Insulin Resistance: Iron, GGT & Oxidative Stress
As on other Science Library pages, we do not present a lengthy narrative on each affected body system or disease, but rather will briefly summarize or quote the most relevant take-home points and/or research conclusions from each study. Article titles are linked to abstracts archived at the U.S. National Library of Science. Our Iron Science Library pages include:
The full text of this 2007 article provides a good comprehensive review of the role of iron in diabetes. The authors introduce their discussion as follows: “In this review, we discuss the role tissue iron and elevated body iron stores play in causing type 2 diabetes and the pathogenesis of its important complications, particularly diabetic nephropathy and cardiovascular disease (CVD). In addition, we emphasize that iron overload is not a prerequisite for iron to mediate either diabetes or its complications. Important in its pathophysiology is the availability of so-called catalytic iron or iron that is available to participate in free radical reactions.”[Health-e-Iron note; Figure 1 from this review appears below]
Figure 1—Pathogenic pathways for iron in induction of diabetes.
This 2007 full text comment on the above review adds important perspective to this discussion. This research group studied 2,499 individuals and confirmed that across a range from low through moderate and elevated ferritin (15 – 400 ng/mL). They reported that both Impaired Fasting Glucose (IFG) and diabetes occurred significantly more often when GGT was elevated (particularly above 36 I/U)[Health-e-iron note; the authors’ findings were described as follows in this excerpt from their full text:]
“Although the prevalence rates of ferritin quartiles increased steadily across IFG/diabetes categories (ranging from 17 to 27% for IFG and from 4 to 8% for diabetes; P<0.0001), these prevalences remarkably varied by GGT quartiles. As GGT increased, the prevalence rates of ferritin quartiles across IFG/diabetes categories strengthened (P<0.001 for interaction). For example, within the lowest GGT quartile, ferritin quartiles were not associated with IFG (ranging from 12.7 to 14.5%) or diabetes (from 1.2 to 1.5%), in contrast to the highest GGT quartile, wherein the prevalence rates ranged from 19.2 to 28.3% for IFG and from 9.4 to 13.5% for diabetes (P<0.01). These results remained significant even after adjustment for sex, age, lipids, and hs-CRP.”
In this study reported from China in 2010 the researchers st out “to investigate the relationship of gamma-glutamyl transferase to ferritin, and their interaction on the risk of type 2 diabetes.” “A total of 436 men and 588 women were recruited. According to levels of GGT and ferritin, they were divided into three groups in each gender of each geological location (Urban or Rural), that is, Group 1 (both GGT and ferritin < median values), Group 2 (only GGT or ferritin ≥ median values), and group 3 (both GGT and ferritin ≥ median values). Odds ratios for T2D in group 2-3 compared with group 1 were analyzed by multiple logistic regressions. The results showed “(1) The prevalence of glucose abnormalities increased across the three groups of female subjects. Correspondingly,MDA levels (a lipid peroxidation product) were also higher in group 3 than other groups. (2) GGT and ferritin were correlated with each other after controlling for BMI. (3) T2D risk was higher in group 3 than that in group 1 in female subjects, which was independent of age, BMI, and T2D family history. The researchers concluded, “GGT and ferritin were correlated with each other, and had synergistic effect on the risk of T2D in women. The mechanism might be involved in enhanced oxidative stress.” [Health-e-Iron note: as in the research reported in the previous article, for women having both ferritin and GGT above median values, and after adjustment for commonly known diabetes risk factors, the risk of diabetes was greater than among women having only ferritin or GGT above the median, and significantly greater than those with neither ferritin nor GGT above the median. Most of the research on the remainder of this page and in our other Science Library pages is focused on the independent predictive value of either ferritin or GGT in relation to diabetes, heart disease and other diseases of aging. As in the case of this study and the one preceding it, the predictive value and oxidative stress is increased when both ferritin and GGT are in the upper-normals level of gender and age-matched populations.]
Oxidative Stress in Diabetes Mellitus (no abstract) (4)
[Health-e-iron note: we’ve included this 2008 manuscript from Egypt that describes oxidative stress markers found in the study of 95 subjects who were healthy (n=20), had type 1 (n=30) or type 2 (n=45) diabetes.]
“The increased level of glycosylated hemoglobin was observed in the diabetic patients and this increase is directly proportional to the blood glucose level. This suggests the increase in oxidative stress due to hyperglycemia.” “Reduced glutathione normally plays the role of an intracellular radical scavenger…” “A marked decreased level of reduced glutathione is reported in the plasma of diabetic patients.” The author concluded, “Diabetic patients undergo an important oxidative stress when compared to control. Oxidative stress is comparatively low in NIDDM (non-insulin dependent diabetes mellitus) when compared to IDDM suggesting metabolic differences between the two types of diabetes. Methemoglobin is an important measure of oxidative stress in diabetic patients. The biophysical parameters such as electrical conductivity, hemoglobin derivatives and auto-oxidation rate of hemoglobin molecule explain the oxidative stress on the molecular level.” [Health-e-Iron note: Figure 1from this paper appears below]
In 2006, these researchers reported a study of 490 Greek individuals with metabolic syndrome. They determined that, “Patients with the metabolic syndrome exhibit an increase in body iron stores as well as elevated concentrations of liver enzymes compared to the individuals who do not fulfill the criteria for the diagnosis of this syndrome.” The researchers also noted that “…ferritin concentration was the most important determinant of gamma-glutamyltranspeptidase (GGT)levels.” And concluded, “Our data support a direct role of increased body iron in the pathogenesis of insulin resistance, whereas iron overload may also contribute to the development of specific features of the metabolic syndrome, such as fatty liver.” [Health-e-Iron note: Tables 2 and 6 from this study appear below. These table demonstrate the correlation of ferritin and GGT and various other biochemical and metabolic parameters]
Ferritin and Transferrin Are Associated With Metabolic Syndrome Abnormalities and Their Change Over Time in a General Population: Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) (6)
In this 2007 study of a group of 944 individuals in France, and over a period of six years, both ferritin and transferrin levels were significantly associated to the development of metabolic syndrome. The researchers noted, “This is the first prospective study associating ferritin and transferrin with the metabolic syndrome and its components. “Higher values of hepatic markers, ALT and GGT, were significantly correlated with both ferritin and transferrin (exceptions were transferrin with ALT in premenopausal women and with GGT in postmenopausal women).” “The odds of an incident IDF-defined metabolic syndrome after 6 years was more than fourfold higher when ferritin and transferrin values were both above the group-specific top tertile, in comparison with participants with both parameters below these thresholds. When both markers of the iron metabolism are elevated, the incidence of the metabolic syndrome is increased in men and both pre-and postmenopausal women.” [Health-e-Iron note: Table 1 & Figure 1 from this study appear below]
Health-e-Iron note: 2 other studies on our GGT-Diabetes page (#8 & #24)cover the role of GGT in diabetes and metabolic syndrome
Figure 1—Age-adjusted ORs (95% CI) for the 6-year incidence of the IDF-defined metabolic syndrome according to high ferritin and transferrin levels (both above the upper tertiles) (A), lower ferritin and high transferrin levels (B), high ferritin and lower transferrin levels (C), and lower ferritin and lower transferrin levels (D). High and low levels were defined according to the three groups: men, premenopausal women, and postmenopausal women (DESIR).
In 2006, data from the above French study was analyzed to determine the association of ferritin and transferrin to glucose metabolism. The investigators stated aim was “to determine, in a cohort of men and women, whether ferritin and transferrin were associated with glucose metabolism and whether they were predictive of the onset of hyperglycemia (impaired fasting glycemia or type 2 diabetes) after 3 years of follow-up. The researchers concluded, “… both transferrin and ferritin were positively associated with the onset of abnormalities in glucose metabolism in a prospective study. These results further support the hypothesis of a causative role of iron metabolism in the onset of insulin resistance and type 2 diabetes.” [Health-e-Iron note; Figure 1 and Table 4 from this study appears below]
Figure 1—Standardized ORs for the 3-year incidence of hyperglycemia (IFG or type 2 diabetes) according to baseline iron biomarkers and CRP (independent variables) after adjustment for baseline age, BMI, WHR, and glucose and insulin concentrations in the DESIR study. (All independent variables and adjustment variables were included in the same multiple logistic regression equation.)
In this 2011 study of more than 12,000 individuals in Korea, the researchers reported, “In NFG (normal fasting glucose) subjects, the age-adjusted OR (odds ratio) for metabolic syndrome in the fourth quartile of ferritin concentration was 2.85… in men and 1.21… in women. In men, the OR was attenuated to 1.58…after adjustment for BMI, liver enzymes, and hsCRP. Increased serum concentrations of ferritin are associated with insulin resistance, type 2 DM, IFG (impaired fasting glucose), and metabolic syndrome in men, but only with IFG in women.” The researchers concluded,”These results suggest that iron overload is associated with insulin resistance in men, but not in women.”
This study in the U.S. of 6,044 adults (the Third National Health and Nutrition Examination Survey) demonstrated that mean serum ferritin values in premenopausal women, postmenopausal women, and men were 33.6, 93.4, and 139.9 ng/dL, respectively. “Metabolic syndrome was more common in those with the highest compared with the lowest levels of serum ferritin in premenopausal women (14.9 vs. 6.4%, P = 0.002), postmenopausal women (47.5 vs. 28.2%, P < 0.001), and men (27.3 vs. 13.8%, P < 0.001). Insulin resistance also increased across quartiles of serum ferritin for men and postmenopausal women and persisted after adjustment for age, race/ethnicity, C-reactive protein, smoking, alcohol intake, and BMI.” The researchers concluded, “Elevated iron stores were positively associated with the prevalence of the metabolic syndrome and with insulin resistance.” [Health-e-Iron note; Table 1 & Figure 1 from this study appear below]
Figure 1—Mean serum ferritin levels by the number of metabolic syndrome components. Geometric mean values of serum ferritin are shown for premenopausal women (black bar), postmenopausal women (white bar), and men (gray bar). Error bars represent upper 95% CI. The trend of increasing mean ferritin values across categories of metabolic syndrome components was significant for all three groups (P < 0.05).
A 2011 cross-sectional study of 6,311 adults in Korea demonstrated that, “Diabetes mellitus was more prevalent in the highest quartile compared with the lowest quartile of serum ferritin concentrations in premenopausal women and men.” And.they concluded, “…elevated serum ferritin concentrations are associated with an increased risk of metabolic syndrome and diabetes mellitus in a representative sample of the adult South Korean population.”
In another 2011 Korean study of 1,691 premenopausal and 1,391 postmenopausal women, the researchers reported, “After adjustments for age; body mass index; alcohol intake; smoking history; exercise; hormone therapy use; hemoglobin, aspartate aminotransferase, and alanine aminotransferase levels; and intake of energy and iron, multivariate logistic regression analysis revealed that postmenopausal women with ferritin levels in the third tertile (top third) had an increased risk of having metabolic syndrome (odds ratio, 1.62; 95% CI, 1.04-2.81) compared with postmenopausal women with levels in the first quartile. No such association was detected in premenopausal women.” The researchers concluded, “Increased ferritin levels may be a determinant for metabolic syndrome in postmenopausal women but not in premenopausal women.”
In this 2005 Italian study of 269 metabolic syndrome and 210 control subjects, ferritin in metabolic syndrome subjects was significantly higher than in controls. The researchers concluded, “Our results suggest that serum ferritin could be added to routine evaluation of metabolic syndrome patients; this would help identify a subgroup of individuals at risk for iron-related tissue damage… in whom further investigations may be appropriate. As a result, Insulin Resistance – Hepatic Iron Overload (IR-HIO) may be prevented by an inexpensive therapeutic approach such as phlebotomy therapy.” [Health-e-Iron note: Note below in Table 1 from this research that the metabolic syndrome subjects had ferritin of 124.0 ng/mL versus ferritin of 82.7 ng/mL in the controls]
In this 2008 study of a population of 110 women with diabetes from Kuwait, researchers found an association of elevated ferritin with diabetes, but not with metabolic syndrome.
In a 2006 study of 1,070 individuals in Germany, the researchers reported, “…a significant correlation between Serum Ferritin (SF) and the presence of insulin resistance syndrome (IRS) criteria in a large representative population. The researches concluded, “This study shows a significant correlation between SF and the presence of IRS criteria in a large representative population. Interestingly,the severity of the IRS seems to be associated with increased SF levels suggesting a causal connection.” [Health-e-Iron note: Figures 1 & 3 from this study appear below]
Figure 1 Serum ferritin levels in male (white boxes) and female (grey boxes) individuals discriminated according to the presence or absence of defining criteria of the insulin resistance syndrome (A–F). Results are depicted as boxplots. The top and bottom of each box indicate the 25th and the 75th percentiles. The line through the box is the median, and the error bars are the 5th and 95th percentiles. Significance levels were determined by the Mann–Whitney U-test and are indicated in the figure.
In this large population study reported in 2007 and conducted in the U.K., subjects were followed over a period of 5+ years. Cases on incident diabetes were examined. Among 360 new cases of diabetes, serum ferritin measured the study baseline was higher in cases than in controls (in men 96.6 vs. 68.7 ng/mL)(in women 45.9 vs. 34.8 ng/mL), which indicated more than a 7-fold risk of new-onset type 2 diabetes when adjusted for age, sex and BMI only. Extensive adjustments (including GGT)attenuated the odds ration to 3.2.” The researchers concluded, “Serum ferritin is an important and independent predictor of the development of diabetes. This finding may have important implications for understanding the aetiology of diabetes.” [Health-e-Iron note: Table 3 and Figure 1from this study appear below. In this study, as generally observed in the others studies on this web site, GGT correlated very strongly with ferritin]
Fig. 1 Odds ratios and 95% CIs for the association of clinically raised ferritin (group 5) vs ferritin in the normal range (groups 1–4) with incident diabetes in men and women, with adjustment for factors as stated (described in methods). FH, family history; LFT, liver function tests (ALT and GGT)
As in the study described directly above, this was a 2012 reported study from the large EPIC epidemiologic survey undertaken in Europe. “The aim of this study was to prospectively examine the association between body iron stores and risk of type 2 diabetes.” “We designed a case-cohort study among 27,548 individuals within the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. During 7 years of follow-up, 849 incident cases of type 2 diabetes were identified. Of these, 607 remained for analyses after exclusion of participants with missing data or abnormal glucose levels at baseline. A sub-cohort of 2,500 individuals was randomly selected from the full cohort, comprising 1,969 individuals after applying the same exclusion criteria.” “After adjustment for age, sex, BMI, waist circumference, sports activity, bicycling,education, occupational activity, smoking habit, alcohol consumption and circulating levels of γ-glutamyltransferase (GGT), alanine aminotransferase (ALT), fetuin-A, high-sensitivity C-reactive protein, adiponectin, HDL-cholesterol and triacylglycerol, higher serum ferritin concentrations were associated with a higher risk of type 2 diabetes (RR in the highest vs lowest quintile, 1.73; 95% CI 1.15, 2.61; p (trend) = 0.002).” The investigators concluded, “High ferritin levels are associated with higher risk of type 2 diabetes independently of established diabetes risk factors and a range of diabetes biomarkers whereas soluble transferrin receptor concentrations are not related to risk. These results support the hypothesis that higher iron stores below the level of haemochromatosis are associated with risk of type 2 diabetes.” [Health-e-Iron note: in the full text the authors note that “…adjustment for GGT and ALT tended to have the strongest effect in terms of attenuating the risk for the association of ferritin with risk of diabetes…” The strong interaction of GGT and iron stores is reported in a number of other studies on this web site. The relative risk of elevated serum ferritin section of Table #3 from this study appears below]
Model 1 is adjusted for age, sex, BMI, waist circumference, sports activity, bicycling, education, occupational activity, smoking habit and alcohol consumption
Model 2 is adjusted for factors in model 1 and GGT, ALT, fetuin-A, hs-CRP, adiponectin, HDL-cholesterol and triacylglycerol concentrations
This study was reported by the Centers for Disease Control and Prevention in 1999. The investigators, “examined the association between serum ferritin concentration and the risk of diabetes. “We examined the cross-sectional associations among ferritin concentration, glucose tolerance status, and concentrations of insulin, glucose, and glycosylated hemoglobin in 9,486 U.S. adults aged > or = 20 years from the Third National Health and Nutrition Examination Survey (1988-1994).” “After adjusting for age, sex, ethnicity, education, BMI, alcohol consumption, alanine aminotransferase concentration, C-reactive protein concentration, and examination session attended, and after dichotomizing ferritin concentration into < 300 and > or = 300 micrograms/l for men and < 150 and > or = 150 micrograms/l for women, the odds ratios for newly diagnosed diabetes were 4.94 (95% CI 3.05-8.01) for men and 3.61 (2.01-6.48) for women. The increased risk of newly diagnosed diabetes was concentrated among participants with transferrin saturations < 45%. All multiple linear regression coefficients between ferritin concentration and concentrations of insulin, glucose, and glycosylated hemoglobin were positive and significant for both men and women.” The investigators concluded, ” “Elevated serum ferritin concentration was associated with an increased risk of diabetes. We were unable to eliminate conclusively the possibility that the observed association reflected inflammation rather than excess body iron stores.” [Health-e-iron note: This research was published in 1999. In more recent research reported on this page and on our Iron Reduction Therapy page the condition of relatively normal transferrin with elevated ferritin has been shown to be a combination of moderate iron overload accompanied by inflammation. This combination of factors has been described in other conditions including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and insulin resistant hepatic iron overload (IR-HIO). This combination of iron measures often predicts hepatic fibrosis. The condition responds well to iron reduction by phlebotomy and/or dietary modifications including restrictions on iron intake. Table 2 from this paper appears below]
This 2007 reported study of incident type 2 diabetes the researchers recruited participants from four clinical centers in the U.S. “After adjustment for age, gender, menopausal status, ethnicity, center,smoking, and alcohol intake, the hazard ratio for diabetes, comparing the fifth quintile of ferritin with the first quintile, was 1.74 (95% confidence interval: 1.14, 2.65; p-trend < 0.001). After further adjustment for body mass index and components of the metabolic syndrome, the hazard ratio was 0.81 (95% confidence interval: 0.49, 1.34; p-trend = 0.87).” “The researchers concluded, “From a causal perspective, there are two alternative interpretations of these findings. Elevated iron stores, reflected in elevated plasma ferritin levels, may induce baseline metabolic abnormalities that ultimately result in diabetes. Alternatively, elevated ferritin may be just one of several metabolic abnormalities related to the underlying process that ultimately results in diabetes, rather than a causal factor for diabetes.” [Health-e-Iron note: a number of other, more recent studies on this web site support the causal role of elevated iron stores]
This 2009 study was based on “a longitudinal population-based study of approximately 6,600 Danes in a nested case-control design with the primary outcome of 5-year conversion to type 2 diabetes. Nondiabetic subjects, aged >or=39 years, with BMI >or=25 kg/m(2) at baseline were selected.” “A model using six biomarkers (adiponectin, C-reactive protein, ferritin, interleukin-2 receptor A, glucose, and insulin) was developed for assessing an individual’s 5-year risk of developing type 2 diabetes.” The researchers provided the following for selecting ferritin as one of the biomarkers, “The six biomarkers selected for this DRS model are involved in various biological pathways. Ferritin serves as an antioxidant by binding excess iron, and elevated serum ferritin is a well-established risk factor for future type 2 diabetes. The research team concluded, “A model incorporating six circulating biomarkers provides an objective and quantitative estimate of the 5-year risk of developing type 2 diabetes, performs better than single risk indicators and a noninvasive clinical model, and provides better stratification than fasting plasma glucose alone.” [Health-e-Iron note: Figure #3from this article appears below]
Figure 3—Performance of the DRS and FPG in the at-risk Inter99 subpopulation defined by BMI ≥25 kg/m2 and age ≥39 years. The green, yellow, and pink regions correspond to the low-, medium-, and high-risk strata, respectively. The results from the study were adjusted using Bayes’ law to reflect the observed 5-year incidence of 5.7% among the 3,032 at-risk individuals in Inter99 (A). On the left axis, absolute risk is indicated, and relative risk is shown on the right axis. ——, Relationship between risk and DRS prediction; ······ , mean upper and lower 95% CIs on the risk, as estimated from the SEM of the individual risk predictions in the study; Δ, deciles of the adjusted study population. The mean observed fraction that converted is plotted versus mean DRS. Details of the development of this risk curve are presented in online Appendix C. Stratification of the at-risk Inter99 subpopulation by fasting plasma glucose status (B) and by DRS risk stratum (C). NFG, normal fasting glucose (≤100 mg/dl); IFG, impaired fasting glucose (>100 mg/dl).
“This 2004 reported study had a case-control design, and was nested in the Nurses’ Health Study, a prospective investigation initiated in 1976 that was designed to study the etiological characteristics of heart disease, cancer, and other major diseases in 121,700 female registered nurses aged 30 to 55 years at baseline.” “Among women who developed type 2 diabetes ferritin was significantly higher than in controls (109 vs. 71 ng/mL). After adjusting for known risk factors, the relative risk of developing diabetes when compared to the lowest quintile (1/5th) of ferritin was 1.09, 1.26, 1.30, and 2.68. The researchers concluded, “Higher iron stores (reflected by an elevated ferritin concentration and a lower ratio of transferrin receptors to ferritin) are associated with an increased risk of type 2 diabetes in healthy women independent of known diabetes risk factors.”[Health-e-Iron note: Table 2 and Figures 1 and 2 from this study appear below]
In this 2010 study from Iran, serum ferritin was measured in 128 pregnant women (64 women with gestational diabetes and 64 age-matched controls). Women with gestational diabetes had higher serum ferritin than controls (112 vs. 65 ng/mL). “Higher iron stores…are associated with an increased risk of type 2 diabetes in healthy women independent of known diabetes risk factors.” The researchers concluded, “Elevated serum ferritin concentrations in mid-pregnancy are associated with an increased risk of GDM independent of C-reactive protein and body mass index. Ferritin levels in GDM cannot be used as an indicator to predict subsequent glucose concentration in early postpartum oral glucose tolerance test.”
This 2011 study was reported by researchers from Division of Epidemiology, Statistics and Prevention at the National Institutes of Health. “The current study is to determine if prepregnancy dietary and supplemental iron intakes are associated with the risk of diabetes mellitus GDM.” “A prospective study was conducted among 13,475 women who reported a singleton pregnancy between 1991 and 2001 in the Nurses’ Health Study II. A total of 867 incident GDM cases were reported. Pooled logistic regression was used to estimate the relative risk (RR) of GDM by quintiles of iron intake controlling for dietary and nondietary risk factors.” “Dietary heme iron intake was positively and significantly associated with GDM risk. After adjusting for age, BMI, and other risk factors, RRs (95% CIs) across increasing quintiles of heme iron were 1.0 (reference), 1.11 (0.87-1.43), 1.31 (1.03-1.68), 1.51 (1.17-1.93), and 1.58 (1.21-2.08), respectively (P for linear trend 0.0001). The multivariate adjusted RR for GDM associated with every 0.5-mg per day of increase in intake was 1.22 (1.10-1.36). No significant associations were observed between total dietary, nonheme, or supplemental iron intake and GDM risk.” The researchers concluded, “These findings suggest that higher prepregnancy intake of dietary heme iron is associated with an increased GDM risk.”
This 2011 study was similar to the study directly-above. Researchers in Sweden “investigated associations of maternal preconceptional and early pregnancy heme and nonheme iron intake with subsequent GDM risk.” “We conducted a prospective cohort study of 3,158 pregnant women. A food frequency questionnaire was used to assess maternal diet. Multivariable generalized linear regression models were used to derive estimates of relative risks (RRs) and 95% CIs.” “Approximately 5.0% of the cohort developed GDM (n=158). Heme iron intake was positively and significantly associated with GDM risk (Ptrend=0.04). After adjusting for confounders, women reporting the highest heme iron intake levels (≥1.52 vs. <0.48 mg per day) experienced a 3.31-fold-increased GDM risk (95% CI 1.02-10.72). In fully adjusted models, we noted that a 1-mg per day increase in heme iron was associated with a 51% increased GDM risk (RR 1.51 [95% CI 0.99-2.36]). Nonheme iron was inversely, though not statistically significantly, associated with GDM risk…” The researchers concluded, “High levels of dietary heme iron intake during the preconceptional and early pregnancy period may be associated with increased GDM risk. Associations of GDM risk with dietary nonheme iron intake are less clear…”
[Health-e-Iron note: This is a 2011 editorial covering the findings describes in the two preceding papers. The single-page text provides a good and current descriptions of the biochemical processes underlying the role or iron in diabetes. The article notes “critical to iron’s importance in biological processes is its (iron’s) ability to cycle reversibly between its ferrous and ferric oxidation states. This precise property, which is essential for its functions, also makes it very dangerous, because free iron can catalyze the formation of free radicals that can damage the cell. Thus, from a pathophysiological standpoint, it is important to measure iron pools that consist of chemical forms that can participate in redox cycling, often referred to as catalytic or labile iron.”]
Association between Iron Status and Lipid Peroxidation in Obese and Non-Obese Women (no abstract) (25)
In another study from Iran in 2008, serum ferritin measurements in 25 obese menstruating women and 25 non-obese menstruating women matched for age were obtained. Serum ferritin and markers of lipid peroxidation were significantly higher in the obese women. The researchers suggested,”…that obese menstruating women are at low risk of depleting iron stores and hence, increasing body iron elevates the coronary heart disease risk by promoting the lipid peroxidation. Therefore, iron fortification programs might be undesirable for such subjects.” [Health-e-Iron note: Table 3from this study appears below]
This report was published in 2008. The researchers first noted,”cardiorespiratory fitness (CRF) and physical activity (PA) are inversely related to the occurrence of type 2 diabetes (T2D). Both play an important role in reducing serum ferritin (SF) concentration. Increased SF concentration is considered a contributing factor for developing T2D.” The researchers “investigated 5,512 adult participants enrolled in the Aerobics Center Longitudinal Study (ACLS) between 1995 and 2001. The subjects completed a comprehensive medical examination and a SF evaluation, and had been followed up until either diabetes onset, death, or the cut-off date of November 2007.” …”SF concentration was significantly higher in males than in females (148.5 +/- 104.7 ng/ml vs. 52.2 +/- 45.9 ng/ml) and was inversely associated with CRF levels. In the high CRF group, 32.7% of participants had a low SF concentration whereas only 16.8% of participants had a high SF concentration level. After adjusting for potential confounders, male participants in the highest SF quartile level had a 1.7 times (HR: 1.67, 95% CI: 1.05, 2.66; p-trend = 0.027) increased risk for developing T2D compared with those in the lowest SF quartile group. Conclusion: Lower SF concentration was associated with lower risk of developing T2D in those regularly participating in CRF. The researchers concluded, “Based on these results clinicians and public health professionals should promote regular physical activity or fitness to reduce the incidence of T2D…and, physicians should measure SF concentrations so as to assess the individual’s potential for developing T2D.”[Health-e-Iron note: Figure 1 from this study appears below. Also, Health-e-Iron concurs with the recommendation that regular fitness activities will lower serum ferritin, but suggests that in conjunction with a fitness routine, participants should consider blood donation or therapeutic phlebotomy as an effective way to more quickly reduce and maintain optimal ferritin levels. Unfortunately, not many people who commit to a regular fitness routine are able to maintain it for more than a relatively short period of months or years. Long-term success might be more achievable through blood donation or phlebotomy.
Figure 1. Cumulative incidence rate of type 2 diabetes for men. The figure shows the incidence rate of diabetes for male study participants in the four serum ferritin (SF) level quartiles. Higher SF levels were significantly associated with a higher diabetes rate. p = 0.023.
In 2008 these researchers examined the expression of iron transport molecules in NAFLD patients with or without iron overload, in hemochromatosis patients and in controls. They concluded that, “Iron accumulation in NAFLD may result from an impaired iron export due to down-regulation of ferroportin and ineffective hepatic iron sensing, as indicated by low hemojuvelin expression.”[Health-e-Iron note: Table 1 from this paper appears below. Note that the subjects with hereditary hemochromatosis (HH) have significantly higher ferritin and transferrin saturation levels than the subjects with NAFLD and high iron. HH patients are not protected from high levels of iron, yet they generally do not load macrophage iron and tend to have significantly lower levels of triglycerides and LDL cholesterol. This is believed to be a reason why many HH patients do not express disease symptoms while individuals with much lower iron levels incur symptoms and diseases]
This 2003 review further differentiates iron loading in NAFLD patients from that observed in hemochromatosis patients, and discusses findings that patients with chronic hepatitis and the C282Y hemochromatosis genotype “are more likely to suffer from advanced hepatic fibrosis or cirrhosis and to do so at younger ages.” and, “A role for modest iron overload in increasing severity of alcohol-induced liver disease has been well established from results of experimental studies. However, it is currently unresolved whether mild-to-moderate hepatic iron deposition or heterozygosity for the C282Y mutation plays a role in human alcoholic liver disease or in nonalcoholic fatty liver disease or nonalcoholic steatohepatitis.” However (again as of 2003), “There is persuasive evidence that iron reduction decreases insulin resistance, and it likely also decreases oxidative stress, two key pathogenic features of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.” [Health-e-Iron note: substantial additional evidence of the benefits of iron reduction exists today and are discussed on our Iron Reduction Therapy page and elsewhere on this web site.]
This is an early study (2000) that explores insulin resistance in NASH and the role of iron. At that time it was noted that, “Excess hepatic iron may occur in insulin resistance-associated iron overload (IRHIO), characterized by hyperferritinemia with normal to mild increases in transferrin saturation. Although patients with IRHIO have a high prevalence of Insulin Resistance-related metabolic disorders, the relationship of IRHIO to NASH is unclear.”[Health-e-Iron note: Over the last decade the clarity of this relationship has improved significantly]
In this 2011 investigation reported in the U.K., the researchers noted, “No specific laboratory/imaging technique exists either to diagnose NASH or to select patients for liver biopsy.” “We evaluated serum ferritin and the features of metabolic syndrome with respect to histological inflammation and/or fibrosis in NAFLD patients. One hundred and eleven patients: median age 52.6, 64 males, obesity 62, diabetes mellitus (DM) 58, arterial hypertension 26 and hyperlipidaemia 40%.” The investigation reported, “40.7% had fatty liver, 30.6% had borderline NASH, 28.7% had NASH and 11% had cirrhosis. Multivariate regression showed that diabetes, serum ferritin concentrations, body mass index (BMI) and AST were independently associated with NASH.” The researchers concluded, “Serum ferritin concentrations and BMI are strongly associated with fibrosis, portal and lobular inflammation in NAFLD patients. Both ferritin and BMI are potential discriminant markers to select patients for liver biopsy and are associated with inflammation and fibrosis.” [Health-e-Iron note: Table 5 from this paper appears below. Not below that subjects more advanced fibrosis or cirrhosis had significantly higher ferritin (377 ng/mL) versus subjects with mild or no fibrosis (117 ng/mL).]
This 2009 research was reported in a study of 38 NASH patients, compared to 24 with simple steatosis (fatty liver) and 10 health subjects. The researchers found that, “…hepatic oxidatively generated damage to DNA tightly correlate each other in NASH patients, suggesting that these three factors may play an important role in the pathogenesis of NASH.” The researchers concluded, “Simple and inexpensive therapies, such as phlebotomy and iron–restricted diet, may be emerging as effective treatment options, which may lead to reduction of hepatocellular carcinoma incidence in NASH patients.”
In this 2009 study, the researchers measured and compared markers of hepatic oxidative stress in 38 patients with non-alcoholic steatohepatitis (NASH), 24 simple steatosis (NAFLD or fatty liver disease) and 10 healthy subjects.Oxidative stress was significantly higher in NASH patients than in those with NAFLD, and was related to iron overload, glucose-insulin metabolic abnormalities, and severity of disease. Iron reduction using phlebotomy significantly reduced oxidative stress in NASH patients and resulted in concomitant reduction in liver serum transferase. The authors concluded, “…iron overload may play an important role in the pathogenesis of NASH by generating oxidative DNA damage and iron reduction therapy may reduce hepatocellular carcinoma incidence in patients with NASH ” [Health-e-Iron note; this study also appears in the IRON-cancer Library Figures 2 and 3 from this study appear below]
This 1999 study done in France characterized insulin resistance associated with hepatic iron overload. The researchers noted a significant greater number people with a hemochromatosis genotype were affected, and concluded, “…patients with unexplained hepatic iron overload are characterized by a mild to moderate iron burden and the nearly constant association of an insulin resistance syndrome irrespective of liver damage.”
in 2009 this group of researchers from Japan reviewed the role of hepatic iron in NASH and suggested,”Iron reduction therapy such as phlebotomy or dietary iron restriction may be promising in patients with NASH/NAFLD to reduce insulin resistance as well as serum transaminase activities.” [Health-e-Iron note: Figure 1 from this review appears below]
Figure 1 Possible mechanisms of hepatic iron deposition and pathogenetic roles of iron in nonalcoholic steatohepatitis/nonalcoholic fatty liver disease. AAT, alpha 1-antitrypsin; FP-1, ferroporitn-1; H. pylori, Helicobacter pylori; RBC, red blood cell; ROS, reactive oxygen species; TfR, transferrin receptor; TNF-α, tumor necrosis factor-α.
In this 2008-reported, large population based survey conducted in Beijing and Shanghai, 3,289 participants aged 50-70 years were examined for fasting plasma ferritin, glucose, insulin, lipid profile, glycohemoglobin, inflammatory markers, adipokines; and dietary profile were collected. “Median ferritin concentrations were 155.7 ng/mL for men and 111.9 ng/mL for women.” By comparing the highest versus the lowest quartile of serum ferritin, the researchers determined that the odds ratios were substantially higher for both type 2 diabetes (3.26) and metabolic syndrome (2.80) in the highest quartile of ferritin compared to the lowest. “These associations remained significant after further adjustment for dietary factors, body mass index, inflammatory markers, and adipokines.” [Health-e-Iron note: Figures 1and 2 from this review appear below]
FIG. 1. OR and 95% confidence interval (CI) for metabolic syndrome (A), type 2 diabetes (B), and IFG (C) according to joint classification of ferritin and CRP concentrations. Adjusted for age, sex, region, residence, BMI, smoking, drinking, physical activity, education levels, dietary factors, and family histories of chronic diseases (A) or family histories of diabetes (B and C). P for interaction = 0.54, 0.54, and 0.36 for metabolic syndrome (MetS), type 2 diabetes, and IFG, respectively. White circles, OR for first quartile of CRP; black circles, OR for second quartile of CRP; white squares, OR for third quartile of CRP; black squares, OR for fourth quartile of CRP; black bars, 95% CI; broken line, odds ratio = 1.
FIG. 2. OR and 95% confidence interval (CI) for type 2 diabetes according to joint classification of metabolic syndrome (MetS) and ferritin concentrations. The ORs were adjusted for age, sex, region, residence, BMI, smoking, drinking, physical activity, education levels, dietary factors, and family histories of diabetes. P for interaction = 0.40. White circles, OR for subjects without MetS; black circles, OR for subjects with MetS; black bars, 95% CI; broken line, odds ratio = 1.
This 1997 research was first to characterize this syndrome of unexplained hepatic iron overload and normal transferrin saturation. Sixty-five patients with high ferritin concentrations, similar to hemochromatosis, but normal transferrin saturation, unlike hemochromatosis. “Most of the patients (95%) had one or more of the following conditions; obesity, hyperlipidaemia, abnormal glucose metabolism, or hypertension.”
This is a 2011 review out of Japan that describes the dysregulation of iron metabolism in NASH patients and suggests that, “Iron reduction therapy such as phlebotomy or iron-restricted diet may be promising in patients with NAFLD/NASH to reduce hepatic injury as well as insulin resistance.”
In a 2011 study of 65 NASH patients in Turkey the investigators measured iron metabolism markets and inflammatory cytokines. The study suggested, “…that liver iron and fat accumulation, oxidant stress, and inflammatory cytokines are closely related. Therefore, levels of serum ferritin, MDA, IL-6, TNF-α and IL-8 could represent the indices of activity and progression of NASH.”
This 2012 study was aimed to examine the relationship between serum ferritin and NAFLD. In patients with iron overload of more than 50% above the upper-normal threshold, greater liver damage was noted (including advanced hepatic fibrosis),and a diagnosis of NASH. The research team stated that ferritin levels elevated to this degree are “an independent predictor of advanced hepatic fibrosis among patients with NAFLD.” The researchers concluded, “(Serum ferritin 50% or more above the upper normal laboratory range) is associated with hepatic iron deposition, a diagnosis of NASH, and worsened histologic activity and is an independent predictor of advanced hepatic fibrosis among patients with NAFLD. Furthermore, elevated SF is independently associated with higher NAS (a fibrosis scoring system), even among patients without hepatic iron deposition. We conclude that SF is useful to identify NAFLD patients at risk for NASH and advanced fibrosis.” [Health-e-Iron note: Table 4 from this study appears below]
In a paper published in 1999, this research team in France examined 161 non-C282Y homozygous patients (i.e. without “classical” hereditary hemochromatosis) with unexplained hepatic iron overload.Gene frequencies for both major HFE gene variants were increased approximately two-fold. The cohort included a high prevalence of (HFE) compound heteroyzgotes who had slightly greater iron burden. The research team concluded, “This study shows that patients with unexplained hepatic iron overload are characterized by a mild to moderate iron burden and the nearly constant association of an IRS irrespective of liver damage.”
This 2010 paper presents a possible molecular explanation for the accumulation of iron in NASH patients. They attribute the process to enhanced expression of transferrin receptors and hyperdynamic state of retinoid (vitamin A) metabolism.
This 2005 review describes the interaction of alcohol with increased iron absorption in alcoholic liver disease patients.
This review discusses several other factors that are likely contributors to the accumulation of iron in alcohol liver disease.
This animal (rat) study provides more insight into alcoholic liver disease and the mechanism of iron accumulation in hepaocytes.
This 2008 Italian investigation examined the high ferritin values (300 ng/mL+) in non-obese patients. Overall, 74.2% had steatosis (fatty liver), and 45.9% had cyptogenic liver damage. The researchers concluded, “In a non-obese cohort of non-alcoholic patients with chronically abnormal LFTs (liver function tests) without HH, (without hereditary hemochromatosis) high serum ferritin level is a risk factor for steatosis.” [Health-e-iron note: Table 2 from this study appears below. Note that the correlation of high GGT with high ferritin is demonstrated below as it it throughout many sections of this web site:]
In this 2008 study 40 patients were evaluated to assess the relationship between hyperferritinemia and the metabolic syndrome. Sixteen patients were phlebotomized to lower their ferritin to under 100 ng/mL. “Fourteen of 16 patients normalized ferritin levels after phlebotomy of a cumulative blood amount corresponding to normal iron stores. Ferritin levels were significantly related to insulin C-peptide level (p,0.002) and age (p,0.002).” The researchers concluded, “The present results suggest that liver steatosis and insulin resistance but not increased iron load is frequently seen in patients referred for suspected hemochromatosis on the basis of hyperferritinemia. The ferritin level seems to be positively associated to insulin resistance.” [Health-e-iron note: Figure 2 from this study appears below]
Figure 2. Relation between logferritin and age.
Similar findings from this 2010 Japanese study showed, “…serum ferritin concentration was significantly higher in the NASH patients than in the patients with simple steatosis (P = 0.006).” And …”In conclusion high serum ferritin concentrations are a distinguishing feature of Japanese NASH patients.”
This 2009 study discusses the role of iron trafficking and fatty acid genes in NAFLD. Interestingly, fatty acid gene expression decreased while iron metabolism gene activity increased as NAFLD disease expression increased. The authors concluded, “Steatosis-related metabolism is attenuated as NAFLD progresses, whereas iron-related metabolism is exacerbated. Appropriate therapies should be considered on the basis of metabolic changes.”
This 2007 study in Japan tested a energy, fat and iron reduced diet in 27 patients with either NAFLD or NASH. “The aim of the present study was to evaluate the grade of hepatic iron accumulation and the therapeutic response to restriction of calories, fat and iron in patients with non-alcoholic fatty liver disease (NAFLD).” After six months of following this diet, the levels of serum transaminase and ferritin were significantly decreased. The investigators concluded, “Dietary restriction of calories, fat and iron improved NAFLD. Reduced serum ferritin levels appear to reduce oxidative stress in the liver.”
In another study in Japan reported in 2004, 22 patients with long-term hepatitis C virus infection that did not respond to (or will unwilling to take) interferon therapy were enrolled in a program featuring diet restriction or fat, calories and iron. After 24 months mean levels of serum alanine aminotransferase decreased significantly from 66 to 49 IU/L. The research team concluded, “These results suggest that restriction of energy, fat, iron, and protein intakes is safely tolerated, so its long-term use should be recommended to patients with long-term infection with hepatitis C virus.”
This 2005 study explored and evaluated oxidative stress levels in NAFLD patients. Oxidative stress, as measured by the expression of heme oxygenase-1 (HO-1), in subjects was observed to correlate with levels of ferritin and lipid peroxidation. Increases in HO-1 reflected the severity of the disease. Also, NASH patients with higher HO-1 expression had lower levels of glutathione. [the inverse relationship of glutathione and GGT is discussed in our GGT Library]. The researchers concluded, “The induction of HO-1 is an adaptive response against oxidative damage elicited by lipid peroxidation and it may be critical in the progression of the disease.”
This 2002 Romanian study evaluated the clinical and biochemical measures that led to the development of fibrosis in NASH. An analysis of 40 NASH patients with fibrosis or cirrhosis was undertaken. Among several biomarkers of fibrosis in NASH patients, the greatest association was found in increased hepatic iron with an increase in lipid peroxidation and a decrease in serum glutathione. [Health-e-Iron note: as noted in study 41, increased GGT equates to decreased glutathione] “Septal fibrosis was present in 30 patients (27%) including cirrhosis in 4 patients (5%). Age > 45 years, B.M.I. >30 Kg/m2, serum tryglycerides >180 mg/dl, hyperglycemia > 220 mg/dl, serum ALT > 3N, increased hepatic iron and transferrin saturation percentage were independently associated with sepal fibrosis. Linear regression analysis showed that increased hepatic iron had the greatest association with the increase of lipid peroxidation… and the decrease of serum gluthatione …”
This 2012 review describes the processes causing fibrosis relating to several organ systems. Although the full text is somewhat technical in nature, the authors suggests that, “Upon injury, prolonged inflammation and oxidative stress may cause pathological wound healing and fibrosis, leading to formation of excessive scar tissue. Fibrogenesis can occur in most organs and tissues and may ultimately lead to organ dysfunction and failure.” The authors focus on the pro-inflammatory and oxidative properties of free heme and free iron in the process and describe the heme-oxygenase in then control of inflammation and oxidative stress. “The microsomal enzyme heme oxygenase (HO) catalyzes the oxidative degradation of free heme, and generates carbon monoxide (CO), ferrous iron(Fe2+), and biliverdin.” “Prolonged inflammatory conditions accompanied by oxidative stress may interfere with the normal wound healing process, leading to an extended presence of myofibroblasts and excessive scar formation, a process known as fibrosis. Fibrosis is not only restricted to dermal wound healing, but also occurs in palatal tissue, lungs, heart, liver, intestine, and joints, and causes major medical problems ranging from disfigurement to progressive disability and even death.”
In this 2012 study from China various regulatory genes were evaluated in terms of their influence on iron overload and diabetes risk in a population of 1,574 Chinese Han from Beijing. The researchers concluded, “These findings suggest that TMPRSS6 variants were significantly associated with plasma ferritin, hemoglobin, risk of iron overload, and type 2 diabetes in Chinese Hans. The type 2 diabetes risk conferred by the TMPRSS6 SNPs is possibly mediated by plasma ferritin.”
These Spanish researchers establish the relationship of glucose metabolism alterations with porphyria cutanea tarda (PCT). [PCT is a skin disorder common among hemochromatosis patients] The researched were able to link the biochemical iron measure of persistently high serum ferritin found in both PCT and iron overload to the development of glucose metabolism alterations and diabetes.
This 2011 research examined the relationship of hepciden (an iron metabolism regulation peptide) with ferritin and type 2 diabetes. They concluded that the positive correlation that exists between elevated ferritin and hepciden may be an indication of an adaptive response to iron and inflammation.
This 2011 research assesses the relationship between genes, oxidative stress and iron stores in metabolic syndrome an type 2 diabetes patients.Type 2 diabetes patients had higher iron deposits, total body iron, and heme oxygenase activity (a suggestion of high oxidative stress condition) than metabolic syndrome subjects and controls. The researchers concluded, “These results imply that type 2 diabetes patients and individuals with metabolic syndrome carrying SM repeats (i.e.genes) might have higher susceptibility to develop diabetes consequences. This increased susceptibility could be Fe-mediated (Iron-mediated) oxidative stress.”
This 2004 Australian study “documents the assessment of plasma iron indices and the correlation between transferrin saturation with biochemical and clinical parameters in a cross-sectional survey of 820 patients with diabetes in long-term follow-up in a single clinic.” “Eighty per cent of patients had Type 2 diabetes.” “The prevalence of elevated transferrin saturation (> 35%) was 3-4-fold higher in patients with diabetes, compared with historical prevalence described in the general population.””Independent associations with elevated transferrin saturation were male gender, low C-reactive protein, and increased fasting plasma glucose (all P < 0.0001). Patients with Type 1 diabetes were also more likely to have an elevated transferrin saturation [odds ratio 3.9 (95% CI 1.9-8.0), P < 0.001].” “Patients with an elevated transferrin saturation were younger, but had a similar duration of diabetes, possibly suggesting an earlier age of onset. There was no correlation between the presence of diabetic complications and the presence of elevated iron indices.” The researchers concluded, “Elevated iron indices are more common in patients with diabetes. Excess iron may have a role in the development of diabetes and subsequently in glycaemic control. This should be balanced by the strong association between iron indices and anaemia in patients with diabetes.”
Serum Ferritin in Type 2 Diabetes Mellitus and its Relationship with HbA1c (no abstract) (59)
This 2004 study in Iran was conducted on 97 (37 males and 60 females) patients with type 2 diabetes (DM). “Ninety-four normal age-matched individuals were included in the study as the control group.” “Mean serum ferritin was significantly higher in diabetics than in the control group (101±73 mg/ml vs. 43.5+42 mg/ml, p<0.001). There was no correlation between serum ferritin and HbA1c in diabetic patients of either sex. Ferritin levels in patients with DM is high, but not related to levels of HbA1c and blood glucose control.” The researchers concluded, “ferritin is higher in diabetics than in controls. There isn’t any correlation between serum ferritin and blood glucose control in diabetics. So, it seems that ferritin may have a role in the pathogenesis of type 2 DM. We propose that more studies need to be performed about the role of ferritin in gestational DM, and patients with impaired glucose tolerance, as cases with some degree of insulin resistance and in the pre-diabetic stage.” [Health-e-Iron note: Figures 1 and 3 from this study appear below]
This is a 2009 review published by researchers from the Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx NY. “The role of micronutrients in the etiology of type 2 diabetes is not well established. Several lines of evidence suggest that iron play may a role in the pathogenesis of type 2 diabetes. Iron is a strong pro-oxidant and high body iron levels are associated with increased level of oxidative stress that may elevate the risk of type 2 diabetes. Several epidemiological studies have reported a positive association between high body iron stores, as measured by circulating ferritin level, and the risk of type 2 diabetes and of other insulin resistant states such as the metabolic syndrome, gestational diabetes and polycystic ovarian syndrome. In addition, increased dietary intake of iron, especially that of heme iron, is associated with risk of type 2 diabetes in apparently healthy populations. Results from studies that have evaluated the association between genetic mutations related to iron metabolism have been inconsistent. Further, several clinical trials have suggested that phlebotomy induced reduction in body iron levels may improve insulin sensitivity in humans. However, no interventional studies have yet directly evaluated the effect of reducing iron intake or body iron levels on the risk of developing type 2 diabetes. Such studies are required to prove the causal relationship between moderate iron overload and diabetes risk.
This 2012 systematic review and meta-analysis was produced by researchers in China. The researchers noted that, “Emerging evidence from biological and epidemiological studies has suggested that body iron stores and heme-iron intake may be related to the risk of type 2 diabetes (T2D). The causative role of elevated iron store levels in the onset of insulin resistance is well established by prospective data as well as evidence that blood donations improve insulin sensitivity by decreasing iron stores. We aimed to examine the association of body iron stores and heme-iron intake with T2D risk by conducting a systematic review and meta-analysis of previously published studies.” “The meta-analysis included 16 high-quality studies: 12 studies analyzed ferritin levels (4,366 T2D patients and 41,091 controls) and 4 measured heme-iron intake (9,246 T2D patients and 179,689 controls). The combined relative risk (RR) comparing the highest and lowest category of ferritin levels was 1.66 (95% CI: 1.15-2.39) for prospective studies, 2.29 (95% CI: 1.48-3.54) for cross-sectional studies with heterogeneity (Q = 14.84, p = 0.01, I(2) = 66.3%; Q = 44.16, p<0.001, I(2) = 88.7%). The combined RR comparing the highest and lowest category of heme-iron intake was 1.31 (95% CI: 1.21-1.43) with heterogeneity (Q = 1.39, p = 0.71, I(2) = 0%). No publication bias was found. Additional 15 studies that were of good quality, had significant results, and analyzed the association between body iron stores and T2D risk were qualitatively included in the systematic review.” “We calculated the combined RRs of prospective studies before and after the adjustments of metabolic factors. Under both conditions, prospective studies indicated a statistically significant association between ferritin levels and T2D risk, suggesting a causal effect for high ferritin level on T2D independent of known diabetes risk factors.” The researchers concluded, “The meta-analysis and systematic review suggest that increased ferritin levels and heme-iron intake are both associated with higher risk of T2D.”
This second 2012 systematic review and meta-analysis was also published by researchers from China. Similar to the directly-above research, the investigators “aimed to systematically evaluate the available evidence for associations between iron intake, body iron stores, and the risk of T2DM.” “We reviewed 449 potentially relevant articles, and 11 prospective studies were included in the analysis. A meta-analysis of five studies gave a pooled RR for T2DM of 1.33 (95% CI 1.19 to 1.48; P<0.001) in individuals with the highest level of heme iron intake, compared with those with the lowest level. The pooled RR for T2DM for a daily increment of 1 mg of heme iron intake was 1.16 (1.09 to 1.23, P<0.001). Body iron stores, as measured by ferritin, soluble transferrin receptor (sTfR) and the sTfR:ferritin ratio, were significantly associated with the risk of T2DM. The pooled RRs for T2DM in individuals with the highest versus the lowest intake of ferritin levels was 1.70 (1.27-2.27, P<0.001) before adjustment for inflammatory markers and 1.63 (1.03-2.56, P = 0.036) after adjustment. We did not find any significant association of dietary intakes of total iron, non-heme, or supplemental iron intake with T2DM risk.” [Health-e-Iron note: notably, but not unexpectedly, the results reported in the preceding study and this one are nearly identical]
This 2010 study was also preformed in Iran. “Fifty-four people with type 2 diabetes and 53 matched healthy participants were included. Serum ferritin, total iron binding capacity, insulin resistance, C-reactive protein and tumor necrosis factor-alpha were measured in both groups.” “Diabetic patients had higher insulin resistance, hemoglobin A(1)C and serum ferritin. Significant positive correlations were observed between insulin resistance with serum ferritin and tumor necrosis factor-alpha and between serum ferritin and tumor necrosis factor-alpha in diabetic patients.” The researchers concluded, “Inter-relationship between insulin resistance, serum ferritin and TNF-alpha was found in type 2 diabetic patients. Serum iron even in the normal range had positive correlation with insulin resistance. It may be because the normal ranges determined for serum ferritin are too wide and the criteria for iron overload are too high.”
This 2008 study was reported from Iran. The researchers stated, “Few data are available on the association of variables of the insulin resistance syndrome and serum ferritin, an indicator of body iron stores. We examined the relationship between serum ferritin levels and impaired fasting glucose, a pre-diabetes stage associated with insulin resistance, in this study.” “One hundred and eighty seven people, including 91 subjects with impaired fasting glucose (IFG) (41 males, 50 females) and 96 healthy people who were well matched for age and sex, were enrolled. Body mass index (BMI) and blood pressure of the participants were measured and serum cholesterol, triglyceride, white blood cells (WBC) count, C-reactive protein (CRP) and ferritin were evaluated. All the data were analysed by t-test, chi2 test and analysis of variance.” “The IFG group had higher serum ferritin concentrations(85.5+/-6.6 microg/L vs. 49.4+/-3.7 microg/L, p=0.001). A positive correlation was found between fasting plasma glucose and serum ferritin (r=0.29, p=0.001). Using multiple regression analysis, we found an association between serum ferritin and blood pressure (0.15, p=0.01), FPG (0.29, p=0.001), triglyceride (0.08, p=0.01) and cholesterol (0.07, p=0.03). The odds ratio for the association of IFG in male subjects with a high serum ferritin level was 8.3 (95% CI: 1.2-11.9, p=0.01) and for females was 3.06 (95% CI: 0.58-15, p=0.1).” The researchers concluded, “Based on the data from our study, a elevation in serum ferritin can be seen in pre-diabetes stage, before the occurrence of an overt diabetes mellitus.” “Reduced dietary iron intake, especially in men and post-menopausal women with additional risk factors for type 2 diabetes, may be advisable. Actively lowering body iron stores may be effective in selected subjects with impaired glucose metabolism.” [Health-e-Iron note: Table 1 from this paper appears below]
The findings of this 2009 study from the Czech Republic match many of the preceding ones. The researchers concluded, “Our results provide evidence for a relationship between plasma ferritin and oxidative modification of lipids as well as proteins in vivo. Higher body iron stores may contribute to impaired insulin sensitivity through increased oxidative stress in a cohort of healthy men.”
This is another study from China in 2010. More than a thousand healthy adults were followed for five years. “we documented 125 incident cases of hyperglycaemia, among them twenty-three were diabetic. Haem Fe (heme iron) intake was positively associated with the risk of hyperglycaemia in men and women: the OR (95 % CI) across increasing quartiles of haem Fe intake was 1.00 (referent), 1.49(0.74, 3.01), 2.16 (1.06, 4.42) and 3.48 (1.71, 7.11), respectively (P for trend <0.001).” [Health-e-iron note: Figure 1 form this study appears below. Note that a significant number of Chinese subjects in this study (28.8%) were anemic. Anemia in the U.S. is far less common. However, as noted in this study, significant levels of heme iron intake can contribute to hyperglycemia even when the subjects are anemic.]
Fig. 1 Joint effects of anaemia and (a) haem iron intake and (b) total iron intake on risk of hyperglycaemia among Chinese adults (adjustment for variables cited in Table 2, model 3): Jiangsu Nutrition Study
The research published in 2012 notes that “Nonalcoholic fatty liver disease (NAFLD) is now recognized as a major cause of chronic liver diseases, including liver cirrhosis and hepatocellular carcinoma (HCC) in Western countries. Like alcoholic liver disease, NAFLD covers a wide spectrum of disorders from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis.Approximately 30% of the US population and 20% of the Korean population have NAFLD.” The authors establish that based on numerous studies published over the last decade, “serum ferritin may be a simple, useful marker for obese patients with NAFLD.” Based on the accumulation of findings the authors state in this review that “Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease.”
This 2008-reported abstract from a Romanian describes insulin resistant hepatic iron overload (IR-HIO), it is notable because it recognizes that “In IR-HIO, fibrosis develops at a much lower hepatic iron burden than in genetic haemochromatosis, and sinusoidal iron, steatosis and inflammation could represent the histological mark of activity and progression of liver disease in IR-HIO.”
This 2008 paper differentiates between hepatic iron overload in hemochromatosis patients and the relatively recent observation in metabolic syndrome patients. And that metabolic syndrome, affected patients load iron through an apparently different mechanism. As in other studies, the researchers describe, “a moderate form of iron overload with a prevalent sinusoidal distribution and a normal transferrin saturation, suggesting the existence of a peculiar pathogenetic mechanism of iron accumulation. These patients may have the typical dysmetabolic iron overload syndrome.” [Health-e-Iron note: Figure 6 from this study appears below. This paper describes the pattern of iron overloading that is associated with dysmetabolic iron overload syndrome. Patients with this syndrome often express high ferritin levels and normal transferrin saturation.]
Figure 6 Distribution of HHII (histological hepatic iron index), transferrin saturation and Sinusoidal/Total Iron Score (SIS/TIS) in patients with 0-1 MS components and absence of steatosis (nM/nS) and patients with 2 MS alterations and steatosis (+M/+S).
In a 2009 report this study group out of Albert Einstein College of Medicine in New York examined soluble transferrin receptors (sTfR) and the risk of type 2 diabetes. The researchers noted that “Compared with controls, cases had higher sTfR levels (3.50 +/- 0.07 vs. 3.30 +/- 0.06 mg/l; p = 0.03), but ferritin levels were not statistically different.” And “Modestly elevated sTfR levels are associated with increased diabetes mellitus risk among overweight and obese individuals with impaired glucose tolerance.”
This 2007 review provides a fairly comprehensive description of the primary cofactors involved in iron overload states. The cofactors include alcohol, Hepatitis C viral infection and processes involving cell and tissue damage, and steatosis and insulin resistance and the increased prevalence of hemochromatosis (HFE) gene expression. The authors conclude, “As shown in Figure 2, a common pathway through steatosis/oxidative stress may be present for the development of liver fibrosis and carcinogenesis by iron.” The research team also concluded, “…the prevalence of HFE mutations and serum ferritin values increased with the severity of steatosis.” [Health-e-Iron note: Tables 1 and 2 and Figure 2 from this article appear below]
Figure 2 Postulated schema of liver damage occurred by alcohol, HCV infection, obesity and insulin resistant. A common pathway through steatosis/oxidative stress may be responsible for the development of liver fibrosis and carcinogenesis by iron.
This 2007 study in Italy included 143 previously untreated, biopsied patients with hepatitis C who were not alcohol abusers. “Increased transferrin saturation was observed in 20%, hyperferritinemia in 22%, and histological iron deposition in 32% of patients. Ferritin was independently correlated with iron stores and host metabolic parameters, whereas hepatic iron deposition was correlated with ferritin and histological severity of hepatitis. Sinusoidal iron deposition was associated with metabolic alterations, including body mass index, insulin resistance, and LDL cholesterol.” The researchers concluded, “Iron genes influence iron overload and steatosis development, but the major burden is related to HCV itself and host metabolic factors.” [Health-e-Iron note: Tables 3 and 4 from this study appear below]
This was a 2010 study of 68 consecutive non-cirrhotic patients with a clinical and biochemical diagnosis of NASH. Coronary artery disease patients (CAD) demonstrated increased C-reactive protein measures and elevated ferritin. “In CAD patients with NASH along with an increase in the levels of serum ferittin (p<0.001), the levels of serum AMG and ceruloplasmin (CP) were also increased (p<0.01). The CAD patients with NASH had a higher proportion of diabetes, hypertension and dyslipidaemia compared to CAD patients.” The researchers could not explain the contribution of increased inflammatory markers in NASH patients with CAD. [Health-e-Iron note: Table 3 from this study appears below]
Note: CRP, C-reactive protein; AAG-alpha-1, acid glycoprotein; AMG, alpha-2 macroglobulin; AAT, alpha-1 anti trypsin; Lp(a), lipoprotein a; CAD, coronary artery disease; NASH, non-alcoholic steatohepatitis; NS, not significant; values are means9standard deviation standard error.
This 2012 U.S. study explored “…the effects of glycation on iron metabolism and innate immunity.” “The results, in addition to data in the literature, support the hypothesis that glycation of serum proteins may effectively increase the available free iron pool for bacteria in blood serum and weaken our innate immunity. This phenomenon may be partially responsible for higher infection rates in some diabetics, especially those with poor glycemic control.”
This 2010 Austrian study was undertaken based on the reported observations that, “Iron overload may contribute to the pathogenesis of insulin resistance.” “We determined body mass index (BMI), waist-to-hip-ratio (WHR), blood pressure, liver ultrasound, serum lipids, insulin, fasting glucose, liver transaminase levels, hsCRP, iron parameters in 325 of 341 (95.3%) students (234 men, 16.7 +/- 1.7 years; 91 women, 16.5 +/- 1.7 years) of one single high school.” “The researcher’s concluded that, “These results provide evidence for linkage among body iron stores, transaminase activity (liver enzyme activity) and the prevalence of cardiometabolic risk factors in apparently healthy, non-obese adolescents even within the range of normal laboratory and anthropomorphic values and suggest that iron stores should be investigated as a potentially modifiable risk factor in healthy teenagers.”
In 2011 this (primarily) U.S. research team studied 506 diabetes mellitus patients for the presence of catalytic iron. They had hypothesized that the presence of catalytic iron “may be higher in patients with diabetes mellitus, and if so higher concentrations could precede the occurrence of proteinuria.” (and a significantly heightened risk of progression to end stage kidney disease) Although they observed a 54% prevalence of increased catalytic iron in the subject population, however concluded, if urinary catalytic iron is associated with future cardiovascular or renal events, that association is likely to be independent of the covariates we examined. Urinary catalytic iron has potential to be useful as an independent predictor of risk of nephropathy and cardiovascular events.”
This 2011 study was conducted as an ancillary study in a subgroup of 9 clinical centers of the NIH-sponsored ACCORD (Action to Control Cardiovascular Risk in Diabetes) Trial. “This cross-sectional study represents an initial step in the development of a biomarker of risk prediction—the demonstration that urinary catalytic iron is abnormal in a population with diabetes mellitus and cardiovascular risk factors but without increased urinary albumin.” The aim of the study was to determine the extent of increased catalytic iron in 167 trial participants with nonpathologic renal function and the absence of microalbuminuria. Reference intervals were established through tests of urine samples of 50 men and 50 women mean age 37.4 years. The researchers reported, “In this cross-sectional study, we observed increased urinary catalytic iron concentrations in 54% of the participants with DM without microalbuminuria and with a nonpathologic renal function.” [Health-e-iron note: Table 1 from this investigation appears below]
This 2010 study undertaken in Brazil was aimed “to determine oxidative stress in patients with untreated chronic hepatitis C (CHC), relating the obtained results with iron status and disease activity markers.” “Serum ferritin correlated with ALT and GGT, whereas serum iron did so with GGT. In conclusion, lower antioxidant capacity, higher levels of pro-oxidants activity, and iron overload occur in untreated patients with CHC. This greater oxidative activity could play an important role in pathogenesis and evolution of hepatitis C and thus further investigations.”
In this 2009 review the authors noted, “Through Fenton reaction, iron as a transit mineral can generate various reactive oxygen or nitrogen species; therefore, abnormal metabolism of iron can lead to several chronic pathogenesis. 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 of insulin resistance and diabetes, but also causes cardiovascular diseases in non-diabetic and diabetic subjects.” “Temporal iron deficiency was found to sensitize insulin action, but chronic iron deficiency with anemia can accelerate the development of cardiovascular diseases in non-diabetic and diabetic patients.” “In this review, therefore, we will first outline iron homeostasis, function, and toxicity, and then mainly summarize the data regarding the roles of iron deficiency and overload in the pathogenesis of diabetes and diabetic complications, as well as the possible links of iron to diabetes and diabetic complications.” [Health-e-Iron note: Figure #1 from this review appears below]
Fig. (1). Schematic illustration of iron metabolism. Panel A is to indicate the overview of iron homeostasis. Panel B is to indicate how heme iron and inorganic iron are absorbed into intestinal cell and exported into blood. Panel C is to illustrate how iron bound Tf is taken into cell and used for heme protein synthesis. Tf: transferrin; RBC, red blood cells; HCP, heme iron transporter; DMT1, divalent metal-ion transporter; DCYTB, duodenal cytochrome b; TfR-1, transferrin receptor 1; IRP, iron-regulatory protein; LIP, labile iron pool; PCBP1, poly (rC)-binding protein 1; mitNEET, a recently identified an outer mitochondrial membrane protein that is an iron-containing protein and plays an important role in the control of maximal mitochondrial respiratory rate . Grx5, glutaredoxin 5. In the panel C, IRPs control the expression of erythroid 5-aminolevlinate synthase (eALAS), the first and rate-limiting enzyme in the heme biosynthetic pathway. IRP activity is modulated by the LIP (IRP1 + IRP2) and by Fe-S-cluster biosynthesis. This figure was made based on the published materials [8,11,13].