Dietary iron restriction or iron chelation protects from diabetes and loss of -cell function in the obese (ob/ob lep-/-) mouse
Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. AJP Endocrinology and Metabolism
(Impact Factor: 3.79).
03/2010; 298(6):E1236-43. DOI: 10.1152/ajpendo.00022.2010
Iron overload can cause insulin deficiency, but in some cases this may be insufficient to result in diabetes. We hypothesized that the protective effects of decreased iron would be more significant with increased beta-cell demand and stress. Therefore, we treated the ob/ob mouse model of type 2 diabetes with an iron-restricted diet (35 mg/kg iron) or with an oral iron chelator. Control mice were fed normal chow containing 500 mg/kg iron. Neither treatment resulted in iron deficiency or anemia. The low-iron diet significantly ameliorated diabetes in the mice. The effect was long lasting and reversible. Ob/ob mice on the low-iron diet exhibited significant increases in insulin sensitivity and beta-cell function, consistent with the phenotype in mouse models of hereditary iron overload. The effects were not accounted for by changes in weight or feeding behavior. Treatment with iron chelation had a more dramatic effect, allowing the ob/ob mice to maintain normal glucose tolerance for at least 10.5 wk despite no effect on weight. Although dietary iron restriction preserved beta-cell function in ob/ob mice fed a high-fat diet, the effects on overall glucose levels were less apparent due to a loss of the beneficial effects of iron on insulin sensitivity. Beneficial effects of iron restriction were minimal in wild-type mice on normal chow but were apparent in mice on high-fat diets. We conclude that, even at "normal" levels, iron exerts detrimental effects on beta-cell function that are reversible with dietary restriction or pharmacotherapy.
Available from: Gemma Flores-Mateo
- "Moreover, the use of iron chelation therapy to reduce serum ferritin levels was associated with improved serum glucose or HDL levels . Houschyar et al. studied the effects of phlebotomy and the control of body iron in patients with metabolic syndrome in a randomized, controlled, single-blind clinical trial. "
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Elevated ferritin levels have been associated with single cardiovascular risk factors but the relationship to the presence of metabolic syndrome is inconclusive.The aim of this systematic review and meta-analysis of published observational studies was to estimate the association between serum ferritin levels and metabolic syndrome in adults.
The Pubmed, SCOPUS and the Cochrane Library databases were searched for epidemiological studies that assessed the association between ferritin levels and metabolic syndrome and were published before September 2013. There were no language restrictions. Two investigators independently selected eligible studies. Measures of association were pooled by using an inverse-variance weighted random-effects model. The heterogeneity among studies was examined using the I2 index. Publication bias was evaluated using the funnel plot.
Twelve cross-sectional, one case-control and two prospective studies met our inclusion criteria including data from a total of 56,053 participants. The pooled odds ratio (OR) for the metabolic syndrome comparing the highest and lowest category of ferritin levels was 1.73 (95% CI: 1.54, 1.95; I2 = 75,4%). Subgroup analyses indicate that pooled OR was 1.92 (95% CI: 1.61, 2.30; I2 = 78%) for studies adjusting for C-reactive protein (CRP), and 1.52 (95% CI:1. 36, 1.69; I2 = 41%) for studies that did not adjust for CRP (P = 0.044). This finding was remarkably robust in the sensitivity analysis. We did not find publication bias.
The meta-analysis suggests that increased ferritin levels are independently and positively associated with the presence of the metabolic syndrome with an odds ratio higher than 1.73.
Available from: Tania Veuthey
- "Although the molecular basis for iron-mediated regulation of LPL activity is not clear, oxidative modification of the enzyme, its substrate, and/or reaction products could interfere with lipolysis (Kim et al., 2013). Clinically, reduction of iron loading in patients by phlebotomy (Casanova- Esteban et al., 2011), chelation (Cutler, 1989) and diet (Cooksey et al., 2010) can help to improve lipid disorders. We also found that reducing serum iron in Belgrade rats by treatment with the uptake inhibitor ferristatin II improved their TG levels, suggesting pharmacological interventions could be helpful (Kim et al., 2013). "
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ABSTRACT: The Belgrade rat is an animal model of divalent metal transporter 1 (DMT1) deficiency. This strain originates from an X-irradiation experiment first reported in 1966. Since then, the Belgrade rat's pathophysiology has helped to reveal the importance of iron balance and the role of DMT1. This review discusses our current understanding of iron transport homeostasis and summarizes molecular details of DMT1 function. We describe how studies of the Belgrade rat have revealed key roles for DMT1 in iron distribution to red blood cells as well as duodenal iron absorption. The Belgrade rat's pathology has extended our knowledge of hepatic iron handling, pulmonary and olfactory iron transport as well as brain iron uptake and renal iron handling. For example, relationships between iron and manganese metabolism have been discerned since both are essential metals transported by DMT1. Pathophysiologic features of the Belgrade rat provide us with a unique and interesting animal model to understand iron homeostasis.
Available from: Wei Bao
- "Previous studies have shown that parenterally administered iron is able to induce diabetes in animals . Moreover, dietary iron restriction or iron chelation has been shown to protect against developing diabetes or to attenuate the pathologic changes in diabetic models [5,6]. "
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Excess iron has been shown to induce diabetes in animal models. However, the results from human epidemiologic studies linking body iron stores and iron intake to the risk of type 2 diabetes mellitus (T2DM) are conflicting. In this study, we aimed to systematically evaluate the available evidence for associations between iron intake, body iron stores, and the risk of T2DM.
A systematic search of the PubMed/MEDLINE and EMBASE databases to the end of 22 April 2012 was performed, and reference lists of retrieved articles were screened. Two reviewers independently evaluated the eligibility of inclusion and extracted the data. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models.
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.
Higher heme iron intake and increased body iron stores were significantly associated with a greater risk of T2DM. Dietary total iron, non-heme iron, or supplemental iron intakes were not significantly associated with T2DM risk.
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