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Insulin Resistance: Iron, GGT & Oxidative Stress

On this page, the rapidly developing science establishing the causal role of iron in insulin resistance is highlighted. The recently-discovered, iron-regulatory hormone, hepcidin, and its relevance to insulin resistance will also be described on this page. Hepcidin promotes macrophage iron loading, atherosclerosis and other adverse consequences.  A few articles below and numerous others found on other pages on this web site summarize the numerous diseases and medical conditions that develop when both iron and GGT are in the upper-normal ranges and above. Our Iron Reduction Therapy page provides important supportive scientific findings demonstrating that reducing iron levels by blood donation or iron reduction therapy, improves insulin resistance and other metabolic risk factors.


Dietary Iron Overload Induces Visceral Adipose Tissue Insulin Resistance (1)

This is a 2013-published study from Italy. "Increased iron stores associated with elevated levels of the iron hormone hepcidin are a frequent feature of the metabolic syndrome. The aim of this study was to assess the effect of dietary iron supplementation on insulin resistance and the role of hepcidin in C57Bl/6 male mice fed a standard or iron-enriched diet for 16 weeks. Iron supplementation increased hepatic iron and serum hepcidin fivefold and led to a 40% increase in fasting glucose due to insulin resistance, as confirmed by the insulin tolerance test, and to threefold higher levels of triglycerides. Iron supplemented mice had lower visceral adipose tissue mass estimated by epididymal fat pad, associated with iron accumulation in adipocytes. Decreased insulin signaling... was detected in the visceral adipose tissue of iron overloaded mice, and gene expression analysis of visceral adipose tissue showed that an iron-enriched diet up-regulated iron-responsive genes and adipokines, favoring insulin resistance, whereas lipoprotein lipase was down-regulated. This resulted in hyperresistinemia and increased visceral adipose tissue expression of suppressor of cytokine signaling-3 (Socs3), a target of resistin and hepcidin implicated in insulin resistance. Acute hepcidin administration down-regulated lipoprotein lipase and up-regulated Socs3 in visceral adipose tissue. In conclusion, we characterized a model of dysmetabolic iron overload syndrome in which an iron-enriched diet induces insulin resistance and hypertriglyceridemia and affects visceral adipose tissue metabolism by a mechanism involving hepcidin up-regulation." [Health-e-Iron note: Hepcidin is an iron regulatory peptide that was discovered in 2000. Research over the last decade has demonstrated that hepcidin is the key regulator of iron metabolism and homeostasis]

 

Increased serum hepcidin levels in subjects with the metabolic syndrome: a population study (2) Free full text

This is another 2013-reported study from Italy. The authors noted, "The recent discovery of hepcidin, the key iron regulatory hormone, has changed our view of iron metabolism, which in turn is long known to be linked with insulin resistant states, including type 2 diabetes mellitus and the Metabolic Syndrome (MetS). Serum ferritin levels are often elevated in MetS (Dysmetabolic hyperferritinemia - DHF), and are sometimes associated with a true mild-to-moderate hepatic iron overload (dysmetabolic iron overload syndrome - DIOS). However, the pathophysiological link between iron and MetS remains unclear. This study was aimed to investigate, for the first time, the relationship between MetS and hepcidin at population level. We measured serum hepcidin levels by Mass Spectrometry in 1,391 subjects from the Val Borbera population, and evaluated their relationship with classical MetS features. Hepcidin levels increased significantly and linearly with increasing number of MetS features, paralleling the trend of serum ferritin. In multivariate models adjusted for relevant variables including age, C-Reactive Protein, and the HFE C282Y mutation, ferritin was the only significant independent predictor of hepcidin in males, while in females MetS was also independently associated with hepcidin. Overall, these data indicate that the fundamental iron regulatory feedback is preserved in MetS, i.e. that hepcidin tends to progressively increase in response to the increase of iron stores. Due to recently discovered pleiotropic effects of hepcidin, this may worsen insulin resistance and contribute to the cardiovascular complications of MetS." [Health-e-Iron note: Figure 1 and Table 2 from this study appear below. Notably, the investigators also reported the following in the full text: "Of note, serum ferritin was the strongest predictor of hepcidin, while in our analyses CRP, the classical systemic marker of inflammation, was not a significant determinant of both parameters."]

 

 

Health-e-Iron note: the following two laboratory studies are as suggested by the authors of the research directly above to demonstrate "some of the newly discovered pleiotrophic effects of hepcidin." 


Hepcidin Destabilizes Atherosclerotic Plaque Via Overactivating Macrophages After Erythrophagocy (3) Free full text

This is a 2012-reported laboratory study that elaborates on the process of how increased hepcidin trapped iron and destabilizes atherosclerotic plaque, and that removal of iron by chelation suppressed lipid accumulation, reactive oxygen species formulation, inflammatory cytokine expression, and apoptosis in erythrophagocytosed macrophages. The investigators concluded, "Hepcidin promotes plaque destabilization partly by exaggerating inflammatory cytokine release, intracellular lipid accumulation, oxidative stress, and apoptosis in the macrophages with iron retention." [Health-e-Iron note: As noted by the authors in the full text, these results confirm what had been first hypothesized by the late Jerome Sullivan's "Iron-Heart hypothesis" more than thirty years earlier, and help confirm Dr. Sullivan's more recent hypothesis that hemochromatosis mutations protect against iron-mediated atherosclerosis {see article # 5} below). Hemochromatosis mutations promote iron overload resulting from low hepcidin expression; however, site-specific macrophage iron loading is very limited. Conditions and diseases resulting from hereditary hemochromatosis are typified by iron loading in non-macrophage tissue sites. Figure 6 from this study is below]

 

Pharmacologic Suppression of Hepcidin Increases Macrophage Cholesterol Efflux and Reduces Foam Cell Formation and Atherosclerosis (4) Free full text

This 2012-reported study was undertaken by a team of investigators in the U.S. The investigators had previously reported that: "lowering of macrophage free intracellular iron increases expression of cholesterol efflux transporters ABCA1 and ABCG1 by reducing generation of reactive oxygen species. In this study, we explored whether reducing macrophage intracellular iron levels via pharmacological suppression of hepcidin can increase macrophage-specific expression of cholesterol efflux transporters and reduce atherosclerosis." The full methods, procedures and results of this study which was conducted among cohorts of subject and control mice are reported in the full text. The investigators noted, "Although current clinical strategies have focused on cholesterol lowering as a way to decrease lipid retention in the arterial wall, increasing macrophage lipid efflux has been suggested to be another promising strategy to limit foam cell formation and atherosclerosis." The investigators concluded based on their research, "These data suggest that pharmacologic manipulation of iron homeostasis may be a promising target to increase macrophage reverse cholesterol transport and limit atherosclerosis." [Health-e-Iron note: although this study was focused on a pharmacologic solution to machrophage iron loading, there are several studies on our "Iron Reduction Therapy" page that prove that iron reduction through blood donation or therapeutic phlebotomy can effect the same results, and has been reported as well-tolerated procedure in virtually all studies it's been utilized]


Do hemochromatosis mutations protect against iron-mediated atherogenesis? (5) Free full text

Health-e-Iron note; In this 2009-published review, Dr. Jerome Sullivan described how the discovery of hepcidin and the rapid expansion of knowledge that had occurred over the short period since had provided the necessary scientific support to further prove the Iron-Heart hypothesis as originally in 1981. This review was cited above in a paper that was published in 2013 and incorporated the more recent laboratory proof that had become available (see directly above). Although Dr. Sullivan's hypothesis had never been disproved, it had to withstand a barrage of alternative hypotheses. Perhaps the strongest opposition would come as a result of the "hemochromatosis paradox." This "apparent" paradox was: "seen as an anomaly that makes the hypothesis untenable for some observers. How can normal  stored iron levels be bad for the vascular system, when massive amounts of stored iron in genetic iron overload do not seem to provoke increased atherosclerosis? In this review, Dr. Sullivan made the case on the science available in 2009. As is demonstrated above and throughout other sections of this web site, the more recent literature adds significant support to what was known in 2009. After demonstrating that moderately elevated hepcidin can trap iron in macrophages inside atherosclerotic plaque, but only in non-hereditary hemochromatotic individuals, and that iron reduction can safely eliminate that potentially dangerous iron, Dr. Sullivan ended this review with three questions: "What duration and degree of iron reduction therapy is required for restoring iron levels in atherosclerotic vessel segments to the much lower level seen in healthy vascular tissue? How much reduction in the level of hepcidin is needed to facilitate the relocation of stored iron from intralesional macrophages to erythroid precursors? Is it possible in normal subjects to inhibit the formation of atherosclerotic foam cells by making their macrophages as iron poor as in those with hemochromatosis mutations? [Health-e-Iron note: below image is courtesy of sciencedirect.com]


 

The Hepcidin-Ferroportin System as a Therapeutic Target in Anemias and Iron Overload Disorders (6) Free full text

This 2011-published review was authored by members of the Department of Pulmonary & Critical Care Medicine, University of California-Los Angeles. "The review summarizes the current understanding of the role of hepcidin and ferroportin in normal iron homeostasis and its disorders. The various approaches to therapeutic targeting of hepcidin and ferroportin in iron-overload disorders (mainly hereditary hemochromatosis and β-thalassemia) and iron-restrictive anemias (anemias associated with infections, inflammatory disorders, and certain malignancies, anemia of chronic kidney diseases, and iron-refractory iron-deficiency anemia) are also discussed." [Health-e-Iron note: Figures 1, 2 and 3 from this review are below]

 

 High levels of iron status and oxidative stress in patients with metabolic syndrome   (7)

This was a 2013-reported study undertaken in Chile. The researchers stated, "Studies concerning oxidative stress (OxE) parameters have increased, mainly because of its important role in cardiovascular diseases and diabetes complications. The main objective of this study was to evaluate iron nutrition status and oxidative stress parameters in subjects that had developed metabolic syndrome (MetS). Subjects from the Research Program of Risk Factors for Cardiovascular Disease (n = 155) were studied (ages ranging from 45 to 65years old) and classified according to the Adult Treatment Panel III criterion. A blood sample was taken after a 12-h fasting period, and basal glucose, insulin, thiobarbituric acid reactive substances (TBARS), oxidized LDL (oxLDL), heme oxygenase (HO) activity, lipid profile, and iron nutrition status were determined. Eighty-five subjects were classified as MetS, and 70 non-MetS. Individuals with MetS showed higher Fe storage (high levels of ferritin, total body iron and low transferrin receptor), oxLDL, TBARS, and homeostatic model assessment for insulin resistance levels. The MetS group showed high levels of oxidative stress parameters (HO activity, oxLDL, and TBARS). The presence of MetS showed an association with LDL oxidation risk (multiple lineal regression according to sex and age, p < 0.001). High levels of triglycerides (p < 0.001) and waist circumference (p < 0.012) were associated with oxLDL levels, as well as an association between TBARS and oxLDL with ferritin levels. Through logistic regression analyses, the highest quartile of ferritin was associated with a threefold risk of developing MetS compared to the lowest quartile; also, TBARS showed a 21-fold risk for the development of MetS. Finally, elevated levels of oxidative stress parameters such us oxLDL, TBARS, HO, and Fe storage were associated to MetS.

 

Adipocyte iron regulates adiponectin and insulin sensitivity  (8) Free full text

This is 2012-reported research from a study in the U.S. The researchers noted, "Iron overload is associated with increased diabetes risk. We therefore investigated the effect of iron on adiponectin, an insulin-sensitizing adipokine that is decreased in diabetic patients. In humans, normal-range serum ferritin levels were inversely associated with adiponectin, independent of inflammation. Ferritin was increased and adiponectin was decreased in type 2 diabetic and in obese diabetic subjects compared with those in equally obese individuals without metabolic syndrome. Mice fed a high-iron diet and cultured adipocytes treated with iron exhibited decreased adiponectin mRNA and protein. We found that iron negatively regulated adiponectin transcription via FOXO1-mediated repression. Further, loss of the adipocyte iron export channel, ferroportin, in mice resulted in adipocyte iron loading, decreased adiponectin, and insulin resistance. Conversely, organismal iron overload and increased adipocyte ferroportin expression because of hemochromatosis are associated with decreased adipocyte iron, increased adiponectin, improved glucose tolerance, and increased insulin sensitivity. Phlebotomy of humans with impaired glucose tolerance and ferritin values in the highest quartile of normal increased adiponectin and improved glucose tolerance. These findings demonstrate a causal role for iron as a risk factor for metabolic syndrome and a role for adipocytes in modulating metabolism through adiponectin in response to iron stores."

 

Iron metabolism is associated with adipocyte insulin resistance and plasma adiponectin: the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study (9)  Free full text

In this 2013-reported study from Europe the investigators noted "Adipocyte insulin resistance (IR) is a key feature early in the pathogenesis of type 2 diabetes mellitus (T2DM), and although scarce, data in the literature suggest a direct role for iron and iron metabolism-related factors in adipose tissue function and metabolism. Serum ferritin and transferrin were shown to be associated with muscle insulin resistance (IR) and T2DM, but little is known about the role of iron metabolism on adipose tissue. We therefore investigated whether markers of iron metabolism were associated with adipocyte IR and plasma adiponectin. Serum ferritin, transferrin, total iron, non-transferrin-bound iron (NTBI), transferrin saturation, and plasma adiponectin were determined in 492 individuals. Adipocyte IR was defined by the product of fasting insulin and nonesterified fatty acids (NEFAs). Using linear regression analyses, we investigated the difference in adipocyte IR or adiponectin (in %) according to differences in iron metabolism markers. Serum ferritin (β = 1.00% increase in adipocyte IR per 10 μg/L [95% CI 0.66-1.34]), transferrin (4.18% per 0.1 g/L [2.88-5.50]), total iron (1.36% per μmol/L [0.61-2.12]), and NTBI (5.14% per μmol/L [1.88-8.52]) were associated with adipocyte IR after adjustment for several covariates, including inflammatory markers. All markers of iron metabolism were also associated with NEFAs (all P < 0.01). In addition, ferritin and transferrin were inversely associated with adiponectin (both P < 0.01)." The researchers concluded, "The observed associations of several markers of iron metabolism with adipocyte IR and adiponectin suggest that factors related to iron and iron metabolism may contribute to adipocyte IR early in the pathogenesis of T2DM." [Health-e-iron note: links to Table 1 and Table 2]

 

Hepcidin expression and iron parameters change in Type 2 diabetic patients  (10) Free full text

This 2011-reported study was undertaken in China. The researchers noted, "Iron may contribute to the pathogenesis of Type 2 diabetes mellitus (DM). The aim of this study was to determine iron regulator hepcidin and iron metabolic parameters in Type 2 DM patients, the relationships among them were evaluated in this specific sub-groups." "The study included sixty-four people: 34 cases of diabetes and 30 age-matched controls. Serum hepcidin, IL-6, hsCRP, ferritin, sTfR, EPO as well as other clinical parameters were detected, and the associations between hepcidin levels and iron/inflammatory parameters were analyzed in diabetes and the controls." "Serum ferritin and hepcidin levels in diabetic patients were significant higher than the controls (p<0.001 respectively). A positive correlation between hepcidin and ferritin, as well as between ferritin and IL-6 levels was existed in diabetes and the control groups (p<0.001 respectively)." The researchers concluded, "All of these data demonstrated that the higher hepcidin levels in diabetic patients may be due to those higher ferritin and IL-6 levels, the elevated hepcidin might have adaptive value through down-regulated iron absorb and play an important role in pathogenesis of Type 2 DM." [Health-e-Iron note: the findings from this study are important as they relate to the finding per se. This paper, however, was published in 2011, and more recent research and interpretations will provide greater insight into this data, particularly in terms of causation. Table 1 from this study is below]

 

Diagnostic and therapeutic implications of the association between ferritin level and severity of nonalcoholic fatty liver disease (11) Free full text

In this 2012-reported review from Italy, the authorss stated, "Nonalcoholic fatty liver disease (NAFLD), defined by excessive liver fat deposition related to the metabolic syndrome, is a leading cause of progressive liver disease, for which accurate non-invasive staging systems and effective treatments are still lacking. Evidence has shown that increased ferritin levels are associated with the metabolic insulin resistance syndrome, and higher hepatic iron and fat content. Hyperferritinemia and iron stores have been associated with the severity of liver damage in NAFLD, and iron depletion reduced insulin resistance and liver enzymes. Recently, Kowdley et al demonstrated in a multicenter study in 628 adult patients with NAFLD from the NAFLD-clinical research network database with central re-evaluation of liver histology and iron staining that the increased serum ferritin level is an independent predictor of liver damage in patients with NAFLD, and is useful to identify NAFLD patients at risk of non-alcoholic steatohepatitis and advanced fibrosis. These data indicate that incorporation of serum ferritin level may improve the performance of noninvasive scoring of liver damage in patients with NAFLD, and that iron depletion still represents an attractive therapeutic target to prevent the progression of liver damage in these patients. [Health-e-Iron note: the authors of this review noted in an earlier study in which they participated that "iron depletion produced a significant larger decrease in insulin resistance (P = 0.0016 for insulin, P = 0.0042 for HOMA-R) compared to nutritional counseling alone, independent of changes in BMI, baseline HOMA-R, and the presence of the metabolic syndrome." (see study #6 on our Iron Reduction Therapy page). Figue 1 from this review is below]


 

[Health-e-Iron note: the above review describes how iron (and its removal) modulates insulin resistance in the context of liver disease. The below review describes how the adverse effects of iron on insulin resistance might contribute to Alzheimer's disease. Other studies describing how iron is linked to neurodegenerative diseases can be accessed on our GGT/IRON Brain page.]


Insulin resistance: an emerging link in Alzheimer's disease (12)

This 2013-published review was authored by researchers from India. "Relentless progression of Alzheimer's disease (AD) poses a grave situation for the biomedical community to tackle. Agents starting as hot favorites in clinical trials have failed in later stages and it is time we reconsidered our approaches to intervene the disease. Quite some interesting work in the last decade has introduced a new school of thought which factors in neuronal glycemic imbalance as a major component for the development of AD. Insulin resistance in the brain has brought forward subsequent sequelae which might work towards amyloid accretion and/or tau hyperphosphorylation. It is also pointed out that insulin works by distributing iron to neuronal tissue and an insulin resistant state throws it off gear leading to iron overloading of neurons which is ultimately detrimental. A relatively recent investigation finds the role of c-Jun-N-terminal kinase (JNK3) in AD which also seems to bear a link with insulin resistance."

 

Changes in iron measures over menopause and associations with insulin resistance  (13) Free full text

Researchers at the University of Michigan reported the results of this study in 2012. Their "objectives were to examine iron measures in individual women at premenopause and at postmenopause and, secondarily, to determine if any changes contributed to insulin resistance." "In a subset of participants (n=70) in a longitudinal study of menopause, we measured ferritin, transferrin, and soluble transferrin receptor (sTfR) once in the premenopause and once in the postmenopause. We also examined associations between menopausal status and change in iron markers after adjustment for age at menopause, race/ethnicity, and waist circumference. In linear regression models, we examined associations between premenopause iron measures and changes in iron markers over menopause with homeostasis model assessment of insulin resistance (HOMA-IR) changes over menopause, before and after adjustment for age at menopause, race/ethnicity, changes in waist circumference, C-reactive protein (CRP), and sex hormone-binding globulin (SHBG) levels." "Women had lower ferritin (p<0.01), higher sTfR:ferritin levels (p<0.01), lower HOMA-IR (p=0.022), and lower glucose (p=0.05) in premenopause compared to postmenopause. After adjustment, lower premenopausal iron levels (sTfR:ferritin levels β=11.0, 95% confidence interval [CI] 0.017-22.0) and larger increases in iron over menopause (changes in sTfR:ferritin β=13.6, 95% CI 0.93-26.3) were associated with larger increases in HOMA-IR." The researchers concluded, "From premenopause to postmenopause, women on average have increases in measures of iron stores. Women who had the greatest changes in iron over menopause (lower measures of premenopausal iron and greater increases in iron measures over the menopause) had the strongest associations between changes in iron and changes in insulin resistance."

 

Iron metabolism and the polycystic ovary syndrome  (14) Free full text

This 2012-published review is from Spain. "The polycystic ovary syndrome (PCOS) is associated with insulin resistance and abnormal glucose tolerance. Iron overload may lead also to insulin resistance and diabetes. Serum ferritin levels are increased in PCOS, especially when glucose tolerance is abnormal, suggesting mild iron overload. Factors contributing to potential iron overload in PCOS include the iron sparing effect of chronic menstrual dysfunction, insulin resistance, and a decrease in hepcidin leading to increased iron absorption. Enhancement of erythropoiesis by androgen excess is unlikely, because soluble transferrin receptor levels are not increased in PCOS. Future venues of research should address the long-term effects of PCOS treatment on iron overload and, conversely, the possible effects of iron lowering strategies on the glucose tolerance of patients with PCOS."

 

Body iron stores and glucose intolerance in premenopausal women: role of hyperandrogenism, insulin resistance, and genomic variants related to inflammation, oxidative stress, and iron metabolism (15) Free full text

In this 2009-reported study, also from Spain, the investigators reported: "Increased serum ferritin levels and iron stores may be involved in the development of abnormal glucose tolerance in women presenting with obesity and/or polycystic ovary syndrome (PCOS). We aimed to study the determinants of serum ferritin levels in premenopausal women among indexes of insulin resistance, adiposity, hyperandrogenism, and genotypes pertaining to inflammation, oxidative stress, and iron metabolism. A total of 257 premenopausal women, classified depending on the presence or absence of PCOS, obesity, and/or abnormal glucose tolerance, underwent a complete metabolic evaluation, serum ferritin, haptoglobin, and C-reactive protein (CRP) measurements, and genotyping for proinflammatory and prooxidant variants and mutations in the HFE gene. Serum ferritin concentrations were increased in women presenting with PCOS and/or abnormal glucose tolerance, independent of obesity. A stepwise multivariate linear regression analysis (R(2) = 0.18, P < 0.0001) retained menstrual dysfunction (beta = 0.14, P = 0.035), free testosterone (beta = 0.14, P = 0.052), insulin sensitivity index (beta = -0.12, P = 0.012), the His63Asp variant in HFE (beta = 0.16, P = 0.008), and abnormal glucose tolerance (beta = 0.15, P = 0.015) as significant predictors of the logarithm of ferritin levels, whereas CRP, haptoglobin, waist-to-hip ratio, or variants in the TNFalpha, TNFRSF1B, IL6, IL6ST, IL6Ralpha, PON1, and HFE Cys282Tyr mutation exerted no influence." the investigators concluded, " Androgen excess (partly because of hyperandrogenemia and partly because of menstrual dysfunction), insulin resistance, abnormal glucose tolerance, and the HFE His63Asp variant correlate with ferritin levels in premenopausal women." [Health-e-Iron note: research reported since 2009 confirms the relationship of ferritin levels to impaired glucose tolerance to be causal, and not just correlative in nature. Figures 1 & 2 from this study appear below]

 

Relationship between free iron and glycated hemoglobin in uncontrolled type 2 diabetes patients associated with complications  (16) Free full text

The authors of this 2008-reported study first noted, "There is considerable current interest in the relationship between insulin and iron pool in the body. Insulin influences the iron uptake and storage by increasing the cell surface transferrin receptors." "Free iron in serum has been found in several disease conditions including diabetes. In the present work, we studied the relationship between free iron, fasting blood glucose (FBG) and glycated haemoglobin (HbA(1c)). Study was carried out on 50 type 2 diabetes cases under poor glycemic control associated with complications, 53 type 2 diabetes cases under good glycemic control and 40 healthy controls. We estimated free iron, both ferrous (Fe(+2)) and ferric (Fe(+3)) form, protein thiols, lipid hydroperoxides, FBG, HbA1c and serum ferritin levels in serum. There was a significant increase in free iron in Fe(+3) state (p <0.01), HbA(1c) (p<0.01), serum ferritin (p<0.01), lipid hydroperoxides (p<0.01) and significant decrease in protein thiols (<0.01) in diabetes cases under poor glycemic control compared to diabetes cases under good glycemic control and healthy controls. Free iron correlated positively with HbA(1c) (p<0.01). Poor glycemic control and increase in glycation of haemoglobin is contributing to the increase in free iron pool which is known to increase oxidant generation." The investigators concluded, "Positive correlation between FBG and HbA1c as well as free iron and HbA1c, indicates hyperglycemia causing increased glycation of haemoglobin and increased release of free iron from glycated proteins like haemoglobin. This makes a vicious cycle of  hyperglycemia, glycation of haemoglobin and increase in levels of free iron." [Health-e-Iron note: Figure 1 from this study is below]

 

Iron-binding antioxidant capacity is impaired in diabetes mellitus (17)

This 2006-published study was undertaken in Belgium. The investigators reported, "Increased lipid peroxidation contributes to diabetic complications and redox-active iron is known to play an important role in catalyzing peroxidation reactions. We aimed to investigate if diabetes affects the capacity of plasma to protect against iron-driven lipid peroxidation and to identify underlying factors. Glycemic control, serum iron, proteins involved in iron homeostasis, plasma iron-binding antioxidant capacity in a liposomal model, and non-transferrin-bound iron were measured in 40 type 1 and 67 type 2 diabetic patients compared to 100 nondiabetic healthy control subjects. Iron-binding antioxidant capacity was significantly lower in the plasma of diabetic subjects (83 +/- 6 and 84 +/- 5% in type 1 and type 2 diabetes versus 88 +/- 6% in control subjects, p < 0.0005). The contribution of transferrin, ceruloplasmin, and albumin concentrations to the iron-binding antioxidant capacity was lost in diabetes (explaining only 4.2 and 6.3% of the variance in type 1 and type 2 diabetes versus 13.9% in control subjects). This observation could not be explained by differences in Tf glycation, lipid, or inflammatory status and was not associated with higher non-transferrin-bound iron levels. Iron-binding antioxidant capacity is decreased in diabetes mellitus."

 

Study of Nonenzymatic Glycation of Transferrin and its Effect on Iron –Binding Antioxidant Capacity (no abstract) (18) Free full text

This is a 2010-reported laboratory study from Iran. The researchers noted, "Nonenzymatic glycosylation (glycation) occurs in many macromolecules in aging and diabetes due to exposure of biomolecules to high level of glucose. Glycation can changes function, activities and structure of many biomolecules. Considering this important role of transferrin (Trf) in iron transport and antioxidant activity in plasma this study was carried out to investigate the effect of glycation in these processes." "We assumed that Trf similar to other antioxidant such as Vit C, was able to protect RBC hemolysis through neutralization of free radicals. Obtained results showed that increasing glycation of Trf decreases antioxidant capacity of Trf and this impairment of antioxidant capacity of Trf increased with increasing the rate of glycation (Table 2) (P< 0.05)." The researchers concluded, "Impairment of antioxidant capacity of glycated Trf can suggest a relationship between glycation of Trf and oxidative stress that occurs due to hyperglycemia in diabetic patients."

 

Nonenzymatic Glycation of Transferrin Decrease of Iron-Binding Capacity and Increase of Oxygen Radical Production (19) Free full text

This 1995-published study was undertaken by Japanese researchers who reported: "The total iron-binding capacity (TIBC) and iron contents of diabetic rat serum, as well as the iron-binding capacity of glycated transferrin and oxygen radical production by the glycated proteins were examined. The TIBC and iron content of diabetic rat sera were found to be much lower than those of control rat sera. Incubation of human serum with glucose in vitro resulted in a significant fall of its unsaturated iron-binding capacity (UIBC) with time. ... The generation of superoxide radical (O2-) and hydroxyl radical (OH.) by the glycated holotransferrin was much greater than that by glycated apotransferrin. Glycated holotransferrin showed significantly accelerated hydroxyl radical production by the hypoxanthine-xanthine oxidase system, while intact holotransferrin did not. Treatment of holotransferrin with glucose caused the fragmentation of the protein, while the same treatment of apotransferrin did not. The researchers concluded, "These results suggest that iron ions in the glycated transferrin molecule are bound loosely to the protein and are redox-active and the glycated holotransferrin produces oxygen radicals including O2- and OH. efficiently, and that the glycated transferrin does not function as an iron-binding protein." The researchers also suggested "It is possible that the the redox-active iron ions in glycated transferrin may contribute to oxidative cell injury of endotheial." [Health-e-Iron note: this "suggested possibility" was from research reported in 1995. The later-reported research summarized on this web site and elsewhere overwhelmingly confirms this "possibility"]


Advanced glycation endproducts--role in pathology of diabetic complications (20)

This 2005-published review is from the U.K. "Diabetes mellitus is a common endocrine disorder characterised by hyperglycaemia and predisposes to chronic complications affecting the eyes, blood vessels, nerves and kidneys. Hyperglycaemia has an important role in the pathogenesis of diabetic complications by increasing protein glycation and the gradual build-up of advanced glycation endproducts (AGEs) in body tissues. These AGE form on intra- and extracellular proteins, lipids, nucleic acids and possess complex structures that generate protein fluorescence and cross-linking. Protein glycation and AGE are accompanied by increased free radical activity that contributes towards the biomolecular damage in diabetes. There is considerable interest in receptors for AGEs (RAGE) found on many cell types, particularly those affected in diabetes. Recent studies suggest that interaction of AGEs with RAGE alter intracellular signalling, gene expression, release of pro-inflammatory molecules and free radicals that contribute towards the pathology of diabetic complications. This review introduces the chemistry of glycation and AGEs and examines the mechanisms by which they mediate their toxicity. The role of AGEs in the pathogenesis of retinopathy, cataract, atherosclerosis, neuropathy, nephropathy, diabetic embryopathy and impaired wound healing are considered. There is considerable interest in anti-glycation compounds because of their therapeutic potential. The mechanisms and sites of action of selected inhibitors, together with their potential in preventing diabetic complications are discussed.


Altered inflammation, paraoxonase-1 activity and HDL physicochemical properties in obese humans with and without Prader-Willi syndrome (21) Full free text

This is a 2012-reported study from Italy. "Prader-Willi syndrome (PWS) represents the most common form of genetic obesity. Several studies confirm that obesity is associated with inflammation, oxidative stress and impairment of antioxidant systems; however, no data are available concerning PWS subjects. We compared levels of plasma lipids and C-reactive protein (CRP) in 30 subjects of 'normal' weight (18.5-25 kg/m(2)), 15 PWS obese (>30 kg/m(2)) subjects and 13 body mass index (BMI)-matched obese subjects not affected by PWS. In all subjects, we evaluated the levels of lipid hydroperoxides and the activity of paraoxonase-1 (PON1), an enzyme involved in the antioxidant and anti-inflammatory properties exerted by high-density lipoproteins (HDLs).  Altogether, our results demonstrated, for the first time, higher levels of lipid hydroperoxides and a lower PON1 activity in plasma of obese individuals with PWS with respect to normal-weight controls. These alterations are related to CRP levels, with a lower PON1:CRP ratio in PWS compared with non-PWS obese subjects. The study of Laurdan fluorescence parameters showed significant modifications of physicochemical properties in HDLs from PWS individuals." The researchers concluded, "Whatever the cause of obesity, the increase of adiposity is associated with inflammation, oxidative stress and alterations in HDL compositional and functional properties." [Health-e-Iron note: Tables 1 and 2 and Figure 1 from this study are below]



High-density lipoprotein impedes glycation of low-density lipoprotein (22) Free full text

In this 2013-reported study from the U.K, the researchers noted, "Glycation of low-density lipoprotein (LDL) increases its atherogenicity, but whether high-density lipoprotein (HDL) can protect LDL against glycation is not known. LDL and HDL were isolated from 32 volunteers with serum HDL cholesterol concentrations ranging from 0.76 to 2.01 (mean = 1.36) mmol/L. ... Glycation of LDL apolipoprotein B (apoB) doubled at glucose 50 and 80 mmol/L (both p < 0.001), and this increase was ameliorated by HDL.... Heterologous HDL from a further study of 12 healthy participants was similarly effective in impeding LDL apoB glycation. HDL impeded not only glycation but also the lipid peroxidation, free amino group consumption and increased electrophoretic mobility of LDL which accompanied glycation. HDL from participants with higher serum paraoxonase1 (PON1) was more effective in impeding glycation and the related processes." The researchers concluded, "HDL can impede the glucose-induced glycoxidation of LDL. PON1 may be important for this function of HDL.


Paraoxonase 1 (PON1) Activity, Polymorphisms and Coronary Artery Disease (book chapter - no abstract) (23) Free full text

[Health-e-Iron note: access links to the complete book "Coronary Artery Disease - New Insights and Novel Approaches" and follow the bibliography at the end of this PDF.]
The authors of this 2012-published chapter introduce their discussion of paraoxonase and its direct relationship with HDL cholesterol as follows: "The protective effect of HDL-C against the development of CAD appears to be complex. A large part of research in this field is centered on the lipid transport function of HDL-C, particularly in reverse cholesterol transport (RCT). In addition, several studies suggest that HDL-C protects LDL-C from peroxidation, thereby protecting cell membranes from lipid peroxide induced vascular damage. This protection of LDL-C from oxidation by HDL-C possibly potentially impedes the initiation and progression of CAD. Recent studies into the mechanism of the prevention of CAD by HDL-C have revealed that its antioxidant effect is because of its association with an enzymeparaoxonase”." The authors note in the section entitled "Modulation of PON1 by exogenous compounds," that iron and several other elements "are highly potent in vitro inhibitors of PON1 192R activity and can inhibit up to 80% of activity." This finding was indicated to be the result of "more recent experiments." By acting in such a capacity, the effect of excess iron would be consistent with, and as reported for, its relationship with many other antioxidants like glutathione. 


Free Radicals and other reactive species in Diseases (no abstract) (24) Free full text

This is a 2001-published article from the "Encyclopedia of Life Sciences.  The author provided a summary of the biochemistry behind the title subject matter. [Health-e-Iron note: Figure 2 from this article is below]



Body iron stores as predictors of insulin resistance in apparently healthy urban Colombian men (25)

This is study reported from Columbia in 2012. "The aim of this study was to evaluate body iron stores as predictors of insulin resistance. We developed a cross-sectional study among 123 men, 25-64 years of age and determined fasting plasma glucose, insulin, serum ferritin, and C-reactive protein levels. A survey was performed to record personal antecedents and family history of non-transmissible chronic diseases. Log-transformed ferritin levels was an independent predictor for log-transformed insulin resistance index assessed by homeostatic model assessment when body mass index or waist circumference were not included in multiple linear regression models. Sedentarism, heart attack family history, and log-C reactive protein levels were also significant predictors for insulin resistance. In conclusion, documented anthropometric predictors affect the significance of ferritin as a potential prediction variable for insulin resistance. Mechanisms of how body fat could influence ferritin levels should be evaluated. To our knowledge, this is the first evaluation of the relationship between body iron stores and insulin resistance in a Latin American population."

 

Insulin sensitivity and liver fat: role of iron load  (26) Free full text

In this 2012-published study from Germany, the researchers noted and reported: "Increased liver fat (LF) is associated with insulin resistance. However, a considerable individual variability between LF and insulin sensitivity (IS) is observed, and at equal levels of LF, insulin-resistant as well as insulin-sensitive individuals are found." "Our objective was to study whether hepatic iron load (HIL) explains some of the variation between IS and LF. HIL was measured using a quantitative T2* magnetic resonance gradient echo imaging technique, and LF was measured by (1)H-magnetic resonance spectroscopy. Low T2* values indicate high HIL. We studied the association of LF and HIL with anthropometric data and IS. A total of 113 healthy nondiabetic subjects [69 females, 44 males; age 47 ± 1 yr; body mass index (BMI) = 28.9 ± 0.5 kg/m(2)] at increased risk for type 2 diabetes were included in the study. T2* values adjusted for age negatively associated with serum ferritin levels (P < 0.0001) and positively associated with IS (P = 0.009). In addition, T2* values associated with LF (P = 0.008) but not with BMI (P = 0.6). In a multivariate model, IS adjusted for gender, age, and BMI was associated with T2* values (P = 0.015). IS adjusted for gender and age was independently associated with LF (P = 0.033) and T2* values (P = 0.004). In a stepwise regression analysis, LF explained 13.5% (P < 0.01) of the variation in IS, and HIL explained an additional 4.1% (P = 0.03). The researchers concluded, "HIL explains part of the variation between LF and IS. The mechanism by which iron load induces insulin resistance is possibly independent of the pathways involved in insulin resistance induced by fatty liver disease."

 

Hepatic iron stores are increased as assessed by magnetic resonance imaging in a Chinese population with altered glucose homeostasis (27) Free full text

In this novel 2011-reported study from China, the investigative team utilized MRI imaging to determine hepatic iron content in subjects with normal glucose tolerance (NGT), prediabetes and type 2 diabetes (T2D). This study is unique for its estimation of hepatic iron content (HIC) in a diabetes-iron study. The results showed that mean HIC (M-HIC)  "values in the prediabetes and T2D groups were significantly higher than in the NGT group (M-HIC: 40.6 ... and 39.3 ... with 27.8... lmol/g; R2* values: 47.9 ...and 47.3 ... compared with 34.9 ...; all P ,< 0.01)." "The liver is a crucial organ at the crossroads of iron and glucose metabolism. As the main iron-storage organ, it also plays a pivotal role in glucose metabolism by regulating glycogen synthesis, glucose output, and insulin catabolism." The investigators concluded, "To our knowledge, our findings provide novel evidence to support the hypothesis of a mild iron overload in patients with prediabetes and T2D. A cohort study concerned with the effect of the attenuation of excess iron on glucose metabolism in a prediabetic population is warranted." [Health-e-Iron note: a s noted by the investigators, "attention" or reduction of iron stores in both prediabetics and T2D patients is warranted based on the evidence of elevated iron stores in this study. Also, there is no reason to believe that similar studies in which only serum iron stores were observed would warrant a different conclusion. Numerous studies on our Iron Reduction Therapy page report highly favorable results, including improvements in biochemical and histological measures and vascular function when iron reduction strategies are employed]

 

Exercise Reduces Inflammation and Oxidative Stress in Obesity-Related Liver Diseases  (28)

This is a 2013-reported study from Japan. The researchers reported: "Weight reduction remains the most common therapy advocated for the treatment of obesity-related liver diseases. Recently, a beneficial effect of exercise regimens for liver dysfunction, independent of weight reduction, has been reported. Therefore, a retrospective analysis was conducted to determine whether exercise training without dietary restriction in obese, middle-aged men influences the pathophysiology of abnormal liver function. A total of 108 subjects who completed a 12-week exercise training program without any dietary restriction were analyzed in this study; these results were compared to those of 104 subjects who completed a 12-week dietary restriction program. Furthermore, 42 of these subjects (from both groups) who had abnormal liver function and suspicious liver fibrosis by NAFLD fibrosis score were analyzed to obtain a more concrete outcome for exercise-training effects. In exercise training, although the magnitude of body-weight reduction (- 3.1% vs. -8.5%), waist circumference (- 4.0% vs. -7.1%), and visceral adipose tissue area (- 12.2% vs. -22.5%) was significantly more modest than that achieved by dietary restriction, exercise training elicited equivalent reductions in serum ALT and γGT levels (i.e., GGT) (- 20.6% vs. -16.1% and - 25.7% vs. -34.0%), and equivalent improvement of insulin resistance (- 29.7% vs. -26.9%). Moreover, exercise training remarkably increased the serum adiponectin level (+ 33.4% vs. + 15.1%). Importantly, for subjects with abnormal liver function and suspicious liver fibrosis, exercise training was effective in reducing the serum levels of inflammation and oxidative stress markers; ferritin and TABRS (- 25.0% vs. + 1.1% and - 33.5% vs. -10.5%)." The researchers concluded, "Exercise training benefits the management of obesity-related liver diseases independent of detectable weight reduction. Particularly, these effects seem to be acquired through an improvement in the hepatic inflammatory condition and its related oxidative stress levels." [Health-e-Iron note: this novel study helps affirm that weight loss by caloric restriction or diet alone generally cannot reduce iron stores and ferritin and cannot solely resolve excessive oxidative stress. Humans have no natural means of excreting iron (in the same way that they have no natural means of excreting calories). Exercise can reduce iron/ferritin over time. For instance, iron deficiency often occurs in female armed services recruits; this is sometimes called "foot-strike anemia." We estimate that the iron/ferritin reduction resulting from this 12-week exercise program could have been replicated by the donation (or therapeutic phlebotomy) of one or two units of blood, which likely would have produced a more significant drop in GGT as well. The other fitness benefits of exercise, however, would not have resulted from blood loss.]


Yogic practice and diabetes mellitus in geriatric patients (29) Free full text (electronically available version)

This is a 2013-published study from India. The authors stated, "stress has negative effect on health and type 2 diabetes patients may be at an increased risk. Abnormally high levels of free radicals and the simultaneous decline of antioxidant defense mechanisms can increase lipid peroxidation and insulin resistance. The objective of the present study was to demonstrate the efficacy of yogic practice in geriatric patients with type 2 diabetes mellitus and also to compare the efficacy with the state of glycaemic control. Seventy three (73) healthy elderly patients of type 2 diabetes mellitus in the age group of 60 to 70 years with a history of diabetes for 5 to 10 years and with poor glycaemic control (HbA(1c) >8 %) residing in Kozhikode district were recruited for the study. The subjects were divided into three groups according to their glycaemic control. Group I with HbA(1c) 8.6-9.7 %, group II with HbA(1c) 9.8-10.7 % and group III with HbA(1c) 10.8-12.7 %. Participants did yogic practice under the supervision of experienced trainer, daily 90 minutes and for three months. Biochemical estimation of HbA(1c), glucose, lipid profile, cortisol, ferritin, malondialdehyde (MDA) and catalase activity were carried out on 0 day and 90(th) day. Seventy patients participated in a comparable control session. The participants in the test group showed statistically significant (P < 0.001) decrease in glucose, HbA(1c), lipids, cortisol, ferritin, MDA and significant increase in catalase activity after yogic practice." The investigators concluded, "Yoga may improve risk profiles induced by stress in geriatric patients with type 2 diabetes and may have promise for the prevention or delay in diabetes complications. And at all stages of the disease a significant improvement can be achieved by yogic practice in geriatric diabetes." [Health-e-Iron note: this is another novel study on how an alternative form of exercise, yoga, provides significant improvement in markers of oxidative stress, insulin resistance/glucose metabolism and ferritin. In this 12-week study, ferritin reductions in the test populations averaged approximately 15% from their respective baseline measures. We recommend reviewing the authors' insightful interpretation of their results in the "Discussion" section of the full paper.]


High risk of cardiovascular disease in iron overload patients  (30)

In this 2011-reported study from Argentina, the researchers noted "Iron overload (IO) is defined as an increase in storage iron, regardless of the presence or absence of tissue damage". ...The investigators set out to"study insulin resistance markers, lipoprotein profile, activities of anti and prooxidant enzymes and cholesteryl ester transfer protein (CETP) in patients with IO." "Twenty male patients with IO were compared with 20 sex- and age-matched controls." ..." The results noted were, "IO patients showed higher levels of HOMA-IR and triglycerides [median (Q1-Q3)] [128 (93-193) vs. 79(51-91) mg dL(-1) , P < 0·0005] while lower high-density lipoprotein (HDL) cholesterol (mean ± SD) (41 ± 9 vs. 52 ± 10 mg dL(-1) , P < 0·0005) in comparison with controls. Moreover, the triglycerides/HDL-cholesterol [3·2 (2·0-5·1) vs. 1·5 (1·0-1·9), P < 0·0005] ratio and oxidized low-density lipoprotein levels [94 (64-103) vs. 68 (59-70) IU L(-1) , P < 0·05] were increased in the patient group.".."Associations between ferritin concentration and the alterations in lipid metabolism were also found. Multiple regression analyses identified HOMA-IR as independent predictor of CETP activity (B = 65·9, P < 0·0001, r(2) = 0·35), as well as ferritin concentration of Lp-PLA(2) activity (B = 3·7, P < 0·0001, r(2) = 0·40) after adjusting for confounding variables." The researchers concluded, "IO patients presented not only insulin resistance but also metabolic alterations that were related to elevated iron stores and are associated with high risk of cardiovascular disease."


Increased serum ferritin predicts the development of hypertension among middle-aged men (31)

In 2012 this research group from Korea "analyzed the association between ferritin/total iron-binding capacity (TIBC) and the subsequent development of hypertension. A total of 8,580 men who visited the Health Promotion Center for a medical checkup in 2005 were followed-up after 4 years" "Of the 8,580 men who were not hypertensive at baseline, 818 were found to be hypertensive at the 4-year follow-up. Compared with those who remained normotensive, these hypertensive subjects had higher levels of ferritin and TIBC at baseline, but had no significant difference in iron levels. After adjustment for age and body mass index (BMI), the odds ratios (OR) was substantially higher for new hypertension (OR 1.54, 95% confidence intervals (CIs) 1.26-1.88; P for trend <0.001) in subjects with the highest ferritin quartiles compared with those in the lowest quartiles. The association of serum ferritin levels with the incidence of hypertension was unchanged after adjustment for baseline blood pressure (BP). Adjustment for insulin resistance as measured by the homeostasis model assessment and the presence of a fatty liver reduced the magnitude of the OR for hypertension (first quartile reference, fourth quartiles OR 1.24, 95% CI 1.01-1.53, P for trend = 0.012), but did not affect their statistical significance." The researchers concluded, "Serum ferritin, but not iron level, was a significant predictor of hypertension in middle-aged Korean men. Fatty liver disease and insulin resistance may be mediators of this high ferritin-hypertension association." [Health-e-Iron note: the prehypertension condition noted here in the presence of elevated ferritin has been reported in a number of studies that suggest that elevated GGT is also a predictor of hypertension. For examples of this, see studies # 47 - 49 on our GGT-Heart page]


Relationship between iron metabolism, oxidative stress, and insulin resistance in patients with systemic lupus erythematosus (32)

The aim of this 2013-reported study undertaken in Brazil "was to assess oxidative stress and iron metabolism in systemic lupus erythematosus (SLE) patients with and without insulin resistance (IR). This study included 236 subjects (125 controls and 111 SLE patients). Patients with SLE were divided in two groups: with (n = 72) or without (n = 39) IR. SLE patients with IR showed higher advanced oxidation protein product (AOPP) levels (p = 0.030) and gamma-glutamyltransferase (GGT) levels (p = 0.001) and lower sulfhydryl groups of proteins (p = 0.0002) and total radical-trapping antioxidant parameter (TRAP) corrected by uric acid (UA) levels (p = 0.04) when compared to SLE patients without IR. However, SLE patients with IR presented lower serum 8-isoprostane (p = 0.05) and carbonyl protein levels (p = 0.04) when compared to SLE patients without IR. Serum ferritin levels were significantly higher in SLE patients (p = 0.0006) than in controls, and SLE patients with IR presented higher serum ferritin levels (p = 0.01) than SLE patients without IR. Patients with SLE showed that IR was inversely correlated to TRAP/UA (r = -0.2724, p = 0.0008) and serum ferritin was positively correlated to AOPP (r = 0.2870, p = 0.004). The researchers concluded, "This study found that oxidative stress was higher in the group of SLE patients with IR, and increased ferritin, whether caused by the inflammatory process per se or hyperinsulinaemia, can favour the redox process. In addition, the preset data reinforce the need to measure oxidative stress with several methodologies with different assumptions." [Health-e-Iron note: an alternate interpretation of these findings would suggest that elevated oxidative stress was more likely to have resulted from the availability of free iron in an environment of inadequate antioxidant protection (as suggested by both elevated ferritin and GGT and the patient group with IR and in the patient group as a whole compared to controls). Since lupus is considered an autoimmune disease, researchers sometimes overlook the traditional tissue and cell damage processes that occur in other, i.e., non-autoimmune diseases. A similar "awareness gap" appears to persist in the differential between osteoarthritis and rheumatoid arthritis.]



Elevated serum gamma-glutamyltransferase is a strong marker of insulin resistance in obese children (33) Free full text

This research from Korea was reported in 2013. "Elevated levels of serum gamma-glutamyltransferase (GGT) levels have been found to predict the development of type 2 diabetes in adults. The role of GGT in insulin resistance (IR) among children is largely unknown. We investigated whether GGT among hepatic enzymes is independently associated with IR in obese Korean children. A total of 1308 overweight (above the 85th BMI percentile of Korean reference) boys (n = 822) and girls (n = 486), aged 9-15 years, were studied. Measures acquired included weight, height, percent body fat (BF%), waist circumference, blood pressure, blood glucose and insulin, C-reactive protein, total cholesterol, triglycerides, HDL-Cholesterol, GGT, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). IR was calculated using the homeostasis model assessment (HOMA-IR). Serum GGT and ALT, but not AST, were positively correlated with HOMA-IR in boys (r = 0.222 for GGT; P < 0.05, r = 0.188 for ALT; P < 0.05) and girls (r = 0.292 for GGT; P < 0.05, r = 0.258 for ALT; P < 0.05). In multiple regression analysis for HOMA-IR as dependent variable, GGT (β = 0.068; P = 0.053 in boys, β = 0.145; P = 0.002 in girls) and ALT (β = 0.074; P = 0.034 in boys, β = 0.130; P = 0.005 in girls) emerged as determinants of HOMA-IR after adjusting age, BMI, tanner stage, and triglycerides. Serum GGT level is a strong marker of IR in obese Korean children.



New evidence for an association between liver enzymes and pancreatic islet β-cell dysfunction in young obese patients (34)

This 2013-reported study was undertaken in China to "explore the relationship between serum liver enzymes and both the glucose tolerance status and insulin secretion in young obese patients. A total of 734 young obese patients (BMI≥25kgm-2) and 231 lean healthy volunteers matched in age (BMI<23kgm-2) were enrolled in this cross-sectional observational study. The 734 obese patients were subdivided to three groups (OB-NGR, OB-IGR, and OB-DM) according to their glucose tolerance status. FSIVGTT was performed to assess the degree of insulin sensitivity (SI) and islet secretion function (AIRg). The disposition index (DI; product of SI and AIRg) was calculated as an integrated measurement of insulin secretion and insulin action after compensating for insulin resistance. One standard deviation increment in ALT and GGT increased the risk of β-cell dysfunction after controlling for potential confounders such as sex, age, BMI, waist-hip ratio, and blood pressure. Even after the adjustment of the serum lipid profile and L/S ratio, the odds ratio of ALT remained statistically significant (OR, 1.603; 95%CI, 1.225-2.096). Serum levels of liver enzymes showed an independent close relationship with insulin secretion capacity. Excluding the impact of a fatty liver, increased ALT and GGT levels indicated a significant association with the attenuation of pancreatic β-cell function. This study provides the possibility that elevated liver enzymes might be treated as simple biomarkers of early insulin secretion deficit in type 2 diabetes, especially in young obese patients."

 

Association analysis of serum γ-glutamyltransferase with risk of metabolic sydrome in Beijing healthy population  (35) Free full text (in Chinese)

This 2013-reported study was undertaken in Beijing. The objective of the study was to "study the association of γ-glutamyltransferase (GGT) with the development of the metabolic syndrome (MS)." "Subjects without MS at baseline in Beijing health-checkup database during 2003 and 2010, from MJ Health Management Centers, with complete key variables and at least two records were selected to derive a cohort, after comparison of the median trend, and analysis with Cox regression models and spline regression models, and to study the association of GGT with the development of MS and the dose-response relationship trend." "Out of 10 076 (46.20/1 000 person-years) in the cohort, 1 181 subjects developed MS after follow-up of 2.54 years on average. With adjustment for age, gender, cigarette smoking, alcohol intake, physical activity, body mass index, family history of cardiovascular disease, systolic blood pressure, white blood cell count, high-density lipoprotein cholesterol, fasting blood glucose, triglycerides and C-reacted protein in Cox regression model, the hazard ratio for MS in quartiles 4 level of GGT was 1.60 (95% confidence interval: 1.18-2.17). After adjustment with the use of spline regression model, the dose-response relationship showed an increasing curve with a degressive slope. The elevated GGT level was associated with an increased risk of MS, but the contribution of GGT augmented less when the GGT level was high." The researchers concluded, "The elevated GGT level, an important risk factor and predictor, may be associated with an increased risk of MS." [Health-e-Iron note: Figure 1 and Table 2 from this study are immediately below.  Further below is Table 2 from a similar population study undertaken in Beijing and Shanghai (study #35 on our IRON-Diabetes page). The fully adjusted model of the ferritin table demonstrates strikingly similar results when compared to the GGT study. As noted throughout this web site, the relationship between serum ferritin and GGT is highly interactive, meaning that the elevation of one will have greater predictive value when the other is elevated as well. Whereas the elevation of only one of the two is comparatively protective, but less so than the elevation of neither one]




 

Role of gamma-glutamyl transferase (GGT) in diagnosis of impaired glucose tolerance and metabolic syndrome: a prospective cohort research from the Kerman Coronary Artery Disease Risk Study (KERCADRS) (36)

This 2012-reported study was undertaken in Iran. The researchers noted "The important role of raised serum gamma-glutamyl transferase (GGT) for predicting diabetes mellitus and insulin resistance is clear; however relationship between increased level of GGT and impaired glucose tolerance (IGT) is now hypothesized. We aimed to show the importance of GGT measurement in diagnosis of IGT." "Two hundred persons were randomly selected from the Kerman Coronary Artery Disease Risk Study (KERCADRS), as a population-based study. All participants underwent GGT analysis test, besides measuring risk factors and components of metabolic syndrome (MS). "The increase in GGT was correlated with increased prevalence of IGT and MS and its different components. In multivariable analysis, a high GGT was positively associated with the presence of IGT after adjustment for age, sex and MS diagnostic criteria. The area under curve (AUC) for GGT was 0.722 for discriminating IGT from normal condition, and 0.847 for discriminating MS from normal status. In ROC curve analysis, the optimal cut-off value for GGT to discriminate IGT from normal condition was 20.5 IU with the sensitivity of 71.6% and the specificity of 66.1%. The best cutoff value for GGT to discriminate MS from normal condition was also 16.5 IU with the sensitivity and specificity of 78.4% and 78.4%, respectively." The researchers concluded, "The measuring GGT can be a sensitive method for early diagnosis and predicting IGT and MS from normal condition. Because this diagnostic test is a low-cost, highly sensitive, accurate and frequently used laboratory test, its measurement is recommended as a useful marker of both IGT and MS."

 

γ-Glutamyl transferase and high-molecular-weight adiponectin levels are synergistically associated with metabolic syndrome and insulin resistance in community-dwelling persons (37)

This is a 2012-reported study undertaken in Japan. The researchers noted "Metabolic syndrome is associated with an increased risk of major cardiovascular events. Decreased high-molecular-weight (HMW) adiponectin levels are associated with metabolic syndrome and its components. Changes in γ-glutamyl transferase (GGT) levels are also associated with metabolic syndrome and could be modulated by HMW adiponectin." "From a single community, we recruited 822 men (mean age, 61±14 years) and 1,097 women (63±12 years) during their annual health examination. We investigated whether increased GGT and decreased HMW adiponectin levels are synergistically associated with metabolic syndrome and insulin resistance as evaluated by homeostasis of model assessment of insulin resistance (HOMA-IR)." "Of these subjects, 141 men (17.2%) and 170 women (15.5%) had metabolic syndrome. In men, the odds ratios (ORs) [(95% confidence interval (CI)] for metabolic syndrome across tertiles of GGT and HMW adiponectin were 1.00, 2.31 (1.25-4.24) and 3.39 (1.75-6.55) and 1.00, 0.51 (0.32-0.82) and 0.30 (0.17-0.54), respectively. In women, the ORs (95% CI) for metabolic syndrome across tertiles of GGT and HMW adiponectin were 1.00, 1.39 (0.81-2.40) and 1.79 (1.06-3.01) and 1.00, 0.35 (0.22-0.55) and 0.27 (0.15-0.46), respectively. The ORs for insulin resistance were increased in relation to GGT only in women, and decreased significantly in relation to HMW adiponectin in both genders. The interaction between increased GGT and decreased HMW adiponectin was a significant and independent determinant for metabolic syndrome and insulin resistance." The researchers concluded, "These results suggested that higher GGT and lower HMW adiponectin levels are synergistically associated with metabolic syndrome and insulin resistance."

 

Association between γ-glutamyltransferase, adiponectin and arterial stiffness (38) Free full text

This 2012-reported study was undertaken in Korea. The investigators noted, "Serum γ-glutamyltransferase (GGT) is used as a marker of hepatic dysfunction. Recently, several studies reported that GGT is significantly associated with cardiovascular mortality and atherosclerosis. Adiponectin is known to play an important role in the development of atherosclerosis, but its physiologic role has yet to be fully determined. In this study, we investigated the relationships among serum GGT, adiponectin and arterial stiffness." "Of 4236 subjects recruited from 17 different medical centers in Seoul, Korea, 2846 subjects were enrolled in our study. The parameters of metabolic syndrome (MetS) were assessed in these subjects, and their plasma adiponectin levels and pulse wave velocity (PWV) were measured along with anthropometric and biochemical profiles, including GGT." "The subjects were stratified into 3 groups according to GGT values. PWV values gradually increased and the adiponectin level decreased with GGT tertiles. Aortic PWV showed a significant correlation with age, SBP, FPG, but there was no correlation among aortic PWV, GGT and adiponectin. Peripheral PWV demonstrated a significant correlation with age, SBP, DBP, BMI, WC, FPG and GGT, but there was no correlation between peripheral PWV and adiponectin. In multiple logistic regression analysis after adjusting for risk factors, GGT was a significant contributor to increased peripheral PWV. The investigators concluded, "These findings indicate that serum GGT is independently associated with increased arterial stiffness, but there was no correlation between adiponectin and arterial stiffness in both males and females." [Health-e-Iron note: The investigators stated further in the full text, "In our study, serum GGT levels were strongly associated with HOMA-IR, which is a marker of insulin resistance in both genders  (r= 0.15 in men, r+0.17 in women p<1.01)."


Roles of the hepcidin-ferroportin axis and iron in cancer (39)

This 2013-reported review is from China. "Hepcidin is a low-molecular-weight hepatic peptide that regulates iron homeostasis, and acts by causing the degradation of its receptor, the cellular iron exporter ferroportin. On the basis of the major role of the hepcidin-ferroportin axis in iron regulation, recently several studies have discussed its expression and influence on the development and prognosis of cancer. Iron plays a pivotal role in homeostasis. However, insights into the mechanisms of normal iron regulation have provided a new perspective on the basic mechanisms, biological rationale, and pathophysiologic implications of changes in iron metabolism in cancer. Besides being a crucial stimulus for cancer, iron dysfunction also causes cancer-related anemia. In this review, we discuss aspects of the hepcidin-ferroportin axis and iron regulation, as well as the inherent connections between them in cancer. We also attempt to consider the possibility in theory of novel targets for further individualized therapy. However, many molecular mechanisms and functions of these regulators remain unclear.

 

Gamma-glutamyltransferase, insulin resistance and cardiometabolic risk profile in a middle-aged African population (40)

This is a 2013-reported study from South Africa. The researchers noted, "Mechanisms linking liver functions with cardiometabolic risk may involve insulin resistance (IR) and non-alcoholic fatty liver disease. We assessed the associations of gamma-glutamyltransferase (GGT) levels with IR and metabolic syndrome (MetS) in an adult South African urban cohort." "1,198 participants aged >15 years (297 men) were drawn from the Bellville-South suburb (Cape Town). The homeostatic model assessment of insulin (HOMA-IR), β-cells function (HOMA-B%), fasting insulin resistance index (FIRI) and the quantitative insulin-sensitivity check index (QUICKI) were calculated, and MetS defined according to the Join Interim Statement 2009 criteria. Associations of GGT levels with covariates were assessed on a continuous scale and across sex-specific quarters of GGT, with adjustment for confounders via generalized linear and logistic regressions." "Indicators of IR (HOMA-IR, FIRI and fasting insulin) increased, whereas those for insulin sensitivity (Sib and QUICKI) diminished significantly linearly and across increasing GGT quarters. In multivariable-adjusted models, adjustment for sex, age, BMI, cigarette smoking and alcohol intake yielded the strongest, significant associations between GGT and all markers of IR/IS and glycemia excluding glucose insulin ratio. In a similar level of adjustments, with/without further adjustment for markers of IR/insulin sensitivity, the prevalence of MetS significantly increased across quarters of GGT." The researchers concluded, "GGT levels were independently associated with insulin sensitivity and MetS in this population. Unaccounted, chronic elevation of GGT may therefore be a cue to screen and monitor individuals for MetS and diabetes, and may warrant consideration as an indicator of high risk for the development of these metabolic disorders."