleukin-6, 8, tumor necrosis factor-alpha, and interferon-gamma), are central to the development of IDA. Other hypothesized mechanisms for iron deficiency include impaired erythropoietin production and release from the kidney and elevated hepcidin levels in the liver. Anemia is driven on by the direct reduction in red blood cell survival mediated by pro-inflammatory cytokines. Similarly, iron deficiency in T2DM increases the levels of angiogenic factors (vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-β), hepatocyte growth factor (HGF), platelet-derived growth factor and hypoxia-inducible factor-1α (HIF-α)) and ultimately anemia. Additionally, iron and pro-inflammatory cytokines induce oxidative stress, which results in endothelial dysfunction and subsequent imbalance in angiogenic factors and ultimately anemia.
Conclusion
The association between T2DM, IDA, and angiogenic factors is highlighted in this review however, future research is required to derive conclusive evidence.
]. T2DM has been shown to cause anemia; despite the uncertainty of the exact mechanism, its contribution to kidney function can partially explain the implicated mechanisms. Kidney through interstitial cells is responsible for the production of erythropoietin [
] which stimulates the production of red blood cells (RBC) from bone marrow. Due to renal dysfunction, the production of RBC is diminished, resulting in anemia. Iron deficiency is prevalent globally; and it results in iron deficiency anemia, a severe health concern [
A wide population of T2DM rely on metformin as a first-line treatment, however, this drug has been proven to cause secondary complications if used in the long term. For example, its prolonged use is associated with vitamin B12 and folate deficiencies [
] and this could predispose the patent to the development of macrocytic anemia. Other explored mechanisms include decreased iron absorption and gastrointestinal bleeding. Increasing evidence from literature supports an association between T2DM and iron deficiency anemia [
]. Despite evidence demonstrating a relationship between T2DM and iron deficiency anemia, the implicated pathway and mechanisms are still poorly understood [
]. The current review focus on the current evidence on the relationship between T2DM and iron deficiency anemia, focusing on factors that influence iron metabolisms, such as hepcidin, ferritin, low-grade chronic inflammation, and angiogenic factors. Although few reviews have explored the relationship between T2DM and iron deficiency anemia, the existing reviews have not focused on or highlighted the role of iron-related parameters and chronic inflammation in T2DM.
Methodology and general features of included studies
A literature search of studies from inception until December 2021 was conducted on MEDLINE, Scopus, and Web of Sciences. The search was based on Mesh terms such as “anemia”, “iron deficiency”, and “type 2 diabetes mellitus”. A total of 33 studies were retrieved, and 15 were determined to be suitable to answer the question of interest in this review. There were no restrictions in study designs; all studies that evaluated the link between T2DM and iron deficiency anemia or any measure/parameters of anemia were assessed. Shortly after the search, selection, and extraction studies, a summary of findings was made from each study and presented in a tabular form (Table 1). The data were extracted from each study using a predefined sheet, including the names of the principal authors, year of publication, sample size, and main findings.
Table 1An overview of studies reporting on parameters and makers of iron deficiency anemia in patients with type 2 diabetes mellitus
Serum ferritin and iron significantly decreased in T2DM patients with anemia compared to those without anemia. Moreover, total iron-binding capacity (TIBC) and serum iron were significantly reduced in patients with total iron deficiency.
Hemoglobin (Hb) and mean cell hemoglobin (MCH) were significantly higher after the study than baseline. Treatment of glycemia and anemia resulted in reduced blood pressure, pulse rate, cardiovascular abnormalities, and improved kidney function.
Correlations between iron metabolism parameters, inflammatory markers and lipid profile indicators in patients with type 1 and type 2 diabetes mellitus.
Hb is significantly lower in diabetes and those with anemia compared to control, HbA1c higher in diabetes. No significant difference was observed in the level of ferritin. Iron is substantially higher in T2DM. Transferrin saturation was higher in T2DM. Transferrin is significantly higher in T2DM and anemia
Effect of iron deficiency anemia and iron supplementation on HbA1c levels – implications for diagnosis of prediabetes and diabetes mellitus in Asian Indians.
Ferritin, iron, Hb, transferrin saturation (TfS), hematocrit (HCT), and red blood cell (RBC), are significantly lower while TIBC and HbA1c significantly higher.
HbA1c and MCV were significantly higher in T2DM compared to control. However, Hb, ferritin, and TIBC were substantially lower in both males and females with T2DM compared to the control group.
Iron, Hb significantly decreased in T2DM compared to control. Serum transferrin and hepcidin increased dramatically in T2DM. No significant difference was observed in the level of ferritin between the groups.
]. Approximately 3–4 grams of iron in the adult body, of which 70% is found in red blood cells and skeletal muscle, are bound to hemoglobin (Hb) and myoglobin, respectively [
], other forms of iron in the body can be obtained from an iron-rich diet or supplements. The primary sites for dietary iron absorption take place in the intestinal enterocytes in the duodenum and jejunum. Ferroportin is the transmembrane protein, an iron exporter in human intestinal enterocytes [
]. It exports iron into the bloodstream via the basolateral membrane of intestinal enterocytes, where it is transported by transferrin and circulates the body [
]. Erythrocytes express transferrin receptor, which binds to iron; cellular transferrin receptor transcription is upregulated to increase iron uptake when iron in the circulation is low. Its expression is downregulated when there is a high level of iron in circulation. In contrast, the iron stored as ferritin in the liver is released in normal states when there is a decrease in iron level in circulation [
The absorption of iron is influenced by individual iron status, food eaten, and the level of vitamin C in the diet. Vitamin C is a cofactor that promotes the absorption of non-heme iron [
]. Individuals with low iron reserve tend to absorb more iron than those with adequate iron stores. This ensures a balanced iron level in the body and protects the body from iron deficiency and overloading. Absorption of iron occurs in the duodenum or jejunum and differs based on the form of iron. Consistently, the absorption of non-heme iron is determined by its transporters and enzymes. In fact, ferric ion (Fe3+), an insoluble form of iron, cannot be absorbed directly through enterocytes; thus, it requires ferric reductase enzyme, duodenal cytochrome B (Dcytb), which converts it into the ferrous form of iron (Fe2+) [
]. Concomitant to that, ferrous iron is transported from the lumen by divalent metal transporter 1 (DMT-1) into the enterocytes, which enter circulation through ferroportin [
]. If there is adequate iron in the circulation, hepcidin will inhibit the influx of iron from enterocytes into the circulation to prevent iron overloading [
]. However, an elevation in hepcidin induces iron deficiency which further causes iron deficiency anemia. In contrast, the heme dietary iron is transported through the lumen into the enterocytes by heme carrier protein-1(HCP-1) [
Fig. 1A brief overview of iron absorption and transport mechanism. Fe2+, a ferrous form of iron that is easily absorbed, Fe3+, a ferric form of iron that is insoluble, DMT-1, divalent metal transporter-1, Dcytb, duodenal cytochrome b reductase, HCP-1, heme carrier protein-1.
]. Various pro-inflammatory cytokines have been reported to interlink T2DM and inflammation. These include interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). Consistently, TNF-α, despite being produced by adipocytes, is also secreted by macrophages and other cells [
]. This cytokine contributes to inflammatory pathways and, at higher levels, may induce the formation of IL-8, which mediates monocyte adherence, thus contributing to the development of CVD and atherosclerosis [
]. Recent literature has demonstrated that increased inflammation coupled with high levels of hepcidin is associated with reduced iron absorption and reduced efficacy of iron-fortified foods [
]. Following inflammation and infection, the acute phase inhibits iron availability through sequestration of iron within macrophages resulting in iron deficiency [
]. Indeed, an elevated iron level within the storage, as demonstrated by a high level of ferritin and low transferrin, is associated with an increased risk of T2DM in males [
Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: Evidence from a case-control study.
]. Several reports show an increased ferritin level in patients with hepatitis C virus infection implying that iron stores link hepatitis C virus infection and diabetes. Previous studies have reported an association between elevated serum ferritin levels and the presence of diabetes in hepatitis C virus-infected patients [
] demonstrating that the hepatitis C virus is responsible for this mechanism.
Iron status in hemopoiesis
Iron is essential in the process of hemopoiesis, and it is found in the normal, fully matured red blood cell as bound to Hb or muscle cells bound to myoglobin. Hb synthesis requires iron and globin chains, and it transports oxygen in the body from the lungs to the tissues [
]. This results in impaired Hb synthesis, ineffective hemopoiesis, and thus iron deficiency anemia. Consistently, in case the iron levels are excessively elevated, they accumulate in the bone marrow and hematopoietic cells compartment resulting in the generation of reactive oxygen species (ROS), thus damaging hematopoietic cells [
Iron overload promotes mitochondrial fragmentation in mesenchymal stromal cells from myelodysplastic syndrome patients through activation of the AMPK/MFF/Drp1 pathway article.
]. Moreover, increased iron levels in the blood due to multiple blood transfusions result in iron overload, damaging organs, and thus leading to liver cirrhosis [
Iron overload promotes mitochondrial fragmentation in mesenchymal stromal cells from myelodysplastic syndrome patients through activation of the AMPK/MFF/Drp1 pathway article.
Summarized clinical and preclinical evidence associating angiogenic factors with anemia and diabetes mellitus
Angiogenic factors are also implicated in the cross-link between anemia with T2DM. This is partially due to iron deficiency which significantly promotes vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-beta (TGF-β) [
]. Therefore, its stores in the human body can be considered a therapeutic target in diabetic individuals. Under normal circumstances, iron promotes insulin activity, leading to increased vasodilation and blood flow [
]. However, these processes are suppressed in anemia with reduced iron, which is attributable to aberrantly activated pro-inflammatory cytokines such as IL-6 and TNF-α [
]. Chronic inflammation has been proposed as one of the mechanisms that interlink T2DM and anemia; this is due to an increased level of pro-inflammatory cytokines such as IL-6, and 8, TNF-α, and interferon-gamma. The activation of these cytokines results in tissue injuries, and in the kidney, it impairs the production of erythropoietin, the important glycoprotein hormone necessary for erythropoiesis. In the liver, this increases the level of hepcidin, which inhibits iron absorption and induces iron deficiency [
Additionally, these reduce the lifespan of red blood cells. Altogether these disturbances lead to a reduced number of red blood cells in the circulation. On the other hand, increased pro-inflammatory cytokines promote the generation of ROS, which further predisposes the cells to oxidative stress. Consistently, this results in endothelial dysfunction as demonstrated by an increased level of angiogenic factors, including VEGF, TGF-β, hepatocyte growth factor (HGF), and platelet-derived growth factor (PDGF) (Fig. 2). Alternatively, iron deficiency in T2DM promotes angiogenesis by angiogenic factors which further leads to anemia [
Fig. 2Mechanisms implicated in relationship between type 2 diabetes and anemia. Notably, chronic inflammation, iron deficiency, and angiogenic factors are key factors that link diabetes mellitus and anemia.
]. Moreover, an association between VEGF and anemia has been reported in animal model studies whereby neuronal nitric oxide synthase (nNOS) and VEGF protein levels were elevated within the cerebral cortex of anemic rats [
Association between the expression of vascular endothelial growth factors and metabolic syndrome or its components: a systematic review and meta-analysis.
]. Although VEGF proteins, including VEGF-A, VEGF-B, VEGF-C, and VEGF-D, have been studied in metabolic disorders, controversial findings still exist, as demonstrated by positive and negative relationships reported. Several studies have observed increased circulatory and adipose tissue VEGF-A in obese individuals compared to lean individuals [
Association between the expression of vascular endothelial growth factors and metabolic syndrome or its components: a systematic review and meta-analysis.
Similarly, the conflicting results on the metabolic role of VEGF-B have been reported as demonstrated by increased circulating and adipose tissue VEGF-B levels [
Association between the expression of vascular endothelial growth factors and metabolic syndrome or its components: a systematic review and meta-analysis.
]. These findings are further supported by Ning and colleagues, who noted that inhibition of VEGF-B signaling has many metabolic benefits, such as preventing tissue lipid accumulation, reducing pancreatic islet triglyceride content, and improving insulin sensitivity and glucose tolerance under T2DM conditions [
]. Interestingly, a study by Karaman et al. (2015) indicated that blockage of VEGF-C and VEGF-D in the animal model reduces inflammation in the adipocytes and improves insulin sensitivity [
Elevated levels of TGF-β are linked to anemia. According to Zhang et al. (2016), TGF-β signaling contributes to bone marrow failure in Fanconi anemia by impairing hematopoietic stem and progenitor cell function [
]. Similarly, a genetic study found that expression of TGF target genes such as transforming growth factor-beta-induced protein (TGFBI), bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), collagen type III alpha 1 (COL3A1), in Diamond Blackfan Anemia (DBA), a hereditary bone marrow failure, the level of the serine protease inhibitor family E member 1 (SERPINE1) was significantly higher [
]. Therefore, blocking TGF-β signaling using a receptor kinase inhibitor increases early cell self-renewal and total erythroblast production, suggesting the benefits of this therapeutic drug in treating anemias [
Brief report hematopoiesis and stem cells TGF-b inhibitors stimulate red blood cell production by enhancing self-renewal of BFU-E erythroid progenitors.
]. In addition, overexpression of the TGF-β1 signaling pathway has been implicated in the progression of chronic kidney disease in human diabetic kidney disease (CKD) [
]. Subsequently, this inhibits erythropoietin production and further impairs hematopoiesis. Therefore, drugs that target TGF-β signaling, primarily naturally derived ones such as Lycopus lucidus and Momordica charantia extracts, may become alternative forms of treatments in managing T2DM [
There is inadequate scientific information regarding the association between hepatocyte growth factor (HGF), anemia, and T2DM. Current literature suggests that there is a positive correlation between Hb and HGF [
Association of hemoglobin concentration with handgrip strength in relation to hepatocyte growth factor levels among elderly Japanese men aged 60-69 years: a cross-sectional study.
], suggesting that reduced HGF is associated with anemia or low Hb levels. HGF is also elevated in metabolic conditions such as insulin resistance and obesity, which are believed to be risk factors for T2DM [
]. PDGF is another study angiogenic factor in relation to anemia and diabetes mellitus. Findings show that PDGF is involved in the pathophysiology of nephropathy in T2DM [
]. In contrast, in vitro studies have documented that platelet-derived growth factor (PDGF), epidermal growth factor (EGF) as well as insulin play a role in GLUT4 translocation and glucose uptake through the activation of PI 3-kinase and Akt pathways [
Platelet-derived growth factor (PDGF) stimulates glucose transport in 3T3-L1 adipocytes overexpressing PDGF receptor by a pathway independent of insulin receptor substrates.
Platelet-derived growth factor stimulates glucose transport in skeletal muscles of transgenic mice specifically expressing platelet-derived growth factor receptor in the muscle, but it does not affect blood glucose levels.
As most of these angiogenic factors are involved in the pathophysiology of both T2DM and anemia, the role of stated angiogenic factors in the pathophysiology of metabolic complications such as obesity, insulin resistance, diabetes mellitus, and anemia explains why there is a strong correlation between T2DM and anemia (Table 2).
Table 2Angiogenic factors in anemia and type 2 diabetes mellitus
Brief report hematopoiesis and stem cells TGF-b inhibitors stimulate red blood cell production by enhancing self-renewal of BFU-E erythroid progenitors.
Association of hemoglobin concentration with handgrip strength in relation to hepatocyte growth factor levels among elderly Japanese men aged 60-69 years: a cross-sectional study.
There is an increased prevalence of non-communicable diseases, including T2DM and associated complications such as iron deficiency anemia, globally in various age and gender groups, suggesting an association between iron-related parameters and diabetes. Despite this potential relationship, there have been a limited number of studies investigating this relationship amongst these parameters. Based on the evidence synthesized in this review, there is increasing evidence in clinical studies conducted from 2003 to 2021 highlighting the relationship between iron-related parameters and anemia in T2DM patients (Table 1). The iron-related markers, including serum ferritin, iron, and transferrin saturation, were substantially reduced in T2DM patients with anemia when compared to T2DM without anemia [
]. Thus, reduced iron and ferritin in T2DM patients would impair Hb synthesis as iron is essential for the formation of the heme part of Hb. According to previous studies [
], Hb concentration was significantly lower in T2DM; since Hb is an essential pigment that gives RBC color, its deficiency would result in reduced RBC production hence anemia.
In contrast, Hb was found significantly raised in T2DM as reported by [
], implying that any form of anemia that may develop in this case is not due to Hb deficiency. These contradicting findings warrant future clinical research to explore this relationship between diabetes and anemia which further assist in finding a therapeutic target against complications associated with both anemia and diabetes mellitus. The mean cell volume and Hb are both markers of blood cells; mean corpuscular volume (MCV) measures the size of the RBC while MCH measures the amount of Hb in RBC; the findings generated in this review also showed conflicting results. One study showed increased MCV in T2DM [
]. An increased MCV coupled with low Hb results in a macrocytic form of anemia, while reduced MCV in combination with low Hb leads to microcytic anemia. MCH was significantly higher as reported by [
], implying that the cells have increased Hb concentration.
Concluding remarks
The association between T2DM, iron deficiency anemia, and angiogenesis is discussed in this review. Although the pathways and mechanisms implicated in these relationships are poorly documented, the scientific evidence suggests that chronic inflammation, angiogenic factors, and iron-related markers associated with diabetes mellitus impair iron metabolism and erythropoiesis (Fig. 2). Due to the global prevalence of T2DM, developing public health protocols and techniques to manage diabetes-related complications is critical. Notably, T2DM patients at high risk of developing iron-deficiency anemia should be regularly screened for iron status so that this can be identified and treated early. In the early stages of iron deficiency anemia, patients rarely exhibit common clinical signs and symptoms of anemia, however, if regular screening for iron is performed in T2DM, this can be prevented or managed. T2DM patients would benefit from routine monitoring of iron status and using iron-related markers. As a result, we recommend, future research with a powered sample size to investigate this causal relationship between T2DM, iron-related parameters, inflammation, and angiogenic markers.
Ethics approval and consent to participate
Not applicable. This study involves the evaluation of studies that are already published; thus, no patients were recruited.
Funding
This study received no external funding from any funding agencies.
Contributor's statement
Mokgalaboni K, Conceptualization; Mokgalaboni K and Phoswa W.N, Data curation; Mokgalaboni K, Formal analysis; Mokgalaboni K, Phoswa W.N, Investigation; Mokgalaboni K, Phoswa W.N, Methodology; Mokgalaboni K, Project administration; Mokgalaboni K, Resources; Mokgalaboni K, Software; Mokgalaboni K, Supervision; Mokgalaboni K and Phoswa W.N, Validation; Mokgalaboni K, Visualization; Mokgalaboni K and Phoswa W.N, Roles/Writing – original draft; Mokgalaboni K and Phoswa W.N, Writing – review & editing. All authors approved the final version of this manuscript.
Availability of data and materials
Not applicable.
Patient consent for publication
Not applicable.
Conflict of interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
Primary authors thanks Prof Khambule-Tsotetsi for her mentorship.
Abbreviations
BAMBI
Bone morphogenetic protein and activin membrane-bound inhibitor
CKD
Chronic kidney disease
COL3A1
collagen type III alpha-1
CRP
C-reactive protein
DBA
Diamond Blackfan Anemia
DMT-1
Divalent metal transporter-1
Hb
Hemoglobin
HbA1c
Glycated hemoglobin
HCT
Hematocrit
HCP-1
Heme carrier protein-1
HGF
Hepatocyte growth factor
HIF-1α
Hypoxia-inducible factor-1α
IL-6
Interleukin-6
MCH
Mean cell hemoglobin
MCV
Mean cell volume
nNOS
Neuronal nitric oxide synthase
SERPINE1
Serine protease inhibitor family E member-1
T2DM
Type 2 diabetes mellitus
TGFβI
Transforming growth factor-beta-induced protein
TGF-β
Transforming growth factor-beta
TIBC
Total iron-binding capacity
TNF-α
Tumor necrosis factor-alpha
RBC
Red blood cell
VEGF
Vascular endothelial growth factor
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The global burden of diabetes and its complications: An emerging pandemic.
Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: Evidence from a case-control study.
Iron overload promotes mitochondrial fragmentation in mesenchymal stromal cells from myelodysplastic syndrome patients through activation of the AMPK/MFF/Drp1 pathway article.
Association between the expression of vascular endothelial growth factors and metabolic syndrome or its components: a systematic review and meta-analysis.
Brief report hematopoiesis and stem cells TGF-b inhibitors stimulate red blood cell production by enhancing self-renewal of BFU-E erythroid progenitors.
Association of hemoglobin concentration with handgrip strength in relation to hepatocyte growth factor levels among elderly Japanese men aged 60-69 years: a cross-sectional study.
Platelet-derived growth factor (PDGF) stimulates glucose transport in 3T3-L1 adipocytes overexpressing PDGF receptor by a pathway independent of insulin receptor substrates.
Platelet-derived growth factor stimulates glucose transport in skeletal muscles of transgenic mice specifically expressing platelet-derived growth factor receptor in the muscle, but it does not affect blood glucose levels.
Correlations between iron metabolism parameters, inflammatory markers and lipid profile indicators in patients with type 1 and type 2 diabetes mellitus.
Effect of iron deficiency anemia and iron supplementation on HbA1c levels – implications for diagnosis of prediabetes and diabetes mellitus in Asian Indians.
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