Ferritin and Transferrin Are Associated With Metabolic Syndrome Abnormalities

OBJECTIVE—The aim of this work was to study cross-sectional and longitudinal relations between iron stocks ( Ferritin ) and the iron transport protein ( transferrin ) with the metabolic syndrome and its abnormalities.

RESEARCH DESIGN AND METHODS—A total of 469 men and 278 premenopausal and 197 postmenopausal women from the French Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort, aged 30–65 years, were followed over 6 years.

RESULTS—Higher concentrations of both ferritin and transferrin were associated with the International Diabetes Federation (IDF) and the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Adult Treatment Panel III original and revised definitions of the metabolic syndrome at baseline: for the IDF definition of the metabolic syndrome , the standardized, age-adjusted odds ratios (95% CI) for log(ferritin) were 1.49 (1.14–1.94) for men, 2.10 (1.27–3.48) for premenopausal women , and 1.80 (1.21–2.68) for postmenopausal women; for transferrin they were, respectively, 1.94 (1.53–2.47), 2.22 (1.32–3.75), and 2.14 (1.47–3.10). After 6 years of follow-up, the change in the presence of the metabolic syndrome was associated with higher baseline values in all three groups: log(ferritin), 1.46 (1.13–1.89), 1.28 (0.85–1.94), and 1.62 (1.10–2.38); and transferrin, 1.41 (1.10–1.81), 1.63 (1.05–2.52), and 1.51 (1.02–2.22). Among syndrome components, hypertriglyceridemia at 6 years was the component most strongly associated with baseline ferritin and transferrin . 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.

CONCLUSIONS—This is the first prospective study associating ferritin and transferrin with the metabolic syndrome and its components. 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.

Diabetes Care 30:1795-1801, 2007
DOI: 10.2337/dc06-2312
Beverley Balkau , INSERM U780, Villejuif 94807, France

Bivariate mixture modeling of transferrin saturation

Bivariate mixture modeling was used to analyze joint population distributions of transferrin saturation (TS) and serum Ferritin concentration (SF) measured in the Hemochromatosis and Iron Overload Screening (HEIRS) Study.

Four components (C1, C2, C3, and C4) with successively age-adjusted increasing means for transferrin saturation and serum ferritin were identified in data from 26,832 African Americans, 12,620 Asians, 12,264 Hispanics, and 43,254 whites. The largest component, C2, had normal mean transferrin saturation Transferrin (21% to 26% for women, 29% to 30% for men) and Serum ferritin (43–82 μg/L for women, 165–242 μg/L for men), which consisted of component proportions greater than 0.59 for women and greater than 0.68 for men. C3 and C4 had progressively greater mean values for transferrin saturation and serum ferritin with progressively lesser component proportions.

C1 had mean Transferrin Saturation values less than 16% for women (<20% for men) and SF values less than 28 μg/L for women (<47 μg/L for men). Compared with C2, adjusted odds of iron deficiency were significantly greater in C1 (14.9–47.5 for women, 60.6–3530 for men), adjusted odds of liver disease were significantly greater in C3 and C4 for African-American women and all men, and adjusted odds of any HFE mutation were increased in C3 (1.4–1.8 for women, 1.2–1.9 for men) and in C4 for Hispanic and white women (1.5 and 5.2, respectively) and men (2.8 and 4.7, respectively). Joint mixture modeling identifies a component with lesser serum ferritin and transferrin saturation at risk for iron deficiency and 2 components with greater SF and TS at risk for liver disease or HFE mutations . This approach can identify populations in which hereditary or acquired factors influence metabolism measurement.

Abbreviations: EM, expectation-maximization; HFE, hemochromatosis gene on chromosome 6p; HEIRS, Hemochromatosis and Iron Overload Screening; SF, serum ferritin concentration; TS, transferrin saturation; wt, wild type

The HEIRS Study was initiated and funded by NHLBI in conjunction with NHGRI. Supported by contracts N01-HC-05185 ( University of Minnesota), N01-HC-05186 (Howard University ), N01-HC-05188 (University of Alabama at Birmingham), N01-HC-05189 (Kaiser Permanente Center for Health Research), N01-HC-05190 (University of California, Irvine), N01-HC-05191 (London Health Sciences Centre), and N01-HC-05192 (Wake Forest University). Also supported by Grant R01 HL083328-01A1 from the National Heart, Lung, and Blood Institute (to C.E.M.); Grant M01-RR00032 from the University of Alabama at Birmingham General Clinical Research Center (GCRC); the Southern Iron Disorders Center (to J.C.B.); Grant M01-RR10284 from Howard University GCRC; Howard University Research Scientist Award UH1-HL03679-05 from the National Heart, Lung, and Blood Institute and the Office of Research on Minority Health (to V.R.G.); and Grant UC Irvine M01RR 00827-29 from the General Clinical Research Centers Program of the National Center for Research Resources National Institutes of Health.

What is Human Transferrin

Human Transferrin is a plasma protein for iron ion delivery. Human Transferrin is a glycoprotein with homologous N-terminal and C-terminal iron binding domains. Transferrin(TF) is related to other iron binding proteins including lactoferrin . When human transferrin loaded with iron encounters a transferrin receptor on the surface of a cell, it binds to it and is consequently transported into the cell in a vesicle. The cell will acidify the vesicle, causing human transferrin(TF) to release its iron ions. Each human transferrin molecule has the ability to carry two iron ions in the ferric form (Fe3+). Commercially purified Human Apo Transferrin and human Holo Transferrin available from diagnostic raw material manufacturers such as Lee Biosolutions, Inc .

The Cytoplasmic Domain of Transferrin Receptor 2 Dictates Its Stability and Response to Holo-transferrin in Hep3B Cells

Transferrin receptor 2 (TfR2) is a homolog of transferrin receptor 1 (TfR1), the receptor responsible for the uptake of iron-loaded transferrin (holo-Tf) into cells.The half-life of the chimera increased 2.7-fold in cells exposed to Human Holo Transferrin holo-Tf like the endogenous TfR2 in HepG2 cells. Like TfR2 and unlike TfR1, the levels of the chimera did not respond to intracellular iron content. These results suggest that although holo-Tf binding to the ectodomain is necessary, the cytoplasmic domain of TfR2 is largely responsible for its stabilization by holo-Tf .