Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The outer mitochondrial membrane protein mitoNEET was discovered as a binding target of pioglitazone, an insulin-sensitizing drug of the thiazolidinedione class used to treat type 2 diabetes (Colca, J. R., McDonald, W. G., Waldon, D. J., Leone, J. W., Lull, J. M., Bannow, C. A., Lund, E. T., and Mathews, W. R. (2004) Am. J. Physiol. 286, E252-E260). We have shown that mitoNEET is a member of a small family of proteins containing a 39-amino-acid CDGSH domain. Although the CDGSH domain is annotated as a zinc finger motif, mitoNEET was shown to contain iron (Wiley, S. E., Murphy, A. N., Ross, S. A., van der Geer, P., and Dixon, J. E. (2007) Proc. Natl. Acad. Sci. U. S. A. 104, 5318-5323). Optical and electron paramagnetic resonance spectroscopy showed that it contained a redox-active pH-labile Fe-S cluster. Mass spectrometry showed the loss of 2Fe and 2S upon cofactor extrusion. Spectroscopic studies of recombinant proteins showed that the 2Fe-2S cluster was coordinated by Cys-3 and His-1. The His ligand was shown to be involved in the observed pH lability of the cluster, indicating that loss of this ligand via protonation triggered release of the cluster. mitoNEET is the first identified 2Fe-2S-containing protein located in the outer mitochondrial membrane. Based on the biophysical data and domain fusion analysis, mitoNEET may function in Fe-S cluster shuttling and/or in redox reactions.
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PMID:The outer mitochondrial membrane protein mitoNEET contains a novel redox-active 2Fe-2S cluster. 1758 44

Iron-sulfur (Fe-S) proteins are key players in vital processes involving energy homeostasis and metabolism from the simplest to most complex organisms. We report a 1.5 A x-ray crystal structure of the first identified outer mitochondrial membrane Fe-S protein, mitoNEET. Two protomers intertwine to form a unique dimeric structure that constitutes a new fold to not only the approximately 650 reported Fe-S protein structures but also to all known proteins. We name this motif the NEET fold. The protomers form a two-domain structure: a beta-cap domain and a cluster-binding domain that coordinates two acid-labile 2Fe-2S clusters. Binding of pioglitazone, an insulin-sensitizing thiazolidinedione used in the treatment of type 2 diabetes, stabilizes the protein against 2Fe-2S cluster release. The biophysical properties of mitoNEET suggest that it may participate in a redox-sensitive signaling and/or in Fe-S cluster transfer.
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PMID:MitoNEET is a uniquely folded 2Fe 2S outer mitochondrial membrane protein stabilized by pioglitazone. 1776 40

Zygomycosis is a frequently lethal invasive infection in high-risk patients such as the immunocompromised [especially haematopoietic stem cell transplant (HSCT) recipients] and patients with type 2 diabetes mellitus. However, zygomycosis has also been reported in individuals without known risk factors. The causative fungi are members of the order Mucorales and individual species within this group require a high level of laboratory skill for their identification. These organisms are resistant to voriconazole and also to the echinocandins, and although zygomycosis is less commonly documented than invasive aspergillosis in leukaemic and HSCT patients, there are recent reports suggesting that it has increased in incidence since the introduction of voriconazole. Zygomycosis can present clinically as rhinocerebral, pulmonary or disseminated disease which progresses rapidly. The management of cases is based on early diagnosis, surgical debridement when possible and aggressive antifungal therapy. Based on clinical experience, but without the benefit of comparative studies, liposomal amphotericin B has become the therapeutic agent of choice. Posaconazole is a new orally administered triazole antifungal and the first member of this class to have comparable in vitro activity to amphotericin B against most zygomycetes. Studies of salvage therapy of zygomycosis with posaconazole have yielded promising results and there are additional case reports of successful outcomes using these and other antifungal drugs as combination therapy. Adjunctive approaches that are showing promise but with limited clinical experience are iron chelation and immunotherapy.
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PMID:Treatment of zygomycosis: current and new options. 1806 3

Antioxidative defence mechanisms of pancreatic beta-cells are particularly weak and can be overwhelmed by redox imbalance arising from overproduction of reactive oxygen and reactive nitrogen species. The consequences of this redox imbalance are lipid peroxidation, oxidation of proteins, DNA damage and interference of reactive species with signal transduction pathways, which contribute significantly to beta-cell dysfunction and death in Type 1 and Type 2 diabetes mellitus. Reactive oxygen species, superoxide radicals (O(2)(*-)), hydrogen peroxide (H(2)O(2)) and, in a final iron-catalysed reaction step, the most reactive and toxic hydroxyl radicals (OH(*)) are produced during both pro-inflammatory cytokine-mediated beta-cell attack in Type 1 diabetes and glucolipotoxicity-mediated beta-cell dysfunction in Type 2 diabetes. In combination with NO(*), which is toxic in itself, as well as through its reaction with the O(2)(*-) and subsequent formation of peroxynitrite, reactive species play a central role in beta-cell death during the deterioration of glucose tolerance in the development of diabetes.
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PMID:Oxidative stress: the vulnerable beta-cell. 1848 54

The role of micronutrients in the etiology of type 2 diabetes is not well established. Several lines of evidence suggest that iron play may a role in the pathogenesis of type 2 diabetes. Iron is a strong pro-oxidant and high body iron levels are associated with increased level of oxidative stress that may elevate the risk of type 2 diabetes. Several epidemiological studies have reported a positive association between high body iron stores, as measured by circulating ferritin level, and the risk of type 2 diabetes and of other insulin resistant states such as the metabolic syndrome, gestational diabetes and polycystic ovarian syndrome. In addition, increased dietary intake of iron, especially that of heme iron, is associated with risk of type 2 diabetes in apparently healthy populations. Results from studies that have evaluated the association between genetic mutations related to iron metabolism have been inconsistent. Further, several clinical trials have suggested that phlebotomy induced reduction in body iron levels may improve insulin sensitivity in humans. However, no interventional studies have yet directly evaluated the effect of reducing iron intake or body iron levels on the risk of developing type 2 diabetes. Such studies are required to prove the causal relationship between moderate iron overload and diabetes risk.
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PMID:The role of iron in type 2 diabetes in humans. 1850 Nov 98

Vegetarian and vegan diets offer significant benefits for diabetes management. In observational studies, individuals following vegetarian diets are about half as likely to develop diabetes, compared with non-vegetarians. In clinical trials in individuals with type 2 diabetes, low-fat vegan diets improve glycemic control to a greater extent than conventional diabetes diets. Although this effect is primarily attributable to greater weight loss, evidence also suggests that reduced intake of saturated fats and high-glycemic-index foods, increased intake of dietary fiber and vegetable protein, reduced intramyocellular lipid concentrations, and decreased iron stores mediate the influence of plant-based diets on glycemia. Vegetarian and vegan diets also improve plasma lipid concentrations and have been shown to reverse atherosclerosis progression. In clinical studies, the reported acceptability of vegetarian and vegan diets is comparable to other therapeutic regimens. The presently available literature indicates that vegetarian and vegan diets present potential advantages for the management of type 2 diabetes.
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PMID:Vegetarian and vegan diets in type 2 diabetes management. 1938 29

Non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C virus (HCV) infection are major causes of liver disease frequently described in outpatient patients with glucose abnormalities. Hyperferritinemia, which suggests that iron overload plays a decisive role in the pathophysiology of insulin resistance and hyperglycemia, is a common finding in both disorders. However, the role of the hepatic iron deposition differs from one to the other. In NAFLD, a moderate liver iron accumulation has been observed and molecular mechanisms, including the downregulation of the liver iron exporter ferroportin-1, have been described. Iron overload will enhance intrahepatic oxidative stress that promotes hepatic fibrosis, interfere with insulin signalling at various levels and may hamper hepatic insulin extraction. Therefore, liver fibrosis, hyperglycemia and hyperinsulinemia will lead to increased levels of insulin resistance and the development of glucose abnormalities. Furthermore, iron depletion by phlebotomy removes liver iron content and reduces serum glucose and insulin resistance in NAFLD patients. Therefore, it seems that iron overload participates in those glucose abnormalities associated with NAFLD. Concerning chronic HCV infection, it has been classically assumed that iron overload contributes to insulin resistance associated with virus infection. However, recent evidence argues against the presence of iron overload in these patients and points to inflammation associated with diabetes as the main contributor to the elevated ferritin levels. Therefore, glucose abnormalities, and specially type 2 diabetes, should be taken into account when evaluating serum ferritin levels in patients with HCV infection.
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PMID:Glucose abnormalities in non-alcoholic fatty liver disease and chronic hepatitis C virus infection: the role of iron overload. 1944 65

It is the position of the American Dietetic Association that appropriately planned vegetarian diets, including total vegetarian or vegan diets, are healthful, nutritionally adequate, and may provide health benefits in the prevention and treatment of certain diseases. Well-planned vegetarian diets are appropriate for individuals during all stages of the life cycle, including pregnancy, lactation, infancy, childhood, and adolescence, and for athletes. A vegetarian diet is defined as one that does not include meat (including fowl) or seafood, or products containing those foods. This article reviews the current data related to key nutrients for vegetarians including protein, n-3 fatty acids, iron, zinc, iodine, calcium, and vitamins D and B-12. A vegetarian diet can meet current recommendations for all of these nutrients. In some cases, supplements or fortified foods can provide useful amounts of important nutrients. An evidence- based review showed that vegetarian diets can be nutritionally adequate in pregnancy and result in positive maternal and infant health outcomes. The results of an evidence-based review showed that a vegetarian diet is associated with a lower risk of death from ischemic heart disease. Vegetarians also appear to have lower low-density lipoprotein cholesterol levels, lower blood pressure, and lower rates of hypertension and type 2 diabetes than nonvegetarians. Furthermore, vegetarians tend to have a lower body mass index and lower overall cancer rates. Features of a vegetarian diet that may reduce risk of chronic disease include lower intakes of saturated fat and cholesterol and higher intakes of fruits, vegetables, whole grains, nuts, soy products, fiber, and phytochemicals. The variability of dietary practices among vegetarians makes individual assessment of dietary adequacy essential. In addition to assessing dietary adequacy, food and nutrition professionals can also play key roles in educating vegetarians about sources of specific nutrients, food purchase and preparation, and dietary modifications to meet their needs.
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PMID:Position of the American Dietetic Association: vegetarian diets. 1956 64

Histone H3 lysine 9 (H3K9) methylation is a crucial epigenetic mark of heterochromatin formation and transcriptional silencing. Recent studies demonstrated that most covalent histone lysine modifications are reversible and the jumonji C (JmjC)-domain-containing proteins have been shown to possess such demethylase activities. However, there is little information available on the biological roles of histone lysine demethylation in intact animal model systems. JHDM2A (JmjC-domain-containing histone demethylase 2A, also known as JMJD1A) catalyses removal of H3K9 mono- and dimethylation through iron and alpha-ketoglutarate dependent oxidative reactions. Here, we demonstrate that JHDM2a also regulates metabolic genes related to energy homeostasis including anti-adipogenesis, regulation of fat storage, glucose transport and type 2 diabetes. Mice deficient in JHDM2a (JHDM2a-/-) develop adult onset obesity, hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hyperleptinemia, which are hallmarks of metabolic syndrome. JHDM2a-/- mice furthermore exhibit fasted induced hypothermia indicating reduced energy expenditure and also have a higher respiratory quotient indicating less fat utilization for energy production. These observations may explain the obesity phenotype in these mice. Thus, H3K9 demethylase JHDM2a is a crucial regulator of genes involved in energy expenditure and fat storage, which suggests it is a previously unrecognized key regulator of obesity and metabolic syndrome.
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PMID:Obesity and metabolic syndrome in histone demethylase JHDM2a-deficient mice. 1962 51

Diabetes Mellitus is a major endocrinopathy, which occurs due transfusional haemosiderosis and is found in 20-30% of adult patients with beta-thalassaemia worldwide, accounting for significant morbidity. It is multifactorial with iron loading being the dominant cause and its management poses a clinical challenge. Diabetes in thalassaemia patients is distinct from type 2 diabetes. It is peculiar in many aspects including its pathophysiology and occurs due to insulin resistance as well as islet cell insufficiency. This article reviews the natural history of diabetes in this presentation with emphasis on prevention monitoring and management. Use of MRI techniques may be useful for future monitoring as well as biochemical monitoring to prevent complications of diabetes. Early intervention with intensified chelation may reverse pancreatic function and structural changes as evident from MRI.
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PMID:New concept in natural history and management of diabetes mellitus in thalassemia major. 2000 15


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