• Users Online: 679
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 31  |  Issue : 4  |  Page : 874-883

Investigation of association of biomarkers of iron metabolism and insulin resistance in Egyptian patients with impaired glucose metabolism and type 2 diabetes


1 Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
2 Department of Medical Biochemistry & Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt

Date of Submission11-Jul-2019
Date of Acceptance01-Oct-2019
Date of Web Publication18-Aug-2020

Correspondence Address:
MD Elham M Yousief
66 Gamaet Eldwal, Mohandseen, Giza, 12511
Egypt
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejim.ejim_100_19

Rights and Permissions
  Abstract 


Introduction Type 2 diabetes is an expanding overall medical issue. A large portion of the enthusiasm for the job of supplements in diabetes is fixated on macronutrients, yet a micronutrient, iron, is additionally closely connected with diabetes.
Aim To study biomarkers of iron metabolism, including serum ferritin, transferrin saturation, iron, and insulin resistance, in diabetic and prediabetes patients.
Patients and methods This is a cross-sectional study directed on a cohort of 50 patients, comprising 25 patients with impaired glucose tolerance and 25 patients recently discovered to have type 2 diabetes mellitus (T2DM), as well as 20 healthy controls of matched age and both sexes. All patients enrolled in the study were subjected to full history taking, full examination, laboratory investigations including iron, total iron-binding capacity, ferritin, insulin, lipid profile, fasting blood glucose, 2-h postprandial glucose, urea, creatinine, complete blood count, alanine aminotransferase, and aspartate aminotransferase.
Results We found that patients with T2DM have significant higher body weight and BMI than prediabetes patients and controls, and also statistically significant difference in serum iron between the studied groups, but no statistical significance in serum ferritin between the studied groups. In addition, we found a positive correlation of serum iron and insulin resistance in T2DM, a significant positive correlation of serum ferritin with low-density lipoprotein and negative correlation with high-density lipoprotein in T2DM, positive correlation of ferritin with cholesterol and triglycerides in impaired glucose tolerance group. Moreover, transferrin saturation was negatively correlated with glycated hemoglobin, BMI, and total iron-binding capacity and is positively correlated with iron and creatinine and hemoglobin among the studied groups.
Conclusion The distinguished relationship of several markers of iron metabolism with hyperglycemia and insulin resistance recommends that iron stores add to the pathogenesis of IGM and T2DM.

Keywords: ferritin, impaired glucose tolerance, iron, type 2 diabetes mellitus, transferrin saturation


How to cite this article:
El Ebrashy IN, Shaker O, Abdelgalil SI, Yousief EM. Investigation of association of biomarkers of iron metabolism and insulin resistance in Egyptian patients with impaired glucose metabolism and type 2 diabetes. Egypt J Intern Med 2019;31:874-83

How to cite this URL:
El Ebrashy IN, Shaker O, Abdelgalil SI, Yousief EM. Investigation of association of biomarkers of iron metabolism and insulin resistance in Egyptian patients with impaired glucose metabolism and type 2 diabetes. Egypt J Intern Med [serial online] 2019 [cited 2020 Oct 1];31:874-83. Available from: http://www.esim.eg.net/text.asp?2019/31/4/874/292183




  Introduction Top


Type 2 diabetes is a typical and increasing overall medical issue. It is very much acknowledged that the most solid indicator for the disease is obesity; therefore, consideration has additionally been paid to the commitment of supplements and supplement-detecting pathways in circumstances of endless caloric abundance. A large portion of the enthusiasm for the job of supplements in diabetes is focused on macronutrients, yet a micronutrient, iron, is likewise intently connected with diabetes [1].

Inherited hemochromatosis, a hereditary issue portrayed by fundamental iron overburden, is accounted for to be related with diabetes [2]. Moreover, an overrepresentation of diabetes cases has likewise been identified among people with states of obtained iron overburden, for example, thalassemia major [3]. This could clarify that abnormal amounts of body iron are a hazard factor for type 2 diabetes in the community, and this may have suggestions for the prevention and treatment of type 2 diabetes. Cross-sectional and prospective studies report a positive relationship between ferritin and type 2 diabetes [4],[5]. Ferritin is additionally an acute phase reactant and is increased in the presence of inflammation, liver disease, and insulin resistance, which are likewise connected with type 2 diabetes [6],[7]. Different biomarkers of iron metabolism may give additional data on the role of iron in the pathogenesis of type 2 diabetes. Transferrin is the iron-binding protein available for use, and its levels increase with growing iron prerequisites. Serum iron is hard to interpret in separation, as it has a diurnal variety and consequently differs altogether without changes in all out-body iron [8]. Transferrin saturation (TSAT) is the extent of transferrin bound to serum iron and is to some extent a marker of iron absorption; it mirrors the extent of coursing iron in the milieu of iron prerequisites. TSAT is raised within the sight of nontransferrin-bound iron, which thus is in charge of iron-related oxidative harm [9],[10].

We research the independent relationship of the markers of iron processing, serum ferritin, transferrin, TSAT, and iron with hyperglycemia and insulin resistance in Egyptian population with impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM), attempting to affirm the role of ferritin in insulin resistance and T2DM.


  Patients and methods Top


The present study included three groups of patients aged 30–45 years. Participants were recruited from Internal Medicine Department and Clinic of Tertiary Care Hospital and were divided into group A, which included 25 patients newly diagnosed with T2DM; group B, which included 25 patients with IGT; and group C, which included 20 healthy controls. The exclusion criteria were (a) type I DM, (b) pregnancy-induced DM, (c) drug-induced diabetes, (d) liver and kidney diseases, and (e) hereditary hemochromatosis.

In all patients, thorough clinical evaluation was performed including fasting blood sugar, 2-h postprandial (2HPP) sugar, glycated hemoglobin (HbA1C), serum triglycerides (TGs), total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, serum aspartate aminotransferase, alanine aminotransferase, serum urea, creatinine, serum insulin measured by radioimmunoassay used in homeostatic measurement assessment insulin resistance (HOMA-IR), serum iron, total iron-binding capacity (TIBC), TSAT, serum ferritin, and albumin-creatinine ratio in urine.

This cross-sectional study was conducted from April 2017 till April 2018 after approval of the institutional ethical committee. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study. All participants signed a written informed consent form before enrollment in the study to complete the requirement of the ethical committee of the faculty of physical therapy, Cairo University, and to ensure complete satisfaction. All patients of the study were informed about the study, its aim, and all risks and expected benefits, and they were also assured of their anonymity and confidentiality of data obtained before signing the informed consent.

Quantitation of ferritin in serum

The serum level of ferritin was measured using an ELISA kit provided by Immunospec Corporation (Canoga Park, California, USA).

Principle of the test

The Immunospec Ferritin Quantitative Test Kit depends on a solid-phase compound-connected immunosorbent examination. The measured framework uses charge interaction of ferritin to the wells of microtiter plate for solid phase immobilization, and then a mouse monoclonal antibody for ferritin conjugated with a neutralizer catalyst (horseradish peroxidase) is added. Ferritin is allowed to interact all the while with the antibodies, bringing about the ferritin atoms being sandwiched between the strong stage and protein-connected antibodies. Following a 30-min incubation at room temperature, the wells are washed to expel unbound antibodies. Then TMB (chromogenic substrate used in staining procedures in immunohistochemistry as well as being a visualizing reagent used in enzyme-linked immunosorbent assays) is included and incubated for 15 min; it interacts with enzyme and brings about the advancement of a blue shading. The shading improvement is ceased with the expansion of stop arrangement, and the shading is changed to yellow and estimated by ELISA peruse at 450 nm. The centralization of ferritin is straightforwardly corresponding to the shading power of the test.

Materials provided with the test kits include the following:
  1. Antibody-covered microtiter plate with 96 wells.
  2. Reference standard set, which contains 0, 15, 50, 200, 400, and 800 ng/ml (fluid, prepared to utilize).
  3. Enzyme conjugate reagent, 12 ml.
  4. TMB substrate, 12 ml.
  5. Stop solution, 12 ml.
  6. Wash buffer concentrate (100×), 15 m.


Materials required but not provided were as follows:
  1. Precision pipettes: 0.5, 50 μl, 0.05, 0.2 ml, and 1.0 ml.
  2. Disposable pipette tips.
  3. Distilled water.
  4. Vortex blender or identical.
  5. Absorbent paper or paper towel.
  6. Graph paper.
  7. Microtiter well peruser.


Reagent preparation:
  1. All reagents were brought to room temperature (18–22°C) before use.
  2. One volume of wash buffer (100×) was weakened with 99 volumes of refined water.


Assay procedures:
  1. 10 μl of standard, examples, and controls was administered into suitable wells.
  2. 100 μl of enzyme conjugate reagent was administered into each well.
  3. Thoroughly blend for 30 s was finished. It is essential to have total blending in this arrangement.
  4. Incubation was done at room temperature (18–22°C) for 30 min.
  5. The hatching blend was evacuated by flicking plate content into a waste holder.
  6. The microtiter wells were washed multiple times with washing cushion (1×).
  7. The wells were stroked pointedly onto permeable paper or paper towels to evacuate all lingering water beads.
  8. 100 μl of TMB substrate was apportioned into each well and blended delicately for 5 s.
  9. Incubation was done at room temperature in obscurity for 15 min.
  10. The response was ceased by including 50 ul of stop solution to each well.
  11. Gently blend was accomplished for 30 s. It is essential to ensure that all the blue shading changes to yellow shading totally.
  12. The optical thickness was perused at 450 nm with a microtiter peruser inside 15 min.


Calculation of results

The mean absorbance esteem (A450) for each arrangement of reference models, examples, controls, and patient examples was determined. A standard bend was made by plotting the mean absorbance acquired from each reference standard against its focus in ng/ml on diagram paper, with absorbance esteems on the vertical or Y hub and fixations on the level or X pivot. The mean absorbance esteems for every example was resolved, and the ferritin fixation was resolved in ng/ml from the standard bend.

Sensitivity of the kit

  1. The minimal sensitivity of the test was 5.0 ng/ml.


Quantitative determination of glycosylated hemoglobin

Principle of the test

Glycosylated hemoglobin (GHb) has been defined operationally as the fast fraction hemoglobins HbA1 (Hb A1a, A1b, and A1c), which elute first during column chromatography. The non-GHb, which consists of the bulk of hemoglobin, has been designated HbAo. A hemolyzed preparation of whole blood is mixed continuously for 5 min with a weakly binding cation-exchange resin. The labile fraction is eliminated during the hemolyzate preparation and during the binding. During this mixing, HbAo binds to the ion exchange resin leaving GHb free in the supernatant. After the maxing period, a filter separator is used to remove the resin from the supernatant. The percent GHb is determined by measuring absorbances of the GHb fraction and the total hemoglobin fraction. The ratio of the absorbances of the GHb and the total hemoglobin fraction of the control and the test is used to calculate the percent GHb of the sample



Sample material

Whole blood preferably fresh is collected in EDTA tube. GHb in the whole blood is reported to be stable for 1 week at 2–8°C.

Procedure



Hemolysate preparation

  1. 0.5 ml lysing reagent was dispensed into tubes labeled as test (T).
  2. 0.1 ml of the reconstituted well mixed blood sample was added into the appropriately labeled tubes; in mixed unit, complete lysis was evident.
  3. The mixture was allowed to stand for 5 min.


Glycosylated hemoglobin separation

  1. Top was expelled from the ion-exchange resin tubes and named as test.
  2. 0.1 ml of the hemolysate from stage A was included into the properly marked ion exchange resin tubes.
  3. A gum separator was embedded into each cylinder so the elastic sleeve was around 1 cm over the fluid degree of the sap suspension.
  4. The cylinders were blended on a rocker, rotator, or a vortex blender ceaselessly for 5 min.
  5. The tar was permitted to settle then the sap separator was pushed into the cylinders until the sap was immovably pressed.
  6. Every supernatant was poured or suctioned legitimately into a cuvette, and every absorbance was estimated against refined water.


Total hemoglobin fraction

  1. 5.0 ml of distilled water was dispensed into tubes labeled as test.
  2. 0.02 ml of hemolysate from step A was added to it into the appropriately labeled tube and mixed well.
  3. Each absorbance was read against distilled water.


Calculations:



Insulin resistance (homeostatic measurement assessment insulin resistance)



(Glucose in mass units mg/dl) [11]



Statistical analysis

Numerical variables were described as mean±SD. Categorical variables were described as percentages. Comparisons were done using Student t test for numerical variables, and χ2 test for categorical variables. Unpaired t test was used to compare quantitative variables, in parametric data (SD<50% mean). Mann–Whitney test was used instead of unpaired t-test in non-parametric data (SD>50%mean). One-way analysis of variance test was used to compare more than two groups regarding quantitative variables. Spearman correlation coefficient test was used to rank variables versus each other positively or inversely. Correlations were plotted and r values (correlation coefficients) were stated. P value was considered significant if less than or equal to 0.05. Univariate and multivariate regression analyses were run to predict potential determinants of insulin resistance. Statistics were calculated using SPSS 21 package. Software package that originated at what formerly was the National Opinion Research Center (NORC), at the University of Chicago.


  Results Top


Demographic, clinical, and laboratory characteristics of participants

Our study was done on an age group ranging from 30 to 45 years old. There were statistically significant differences between the studied groups regarding sex (P<0.001) with more females than males in group A and group B than group C (P=0.002), and there was no significant difference in age among the three groups. Moreover, we found a statistically highly significant difference between the studied groups regarding BMI (P<0.001). Serum glucose level (fasting, 2HPP, and HbA1C) was higher in group A compared with group B and group C (P<0.001); however, group B had higher levels of both fasting blood sugar and 2HPP blood sugar and HbA1C than group C. Albumin-creatinine ratio was higher in group A and group B compared with controls (P<0.001). There was a statistically highly significant difference between the studied groups regarding fasting insulin, which was higher in group A than group B and group C (P<0.001). The cholesterol level was significantly higher in group A and group B than in control group (P=0.019). LDL level was statistically significantly higher in group A than in group B and control group (P<0.001). HDL level was significantly lower in group A compared with group B and control group (P<0.001), and there was no significant difference between the studied groups regarding TGs level (P=0.087). We found a statistically significance difference in Hb level among the studied groups, with higher Hb level in control group than group A and group B (P=0.012). Moreover, there was a statistically significant difference in serum iron among the studied groups, with high serum iron in control group than group A and group B (P=0.033). No statistically significant differences were found between the studied groups regarding serum TIBC, TSAT, and serum ferritin; however, serum ferritin was higher in group A and group B than control group. Moreover, we found that insulin resistance (HOMA-IR) was significantly higher in group A than in group B and group C (P<0.001). Lastly, we found no significant difference of liver and kidney function between the studied groups ([Table 1]).
Table 1 Demographic, clinical, and laboratory characteristics of participants

Click here to view


Correlations between insulin resistance (homeostatic measurement assessment insulin resistance) with ferritin, fasting blood sugar, 2 h postprandial, lipid profile, and age in each group separately

There was no significant correlation between HOMA-IR index and different laboratory data in the studied groups except positive correlation between ferritin and FBG in prediabetes group ([Table 2]).
Table 2 Correlations between insulin resistance (homeostatic measurement assessment insulin resistance) with ferritin, fasting blood sugar, 2 h postprandial, lipid profile and age in each group separately

Click here to view


Correlation between serum iron and insulin resistance (homeostatic measurement assessment insulin resistance) in newly diagnosed type 2 diabetes mellitus (group A)

There was a significant positive correlation between serum iron and insulin resistance represented by HOMA-IR index in newly diagnosed T2DM ([Figure 1]).
Figure 1 Correlation between serum iron and insulin resistance (HOMA-IR) in newly diagnosed type 2 diabetes mellitus group. HOMA-IR, homeostatic measurement assessment insulin resistance.

Click here to view


Correlation between ferritin versus different variables among patients with impaired glucose tolerance

We found a significant positive correlation between (HbA1C, cholesterol, and TGs) and ferritin level in IGT group ([Figure 2] and [Figure 3]).
Figure 2 Positive correlation between ferritin level and TGs and cholesterol in IGT group. IGT, impaired glucose tolerance; TG, triglyceride.

Click here to view
Figure 3 Correlation between ferritin level and HDL and LDL levels in newly diagnosed diabetic patients. HDL, high-density lipoprotein; LDL, low-density lipoprotein.

Click here to view


Correlation between ferritin versus different variables among newly type 2 diabetes mellitus group

There was a significant positive correlation between ferritin level and LDL and negative correlation with HDL levels in newly diagnosed diabetic patients.

Correlation between ferritin versus different variables among controls

There was no significant correlation between ferritin and other variables in the control group.

Comparison between males and females regarding ferritin among the studied groups

There was a significant positive correlation between males and females in the newly diagnosed T2DM (group A) regarding ferritin, which was significantly higher in males than in females, but there was no statistically significant correlation between males and females in IGT group or control group ([Figure 4]).
Figure 4 Correlation between males and females in the studied groups regarding ferritin.

Click here to view


Correlation between transferrin saturation and other variables between the studied groups

TSAT was negatively correlated with HbA1C, BMI, and TIBC and is positively correlated with iron and creatinine and hemoglobin ([Figure 5],[Figure 6],[Figure 7]).
Figure 5 Negative correlation between TSAT and HbA1C. HbA1C, glycated hemoglobin; TSAT, transferrin saturation.

Click here to view
Figure 6 Negative correlation between TSAT and BMI. TSAT, transferrin saturation.

Click here to view
Figure 7 Positive correlation between TSAT and creatinine. TSAT, transferrin saturation.

Click here to view


Validity of ferritin in prediction of insulin resistance

We detected that serum ferritin is better positive than negative in prediction of insulin resistance ([Table 3]).
Table 3 Validity of ferritin in prediction of insulin resistance

Click here to view



  Discussion Top


Our study showed a very high statistically significant difference in weight and BMI among study groups (P<0.001), with increased values in patients with type 2 diabetes and IGT than controls. Moreover, fasting plasma glucose, fasting insulin, HbA1C, and insulin resistance were significantly higher in T2DM compared with patients with prediabetes and controls. In agreement with our results, Kim et al. [12] discovered altogether higher BMI, fasting plasma glucose, fasting insulin, and insulin opposition in T2DM in contrast with controls. Likewise, Hu et al. [13] revealed that insulin resistance and risk of T2DM increased with increment in body fat.

Our study showed a statistically significant difference in serum iron between the studied groups, with higher serum iron present in the controls than patients with type 2 diabetes and prediabetes. Additionally, we found no statistically significant correlation between serum ferritin among the studied groups; however, serum ferritin is higher in diabetic patients than prediabetes and control groups. This comes in accordance with an examination done by Podmore et al. [14] who found that higher ferritin level was related with an increased ri of type 2 diabetes among people.

The relationship of ferritin with type 2 diabetes [4] has recently been mentioned in most recent meta- analysis of forthcoming examination done by Kunutsor and colleagues. Additionally, the aftereffects of our examination were bolstered by an investigation done by Fumeron et al. [15], who found that ferritin and transferrin are both prescient of the beginning of hyperglycemia in people over more than 3 years.

As opposed to our outcomes, Kim et al. [12] found no elevation in serum ferritin in patient with T2DM compared with controls. Likewise, Dinneen et al. [16] revealed that type 2 diabetes was not related with a considerable degree of iron overburden. We found no measurably statistically significant difference in the level of TSAT between the studied groups; however, patients with diabetes and prediabetes have lower TSAT than control and could contribute to the risk of development of insulin resistance and type 2 diabetes. Moreover, we found that the level of TSAT was negatively correlated with HbA1C, BMI, and TIBC and is positively correlated with iron and creatinine and hemoglobin among the studied groups. This comes in accordance with Podmore et al. [14] who found that high level of TSAT was related with a lower risk of type 2 diabetes in women, when a cutoff of 45% was utilized in light of the fact that higher TSAT could reflect increasingly fruitful searching of non-transferrin-bound iron and in this way be protective against type 2 diabetes. Moreover, Misra et al. [17] discovered that increases in the degrees of serum free iron and serum TSAT levels with poor glycemic control show a significant role of free iron in the advancement of diabetic complications.

Results from prospective studies of TSAT with type 2 diabetes are clashing. An investigation utilizing information from the National Health and Nutrition Examination Survey did not discover any relationship among TSAT and type 2 diabetes utilizing distinctive cutoffs for TSAT [18].

Conversely, a meta-examination of three Danish investigations found that TSATs more than or equal to 50% was related with a higher danger of type 2 diabetes [19]. In any case, these were small studies, with less than 1500 cases in each.

Huth et al. [20] found through cross-sectional studies comparable relationship of high ferritin and low TSAT among people with prediabetes.

TSAT is a helpful biomarker of iron metabolism notwithstanding ferritin [21] in light of the fact that TSAT levels are less influenced by inflammation than ferritin [22] and are thought to reflect levels of nontransferrin-bound iron [9].

In patients with hemochromatosis, which is described by high iron absorption, TSAT is raised first, trailed by ferritin once iron accumulates in tissues [2].

Nontransferrin-bound iron is believed to be a significant wellspring of organ iron deposition and toxicity, as it is ardently taken up by tissues, independent of transferrin receptor [10], and deposition have been demonstrated to be higher in patients with type 2 diabetes contrasted and control [23].

We found a significant positive correlation between serum iron and insulin resistance in patients with type 2 diabetes, and no correlation between serum iron and insulin resistance in prediabetic and control groups. In addition, there is proof that high body iron may affect both insulin secretion and sensitivity [24], and numerous past investigations have uncovered the connection of high serum ferritin levels with an assortment of conditions that add to the metabolic disorder and T2DM. These studies have reflected high ferritin as an impression of iron overburden [25]. Our result disagrees with a study done by Fumeron et al. [15] who discovered absence of relationship among serum iron and type 2 diabetes.

Our study demonstrated a positive correlation between ferritin and each of HbA1C (P<0.001), cholesterol (P<0.023), and TGs level (P <0.001) in IGT group. This in agreement with a study done by Sharifi et al. [26] who discovered a positive relationship among ferritin and each of HgA1c, cholesterol, and TG levels in patient with IGT and inferring that hyperferritinemia happens before elevation of plasma glucose over 126 mg/dl. Hepatic iron over-burden disorder, unrelated to genetic hemochromatosis, has been portrayed and is described by hyperferritinemia, normal TSAT, and expanded predominance of glucose intolerance and diabetes [27].

Mendler et al. [28] announced that patients with unexplained hepatic iron over-burden are portrayed by mild to moderate iron load and a positive relationship of insulin resistance regardless of liver harm. The metabolic syndrome is carefully connected to insulin resistance, and numerous investigations demonstrate a connection to hepatic iron overburden. Increased serum ferritin, reflecting hepatic iron over-burden is regularly connected with insulin resistance [29]. Bozzini et al. [30] announced expanded pervasiveness of body iron overabundance in patients with the metabolic syndrome.

In our study, there is a significant positive correlation between serum ferritin and LDL and negative correlation with HDL in patients with type 2 diabetes. This is in agreement with Raghavani and Sirajwala [31], who found higher ferritin in patients with type2 diabetes with positive relationship with LDL and negative connection with HDL, and it may add to cardiovascular ailment in type 2 diabetic patients.

In our study, no correlation was found between serum ferritin and blood sugar, TSAT, or insulin resistance in type 2 diabetic patients. In agreement with our result, Kim et al. [12] did not find a relationship between ferritin and insulin resistance. Jehn et al. [32] also revealed no unfaltering relationship between serum ferritin and insulin opposition in premenopausal women, and see a pattern of increasing insulin resistance with increment serum ferritin in postmenopausal ladies and men. As opposed to this outcome, an investigation done by Haap et al. [6] found that ferritin was related with 2-h glucose level and contrarily with insulin sensitivity in people without type 2 diabetes. Sultan et al. [33] found a statistically positive relationship in diabetic patients between serum ferritin and insulin resistance. Additionally, ongoing investigation demonstrated that ferritin was linked with hepatic, muscular, and adipocyte insulin resistance [34].

There was a significant correlation between males and females in the newly diagnosed T2DM regarding ferritin, which was significantly positively correlated in males than in females. In contrast to our result, Podmore et al. [14] found that the relationship of iron bio-markers incorporating ferritin with type 2 diabetes were more grounded in women than in men. This likely uncovers physiological changes in iron metabolism and absorption among people, causing the overall danger of supreme biomarker contrasts to be more prominent in women.

Ultimately ferritin can be viewed as a better positive indicator of insulin resistance, and this concurs with an examination done by Kim et al. [35] who found that increased serum ferritin levels were related with an increased risk of insulin resistance in postmenopausal women. Jung et al. [36] uncovered that higher degree of serum ferritin as a pattern was related with episode type 2 diabetes in an Asian population. Likewise, Podmore et al. [14] uncovered a direct relation among ferritin and the danger of type 2 diabetes.

Iron is a transitional metal that can be effectively turned out to be oxidized, and in this manner, goes about as an oxidant. The general effect of synergist iron is to change over ineffectively responsive free radicals, for example, hydrogen peroxide, into exceptionally receptive radicals, for example, the hydroxyl radical. Increased accumulation of iron influences insulin release in the pancreas [37] and interferes with the insulin extrication limit of the liver [38], and iron overload in the muscles diminishes glucose take-up in view of muscle damage [39]. In contrast, insulin animates cell iron take-up through increased transferrin receptor externalization [40]. Iron accumulation in the liver may likewise cause insulin resistance by meddling with the capacity of insulin to stifle hepatic glucose generation [12]. The causes and outcomes of the insulin resistance-hepatic iron overload are obscure. Treatment of insulin resistance-hepatic iron overload is centered around metabolic disorder, and phlebotomies are flawed on the grounds that the over-burden is unobtrusive and intestinal retention of iron has all the earmarks of being low [41]. Overall, 50% of transfusion-treated patients with thalassemia have an unusual glucose resistance [42], and up to 65% of inherited hemochromatosis patients are affected by DM [43], and the connection between high iron intake exceedingly body stores outside the setting of hereditary iron over-burden and type 2 diabetes is notable [44]. Loma Lind University’s Adventist Health Study was the first to report the relationship between meat intake and type 2 diabetes hazard [45]. Many investigations have affirmed that this connection is identified with the high heme substance of meat and expanded dietary heme consumption [46]. High body iron stores have been related to insulin resistance [47] and metabolic disorder [31]. Treatment with an iron-chelating operator prompted an expansion in the control of diabetes in a gathering of patients with ineffectively controlled T2DM [48]. Increased iron stores anticipated the advancement of diabetes in epidemiological investigations [44]. It is fascinating that a lower event of diabetes was noted among successive blood givers [49]. Reactive oxygen species influence insulin signaling at different levels, declining insulin take-up through an immediate effect on insulin receptor work [50] and hindering the translocation of GLUT4 in the plasma membrane [51].


  Conclusion Top


The example of relationship of these markers of iron metabolism and type 2 diabetes proposes an increasingly perplexing affiliation and being a hazard factor for type 2 diabetes. It stays to be enlightened whether the relationship of higher ferritin and transferrin with type 2 diabetes is because of the role of iron in the pathogenesis of type 2 diabetes or whether it mirrors the basic progression of insulin resistance. The hereditary qualities of iron metabolism in general and explicitly of various issue of iron metabolism dependent on their mechanism might be important in tending to these inquiries.

Acknowledgements

All authors acknowledge their gratitude to the staff members of inpatient and clinics of Internal Medicine Department for their help and support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Zafon C, Lecube A, Simo R. Iron in obesity. An ancient micronutrient for a modern disease. Obes Rev 2010; 11:322–328.  Back to cited text no. 1
    
2.
Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. Gastroenterology 2010; 139:393–408. 408.e1–e2.  Back to cited text no. 2
    
3.
Noetzli LJ, Mittelman SD, Watanabe RM, Coates TD, Wood JC. Pancreatic iron and glucose dysregulation in thalassemia major. Am J Hematol 2012; 87:155–160.  Back to cited text no. 3
    
4.
Kunutsor SK, Apekey TA, Walley J et al. Ferritin levels and risk of type 2 diabetes mellitus: an updated systematic review and meta-analysis of prospective evidence. Diabetes Metab Res Rev 2013; 29:308–318.  Back to cited text no. 4
    
5.
Orban E, Schwab S, Thorand B et al. Association of iron indices and type 2 diabetes: a meta-analysis of observational studies. Diabetes Metab Res Rev 2014; 30:372–394.  Back to cited text no. 5
    
6.
Haap M, Fritsche A, Mensing HJ et al. Association of high serum ferritin concentration with glucose intolerance and insulin resistance in healthy people. Ann Intern Med 2003; 139:869–871.  Back to cited text no. 6
    
7.
Lontchi-Yimagou E, Sobngwi E, Matsha TE, Kengne AP. Diabetes mellitus and inflammation. Curr Diab Rep 2013; 13:435–444.  Back to cited text no. 7
    
8.
Worwood M. The laboratory assessment of iron status − an update. Clin Chim Acta 1997; 259:3–23.  Back to cited text no. 8
    
9.
Fleming RE, Ponka P. Iron overload in human disease. N Engl J Med 2012; 366:348–359.  Back to cited text no. 9
    
10.
Brissot P, Ropert M, Le Lan C, Loréal O. Non-transferrin bound iron: a key role in iron overload and iron toxicity. Biochim Biophys Acta 2012; 1820:403–410.  Back to cited text no. 10
    
11.
Matthews DR, Hosker JP, Rudenski AS et al. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28:412–419.  Back to cited text no. 11
    
12.
Kim NH, Oh JH, Choi KM et al. Serum ferritin in healthy subjects and type 2 diabetic patients. Yonsei Med J 2000; 41:387–392.  Back to cited text no. 12
    
13.
Hu FB, Manson JE, Stampfer MJ et al. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. New Engl J Med 2001; 345:790–797.  Back to cited text no. 13
    
14.
Podmore C, Meidtner K, Schulze MB et al. Association of multiple biomarkers of iron metabolism and type 2 diabetes: the EPIC-InterAct study. Diabetes Care 2016; 39:572–581.  Back to cited text no. 14
    
15.
Fumeron F, Péan F, Driss F et al. Ferritin and transferrin are both predictive of the onset of hyperglycemia in men and women over 3 years. Diabetes Care 2006; 29:2090–2094.  Back to cited text no. 15
    
16.
Dinneen SF, Silverberg JD, Batts KP et al. Liver iron stores in patients with non-insulin-dependent diabetes mellitus. Mayo Clin Proc 1994; 69:13–15.  Back to cited text no. 16
    
17.
Misra G, Bhatter SK, Kumar A et al. Iron profile and glycaemic control in patients with type 2 diabetes mellitus. Med Sci 2016; 4:22.  Back to cited text no. 17
    
18.
Mainous IIIAG, King DE, Pearson WS et al. Is an elevated serum transferrin saturation associated with the development of diabetes? (Original Research). J Fam Pract 2002; 51:933–937.  Back to cited text no. 18
    
19.
Ellervik C, Mandrup-Poulsen T, Andersen HU et al. Elevated transferrin saturation and risk of diabetes three population-based studies. Diabetes Care 2011; 34:2256-2258.  Back to cited text no. 19
    
20.
Huth C, Beuerle S, Zierer A et al. Biomarkers of iron metabolism are independently associated with impaired glucose metabolism and type 2 diabetes: the KORA F4 study. Eur J Endocrinol 2015; 173:643–653.  Back to cited text no. 20
    
21.
Cheung CL, Cheung TT, Lam KS, Cheung BM, Kuwahara K, Matsushita Y et al. High ferritin and low transferrin saturation are associated with pre-diabetes among a national representative sample of US adults. Clin Nutr 2013; 32:1055–1060.  Back to cited text no. 21
    
22.
Szőke D, Panteghini M. Diagnostic value of transferrin. Clin Chim Acta 2012; 413:1184–1189.  Back to cited text no. 22
    
23.
Lee DH, Liu DY, Jacobs DR, Shin HR, Song K, Lee IK et al. Common presence of non–transferrin-bound iron among patients with type 2 diabetes. Diabetes Care 2006; 29:1090–1095.  Back to cited text no. 23
    
24.
Rajpathak SN, Crandall JP, Wylie-Rosett J et al. The role of iron in type 2 diabetes in humans. Biochim Biophy Acta 2009; 1790:671–681.  Back to cited text no. 24
    
25.
Fernandez-Real JM, Penarroja G, Castro A, García-Bragado F, Hernández-Aguado I, Ricart W. Bloodletting in high-ferritin type 2 diabetes: effects on vascular reactivity. Diabetes Care 2002; 25:2249–2255.  Back to cited text no. 25
    
26.
Sharifi F, Nasab NM, Zadeh HJ. Elevated serum ferritin concentrations in prediabetic subjects. Diabetes Vasc Dis Res 2008; 5:15–18.  Back to cited text no. 26
    
27.
Dandona P, Hussain MAM, Varghese Z, Politis D, Flynn DM, Hoffbrand AV. Insulin resistance and iron overload. Ann Clin Biochem 1983; 20:77–79.  Back to cited text no. 27
    
28.
Mendler MH, Turlin B, Moirand R et al. Insulin resistance–associated hepatic iron overload. Gastroenterology 1999; 117:1155–1163.  Back to cited text no. 28
    
29.
Wrede CE, Buettner R, Bollheimer LC et al. Association between serum ferritin and the insulin resistance syndrome in a representative population. Eur J Endocrinol 2006; 154:333–340.  Back to cited text no. 29
    
30.
Bozzini C, Girelli D, Olivieri O, Martinelli N, Bassi A, De Matteis G et al. Prevalence of body iron excess in the metabolic syndrome. Diabetes Care 2005; 28:2061–2063.  Back to cited text no. 30
    
31.
Raghavani PH, Sirajwala HB. Serum ferritin level in patients with type-2 diabetes mellitus. Int J Biomed Adv Res 2014; 5: 272–274.  Back to cited text no. 31
    
32.
Jehn M, Clark JM, Guallar E. Serum ferritin and risk of the metabolic syndrome in US adults. Diabetes Care 2004; 27:2422–2428.  Back to cited text no. 32
    
33.
Sultan S, AL-Meligi AM, Altaweel N. Ferritin and insulin resistance in patients with type 2 diabetes mellitus. Med J Cairo Univ 2009; 77:201-206.  Back to cited text no. 33
    
34.
Wlazlo N, van Greevenbroek MM, Ferreira I et al. Iron metabolism is prospectively associated with insulin resistance and glucose intolerance over a 7-year follow-up period: the CODAM study. Acta Diabetol 2015; 52:337–348.  Back to cited text no. 34
    
35.
Kim MK, Chon SJ, Jung YS et al. The relationship between serum ferritin levels and insulin resistance in pre-and postmenopausal korean women: KNHANES 2007–2010. PloS One 2016; 11:e0157934.  Back to cited text no. 35
    
36.
Jung CH, Lee MJ, Hwang JY et al. Elevated serum ferritin level is associated with the incident type 2 diabetes in healthy Korean men: a 4 year longitudinal study. PloS One 2013; 8:e75250.  Back to cited text no. 36
    
37.
Rahier J, Loozen S, Goebbels RM et al. The haemochromatotic human pancreas: a quantitative immuno-histochemical and ultrastructural study. Diabetologia 1987; 30:5–12.  Back to cited text no. 37
    
38.
Niederau C, Berger M, Stremmel W et al. Hyperinsulinaemia in non-cirrhotic haemochromatosis: impaired hepatic insulin degradation?. Diabetologia 1984; 26:441–444.  Back to cited text no. 38
    
39.
Merkel PA, Simonson DC, Amiel SA, Plewe G, Sherwin RS, Pearson HA, Tamborlane WV. Insulin resistance and hyperinsulinemia in patients with thalassemia major treated by hypertransfusion. New Engl J Med 1988; 318:809–814.  Back to cited text no. 39
    
40.
Davis RJ, Corvera S, Czech MP. Insulin stimulates cellular iron uptake and causes the redistribution of intracellular transferrin receptors to the plasma membrane. J Biol Chem 1986; 261:8708–8711.  Back to cited text no. 40
    
41.
Ruivard M. Genetic iron overloads and hepatic insulin-resistance iron overload syndrome: an update. Rev Med Interne 2009; 30:35–42.  Back to cited text no. 41
    
42.
Saudek CD, Hemm RM, Peterson CM. Abnormal glucose tolerance in β-thalassemia major. Metabolism 1977; 26:43–52.  Back to cited text no. 42
    
43.
Adams PC, Kertesz AE, Valberg LS. Clinical presentation of hemochromatosis: a changing scene. Am J Med 1991; 90:445–449.  Back to cited text no. 43
    
44.
Ford ES, Cogswell ME. Diabetes and serum ferritin concentration among US adults. Diabetes Care 1999; 22:1978–1983.  Back to cited text no. 44
    
45.
Snowdon DA, Phillips RL. Does a vegetarian diet reduce the occurrence of diabetes?. Am J Public Health 1985; 75:507–512.  Back to cited text no. 45
    
46.
Rajpathak S, Ma J, Manson J, Willett WC, Hu FB. Iron intake and the risk of type 2 diabetes in women. Diabetes Care 2006; 29:1370–1376.  Back to cited text no. 46
    
47.
Sheu WHH, Chen YT, Lee WJ, Wang CW, Lin LY. A relationship between serum ferritin and the insulin resistance syndrome is present in non‐diabetic women but not in non‐diabetic men. Clin Endocrinol 2003; 58:380–385.  Back to cited text no. 47
    
48.
Cutler P. Deferoxamine therapy in high-ferritin diabetes. Diabetes 1989; 38:1207–1210.  Back to cited text no. 48
    
49.
Facchini FS, Hua NW, Stoohs RA. Effect of iron depletion in carbohydrate-intolerant patients with clinical evidence of nonalcoholic fatty liver disease. Gastroenterology 2002; 122:931–939.  Back to cited text no. 49
    
50.
Qian M, Liu M, Eaton JW. Transition metals bind to glycated proteins forming redox active ‘glycochelates’: implications for the pathogenesis of certain diabetic complications. Biochem Biophys Res Commun 1998; 250:385–389.  Back to cited text no. 50
    
51.
Bertelsen M, Änggård EE, Carrier MJ. Oxidative stress impairs insulin internalization in endothelial cells in xsvitro. Diabetologia 2001; 44:605–613.  Back to cited text no. 51
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Patients and methods
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed301    
    Printed4    
    Emailed0    
    PDF Downloaded24    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]