Dietary iron restriction or iron chelation protects from diabetes and loss of beta-cell function in the obese (ob/ob lep(-/-)) mouse
ABSTRACT 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.
- SourceAvailable 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). "
Article: Pathophysiology of the Belgrade rat[Show abstract] [Hide abstract]
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.Frontiers in Pharmacology 04/2014; 5:82. DOI:10.3389/fphar.2014.00082
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- "Lowering elevated serum ferritin levels with desferroxamine (DFO) in type 2 diabetic patients or animal diabetes models correlated with improvements in glycemia, insulin sensitivity and secretion, and triglyceride levels    . "
ABSTRACT: The past decade has provided exciting insights into a novel class of central (small) RNA molecules intimately involved in gene regulation. Only a small percentage of our DNA is translated into proteins by mRNA, yet 80% or more of the DNA is transcribed into RNA, and this RNA has been found to encompass various classes of novel regulatory RNAs, including, e.g., microRNAs. It is well known that DNA is constantly oxidized and repaired by complex genome maintenance mechanisms. Analogously, RNA also undergoes significant oxidation, and there are now convincing data suggesting that oxidation, and the consequent loss of integrity of RNA, is a mechanism for disease development. Oxidized RNA is found in a large variety of diseases, and interest has been especially devoted to degenerative brain diseases such as Alzheimer disease, in which up to 50-70% of specific mRNA molecules are reported oxidized, whereas other RNA molecules show virtually no oxidation. The iron-storage disease hemochromatosis exhibits the most prominent general increase in RNA oxidation ever observed. Oxidation of RNA primarily leads to strand breaks and to oxidative base modifications. Oxidized mRNA is recognized by the ribosomes, but the oxidation results in ribosomal stalling and dysfunction, followed by decreased levels of functional protein as well as the production of truncated proteins that do not undergo proper folding and may result in protein aggregation within the cell. Ribosomal dysfunction may also signal apoptosis by p53-independent pathways. There are very few reports on interventions that reduce RNA oxidation, one interesting observation being a reduction in RNA oxidation by ingestion of raw olive oil. High urinary excretion of 8-oxo-guanosine, a biomarker for RNA oxidation, is highly predictive of death in newly diagnosed type 2 diabetics; this demonstrates the clinical relevance of RNA oxidation. Taken collectively the available data suggest that RNA oxidation is a contributing factor in several diseases such as diabetes, hemochromatosis, heart failure, and β-cell destruction. The mechanism involves free iron and hydrogen peroxide from mitochondrial dysfunction that together lead to RNA oxidation that in turn gives rise to truncated proteins that may cause aggregation. Thus RNA oxidation may well be an important novel contributing mechanism for several diseases.Free Radical Biology and Medicine 01/2012; 52(8):1353-61. DOI:10.1016/j.freeradbiomed.2012.01.009 · 5.71 Impact Factor
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ABSTRACT: Stereotactic neurosurgery aims at placing therapeutic lesions or chronic stimulating electrodes at very precise locations within the brain. Microelectrode recording and macrostimulation are used in addition to anatomoradiological techniques to optimize targeting. Recently, the usefulness of electrophysiological procedures has been questioned. Based on more than 500 therapeutic stereotactic lesions in the last 10 years at the thalamic and subthalamic levels, we evaluate here retrospectively the utility of the two electrophysiological procedures. In two of the three stereotactic targets considered in this study, intraoperative electrophysiological confirmation is mandatory because of the target size with respect to interindividual anatomical variations and of the more or less close vicinity of eloquent structures.Neurophysiologie Clinique/Clinical Neurophysiology 09/2001; 31(4):230-8. DOI:10.1016/S0987-7053(01)00261-1 · 1.46 Impact Factor