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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper is a review of three topics related to bio-trace metals. First, the transfer of metals into tissues of patients with chronic diseases treated with hemodialysis is examined. Such diseases include chronic hepatitis, diabetes, and chronic renal failure. In these diseases, metal contents from fingernails were flexible but non-specific. Toxicity may appear as the amount of heavy metals in tissues of patients with chronic renal failure treated with hemodialysis. For example, cadmium and lead were not excreted from the blood of patients during the hemodialysis treatment, and, therefore, their amounts gradually increased in the blood of patients. The level of zinc increased and was excreted in the urine of diabetic patients and experimental animals. Calcium accumulated in the kidney of streptozotocin (STZ)-induced diabetic rats that were fed low zinc diets; and, as a result, severe renal failure occurred. From these results, complication syndromes of either metal deficiency or excesses may occur in tissues of patients with chronic diseases. Second, the role of metallothionein (MT), an inducible protein, and the properties of MT isoforms have been studied on experimental animals. In the exocrine cells of the pancreas, MT was induced by various stresses such as zinc, STZ, alloxan and 4-aminopyrazolo-(3,4-d) pyrimidine, but the effects of those stresses were not clear in the endocrine cells. Therefore, MT may have a role in the exocrine cells of the pancreas. In addition, we were able to separate completely MT-1 and MT-2 isoforms in cytosol fractions of tissues using a capillary zone electrophoresis system at neutral pH without any detergents. Each role of the MT isoforms in the tissues soon started to become clear. Third, cisplatin, a platinum-containing anti-tumor drug, did not penetrate into the brain tissue under physiological conditions, as there is a blood-brain barrier to cerebral tissues; however, it did penetrate with either short-term hypoxia or in the case of lipopolysaccharide-treated experimental animals. Nitric oxide, prostaglandin, and free radicals are related to the penetration. Older rats had a higher sensitivity to cisplatin than younger rats.
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PMID:[Studies of metals and metallothionein in tissue]. 1072 70

The zinc content in the pancreatic beta cell is among the highest of the body, but information about which proteins might handle zinc in the beta cell is unknown. In the present work RT-PCR was used to obtain clues about the developmental expression of genes encoding metal complexing proteins in the pancreatic islets of the normal Sprague-Dawley rat and the BB diabetes resistant (BBDR) rat. The BBDR rat possesses beta cells genetically identical to the BB diabetes prone (BBDP) rat which exhibits an autoimmune diabetes quite similar to type 1 diabetes in humans, but in contrast to the BBDP rat, the islets of the BBDR rat are amenable to study because they are not destroyed by immune attack. There was no difference in the expression of any of the genes studied between the two strains of rats. mRNAs encoding zinc transport proteins ZnT-1 and ZnT-4, as well as calreticulin, ferritin heavy and light chains, metallothionein 1, metallothionein 3, Nramp1, Nramp2, transferrin, and the transferrin receptor were readily detected in pancreatic islets of 10-day-old, 5-week-old, and adult (60 to 90-day-old) rats. In contrast to the islet, mRNAs encoding metallothionein 3, Nramp1, Nramp2, ZnT-2, ZnT-3, and ZnT-4 and transferrin were not detected in the whole pancreas of adult Sprague-Dawley rats. In the whole pancreas of 3-day-old rats, ZnT-1 was the only zinc transporter mRNA detected and its level was moderate. Moderate to high levels of mRNA encoding calreticulin and the light and heavy chains of ferritin, as well as transferrin and the transferrin receptor, were detected in whole pancreas at 3 days. ZnT-2 and ZnT-3 mRNAs were present in low to moderate levels in pancreatic islets of 10-day and 5-week-old rats, but were absent in 3-day-old pancreas and islets of adult animals. These results indicate that expression of these proteins is developmentally regulated in the islet. In both Sprague-Dawley and BB rats, high levels of mRNAs encoding known beta cell proteins as controls (cytochrome b558, quinone reductase, the tricarboxylic acid transport protein and the receptors for IGF-1 and IGF-2 and insulin) were present in islets from 10 days to adulthood. Levels of mRNAs encoding quinone reductase, the tricarboxylic acid transport protein cytochrome b558 and the receptors for IGF-2 and insulin, were low or absent in 3-day-old and adult pancreas. BB rats were studied in an attempt to discern a difference between normal rats and the BB strain of rats, because, perhaps, delayed expression of a beta cell protein results in failure of immune tolerance against the beta cell. According to this paradigm none of the proteins examined in the current study appear to be a candidate for initiating an immune response in the BB rat.
Diabetes Res Clin Pract 2000 Aug
PMID:Survey of mRNAs encoding zinc transporters and other metal complexing proteins in pancreatic islets of rats from birth to adulthood: similar patterns in the Sprague-Dawley and Wistar BB strains. 1096 17

Vascular endothelial cells are constantly exposed to oxidative stress and must be protected by physiological responses. In diabetes mellitus, endothelial cell permeability is impaired and may be increased by high extracellular glucose concentrations. It has been postulated that metallothionein (MT) can protect endothelial cells from oxidative stress with its increased expression by cytokines, thrombin, and endothelin (ET)-1. In this study, we demonstrate that high glucose concentration can induce MT expression in endothelial cells through a distinct ET-dependent pathway. Exposure of human umbilical vein endothelial cells (HUVEC) to increasing concentrations of glucose resulted in a rapid dose-dependent increase in MT-2 and ET-1 mRNA expression. MT expression may be further augmented with addition of ET-1. Preincubation of the cells with the specific ET(B) antagonist BQ-788 blocked MT-2 mRNA expression more effectively than the ET(A) inhibitor TBC-11251. High glucose also increased immunoreactive MT protein expression and induced translocation of MT into the perinuclear area. Perinuclear localization of MT was related to high-glucose-induced reorganization of F-actin filaments. These results demonstrate that an increase in extracellular glucose in HUVEC can lead to a rapid dose-dependent increase in MT-2 mRNA expression and to perinuclear localization of MT protein with changes to the cytoskeleton. These effects are mediated via the ET receptor-dependent pathway.
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PMID:High-glucose-induced metallothionein expression in endothelial cells: an endothelin-mediated mechanism. 1150 67

The traditional role attributed to white adipose tissue is energy storage, fatty acids being released when fuel is required. The metabolic role of white fat is, however, complex. For example, the tissue is needed for normal glucose homeostasis and a role in inflammatory processes has been proposed. A radical change in perspective followed the discovery of leptin; this critical hormone in energy balance is produced principally by white fat, giving the tissue an endocrine function. Leptin is one of a number of proteins secreted from white adipocytes, which include angiotensinogen, adipsin, acylation-stimulating protein, adiponectin, retinol-binding protein, tumour neorosis factor a, interleukin 6, plasminogen activator inhibitor-1 and tissue factor. Some of these proteins are inflammatory cytokines, some play a role in lipid metabolism, while others are involved in vascular haemostasis or the complement system. The effects of specific proteins maybe autocrine or paracrine, or the site of action maybe distant from adipose tissue. The most recently described adipocyte secretory proteins are fasting-induced adipose factor, a fibrinogen-angiopoietin-related protein, metallothionein and resistin. Resistin is an adipose tissue-specific factor which is reported to induce insulin resistance, linking diabetes to obesity. Metallothionein is a metal-binding and stress-response protein which may have an antioxidant role. The key challenges in establishing the secretory functions of white fat are to identify the complement of secreted proteins, to establish the role of each secreted protein, and to assess the pathophysiological consequences of changes in adipocyte protein production with alterations in adiposity (obesity, fasting, cachexia). There is already considerable evidence of links between increased production of some adipocyte factors and the metabolic and cardiovascular complications of obesity. In essence, white adipose tissue is a major secretory and endocrine organ involved in a range of functions beyond simple fat storage.
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PMID:Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. 1168 7

Many diabetic patients suffer from cardiomyopathy, even in the absence of vascular disease. This diabetic cardiomyopathy predisposes patients to heart failure and mortality from myocardial infarction. Evidence from animal models suggests that reactive oxygen species play an important role in the development of diabetic cardiomyopathy. Our laboratory previously developed a transgenic mouse model with targeted overexpression of the antioxidant protein metallothionein (MT) in the heart. In this study we used MT-transgenic mice to test whether an antioxidant protein can reduce cardiomyopathy in the OVE26 transgenic model of diabetes. OVE26 diabetic mice exhibited cardiomyopathy characterized by significantly altered mRNA expression, clear morphological abnormalities, and reduced contractility under ischemic conditions. Diabetic hearts appeared to be under oxidative stress because they had significantly elevated oxidized glutathione (GSSG). Diabetic mice with elevated cardiac MT (called OVE26MT mice) were obtained by crossing OVE26 transgenic mice with MT transgenic mice. Hyperglycemia in OVE26MT mice was indistinguishable from hyperglycemia in OVE26 mice. Despite this, the MT transgene significantly reduced cardiomyopathy in diabetic mice: OVE26MT hearts showed more normal levels of mRNA and GSSG. Typically, OVE26MT hearts were found to be morphologically normal, and elevated MT improved the impaired ischemic contractility seen in diabetic hearts. These results demonstrate that cardiomyocyte-specific expression of an antioxidant protein reduces damage to the diabetic heart.
Diabetes 2002 Jan
PMID:Overexpression of metallothionein reduces diabetic cardiomyopathy. 1175 38

Type I diabetes is considered a multifactorial autoimmune process initiated by an environmental factor. There is evidence that reactive oxygen species are involved in destructing insulin-producing beta-cells. In mice, reactive oxygen species and nitric monoxide contribute to beta-cell damage in the non-obese diabetic strain developing spontaneously diabetes and in diabetes induced with multiple low doses of streptozotocin. Previously, we found that zinc sulfate induced metallothionein in pancreatic islets, protected beta-cells against streptozotocin toxicity in vitro, and prevented diabetes induced with multiple low doses of streptozotocin. Since metallothionein is known to scavenge hydroxyl radicals in cell-free systems, we hypothesize that the protective effect of zinc sulfate results from metallothionein induction scavenging hydroxyl radicals generated by multiple low doses of streptozotocin. Therefore, we studied whether levels of hydroxyl radicals are increased by streptozotocin in isolated islets in vitro. Here, we demonstrate basal and streptozotocin-stimulated hydroxyl radicals by electron spin resonance spectroscopy in combination with hydroxyl radical-specific spin trapping in islet homogenates. Furthermore, in islet cultures, streptozotocin augmented generation of reactive oxygen species as determined by fluorescence. Of the group of reactive oxygen species, the streptozotocin-augmented generation of hydrogen peroxide was also specifically determined. We conclude that streptozotocin-mediated hydroxyl radicals and generation of reactive oxygen species may be crucial effectors in beta-cell damage.
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PMID:Generation of hydroxyl radicals mediated by streptozotocin in pancreatic islets of mice in vitro. 1240 53

In the present study, the role of endothelin-1 (ET-1) on alterations of hepatic and renal metallothionein (MT) and trace metals (Zn, Cu, and Fe) were investigated in streptozotocin (STZ)-induced diabetic rats. Diabetic rats, age- and sex-matched controls, as well as control and diabetic animals on a dual ETA/ETB receptor blocker, bosentan, were investigated after 6 months of follow-up. MT was measured by cadmium-heme assay. Metals were measured by atomic absorption spectrometer. ET-1 mRNA was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) technique. Hepatic and renal ET-1 mRNA was increased in diabetic rats as compared to control rats, along with an increase in both hepatic and renal MT proteins. The increased hepatic MT protein level was associated with decreases in hepatic Cu and Fe, whereas increased renal MT was associated with increases in renal Cu and Fe accumulation. Zn levels were unaltered in both organs in diabetic rats. Bosentan treatment partially prevented the increase in MT levels in both liver and kidney, along with reduced serum creatinine and increased urinary creatinine levels. Further bosentan treatment corrected the increased Cu and Fe levels in the kidney in diabetic rats, but reduced hepatic Cu and Fe levels. No significant effects of bosentan treatment on nondiabetic rats were observed. The data suggest that the possible effects of ET antagonism in diabetes may be mediated via changes in MT and trace metals.
Int J Exp Diabetes Res
PMID:Endothelin-1-mediated alteration of metallothionein and trace metals in the liver and kidneys of chronically diabetic rats. 1245 61

Many individuals with diabetes experience impaired cardiac contractility that cannot be explained by hypertension and atherosclerosis. This cardiomyopathy may be due to either organ-based damage, such as fibrosis, or to direct damage to cardiomyocytes. Reactive oxygen species (ROS) have been proposed to contribute to such damage. To address these hypotheses, we examined contractility, Ca(2+) handling, and ROS levels in individual cardiomyocytes isolated from control hearts, diabetic OVE26 hearts, and diabetic hearts overexpressing antioxidant protein metallothionein (MT). Our data showed that diabetic myocytes exhibited significantly reduced peak shortening, prolonged duration of shortening/relengthening, and decreased maximal velocities of shortening/relengthening as well as slowed intracellular Ca(2+) decay compared with control myocytes. Overexpressing MT prevented these defects induced by diabetes. In addition, high glucose and angiotensin II promoted significantly increased generation of ROS in diabetic cardiomyocytes. Chronic overexpression of MT or acute in vitro treatment with the flavoprotein inhibitor diphenyleneiodonium or the angiotensin II type I receptor antagonist losartan eliminated excess ROS production in diabetic cardiomyocytes. These data show that diabetes induces damage at the level of individual myocyte. Damage can be attributed to ROS production, and diabetes increases ROS production via angiotensin II and flavoprotein enzyme-dependent pathways.
Diabetes 2003 Mar
PMID:Metallothionein prevents diabetes-induced deficits in cardiomyocytes by inhibiting reactive oxygen species production. 1260 20

Exposure to toxic metals has become an increasingly recognized source of illness worldwide. Both cadmium and arsenic are ubiquitous in the environment, and exposure through food and water as well as occupational sources can contribute to a well-defined spectrum of disease. The symptom picture of arsenic toxicity is characterized by dermal lesions, anemia, and an increased risk for cardiovascular disease, diabetes, and liver damage. Cadmium has a significant effect on renal function, and as a result alters bone metabolism, leading to osteoporosis and osteomalacia. Cadmium-induced genotoxicity also increases risk for several cancers. The mechanisms of arsenic- and cadmium-induced damage include the production of free radicals that alter mitochondrial activity and genetic information. The metabolism and excretion of these heavy metals depend on the presence of antioxidants and thiols that aid arsenic methylation and both arsenic and cadmium metallothionein-binding. S-adenosylmethionine, lipoic acid, glutathione, selenium, zinc, N-acetylcysteine (NAC), methionine, cysteine, alpha-tocopherol, and ascorbic acid have specific roles in the mitigation of heavy metal toxicity. Several antioxidants including NAC, zinc, methionine, and cysteine, when used in conjunction with standard chelating agents, can improve the mobilization and excretion of arsenic and cadmium.
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PMID:Toxic metals and antioxidants: Part II. The role of antioxidants in arsenic and cadmium toxicity. 1277 58

Islet transplantation is a promising therapy for Type 1 diabetes, but many attempts have failed due to early graft hypoxia or immune rejection, which generate reactive oxygen species (ROS). In the current study, we determined that transgenic overexpression of the antioxidant metallothionein (MT) in pancreatic beta cells provided broad resistance to oxidative stress by scavenging most kinds of ROS including H2O2, peroxynitrite radical released from streptozotocin, 3-morpholinosydnonimine (SIN-1), and superoxide radical produced by xanthine/xanthine oxidase. MT also reduced nitric oxide-induced beta cell death. A direct test of hypoxia/reperfusion sensitivity was made by exposing FVB and MT islets to hypoxia (1% O2). MT markedly reduced ROS production and improved islet cell survival. Because MT protected beta cells from a broad spectrum of ROS and from hypoxia, we considered it to be an ideal candidate for improving islet transplantation. We first tested syngeneic transplantation by implanting islets under the kidney capsule of the same strain, FVB mice, thereby eliminating the immune rejection component. Under these conditions, MT islets maintained much greater insulin content than control islets. Allotransplantation was then tested. MT transgenic and normal FVB islets were implanted under the kidney capsule of BALB/c mice that were previously treated with streptozotocin to induce diabetes. We found that MT islets extended the duration of euglycemia 2-fold longer than nontransgenic islets. The benefit of MT was due to protection from ROS since nitrotyrosine staining, an indicator of free radical damage, was much lower in MT grafts than in FVB grafts. The time course of protection suggested that the major mode of MT action may have been protection from hypoxia or hypoxia/reperfusion. These data demonstrate that treatment with a broad spectrum antioxidant protects islets from ROS damage such as that produced during the early phase of islet transplantation.
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PMID:Metallothionein protects islets from hypoxia and extends islet graft survival by scavenging most kinds of reactive oxygen species. 1457 62


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