metallothionein and Diabetes-Mellitus--Type-1

Zn is an essential trace element, involved in many different cellular processes. A relationship between Zn, pancreatic function and diabetes was suggested almost 70 years ago. To emphasise the importance of Zn in biology, the history of Zn research in the field of diabetes along with a general description of Zn transporter families will be reviewed. The paper will then focus on the effects of Zn on pancreatic β-cell function, including insulin synthesis and secretion, Zn signalling in the pancreatic islet, the redox functions of Zn and its target genes. The recent association of two 'Zn genes', i.e. metallothionein (MT) and Zn transporter 8 (SLC 30A8), with type 2 diabetes at the genetic level and with insulin secretion in clinical studies offers a potential new way to identify new drug targets to modulate Zn homeostasis directly in β-cells. The action of Zn for insulin action in its target organs, as Zn signalling in other pancreatic islet cells, will be addressed. Therapeutic Zn-insulin preparations and the influence of Zn and Zn transporters in type 1 diabetes will also be discussed. An extensive review of the literature on the clinical studies using Zn supplementation in the prevention and treatment of both types of diabetes, including complications of the disease, will evaluate the overall beneficial effects of Zn supplementation on blood glucose control, suggesting that Zn might be a candidate ion for diabetes prevention and therapy. Clearly, the story of the links between Zn, pancreatic islet cells and diabetes is only now unfolding, and we are presently only at the first chapter.

Topics: Carrier Proteins; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dietary Supplements; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Metallothionein; Signal Transduction; Zinc

Molecular and cellular studies have demonstrated several roles for zinc (Zn) in insulin production and the consequent actions of insulin on metabolism. Clinical and epidemiological studies suggest that reduced Zn status is associated with diabetes. Investigations of Zn in rodent models of diabetes have provided a valuable link for understanding the molecular, cellular, clinical and epidemiological observations in the context of inter-organ metabolism and the metabolic disturbances of diabetes. This review highlights some of the current knowledge and future research directions for the role of Zn in the pancreas and diabetes based on rodent studies and experimental manipulations of Zn. Overall, Zn supplementation is effective for preventing or ameliorating diabetes in several rodent models of Type 1 and Type 2 diabetes. Studies with chemically-induced Type 1 diabetes indicate that the protective effects of Zn involve antioxidant mechanisms whether it is Zn alone (as an antioxidant), Zn induction of metallothionein or Zn inhibition of redox-sensitive transcription factors. Further studies are needed to identify the mechanism(s) for Zn protection in Type 2 diabetes, including pancreatic and peripheral effects. Experimental manipulations of Zn status in rodent models of diabetes provide a valuable approach to explore mechanisms for the protective effects of Zn; however, long term clinical studies establishing safety (lack of toxicity) and efficacy are required before any recommendations can be made for people with diabetes.

Topics: Animals; Antioxidants; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Insulin; Insulin-Secreting Cells; Metallothionein; Pancreas; Rats; Streptozocin; Zinc

Disturbances of zinc homeostasis have been observed in several diseases, including diabetes mellitus. To further characterize the association between zinc and diabetes, we recruited 75 patients with type 1 or type 2 diabetes and 75 nondiabetic sex-/age-matched control subjects in order to analyze differences concerning human zinc transporter 8 (hZnT-8) expression, single nucleotide polymorphisms (SNPs) in the genes of hZnT-8 as well as metallothionein 1A and serum/intracellular zinc. Furthermore, we investigated the relation between insulin and zinc homeostasis in type 2 diabetic subjects and consolidated our results by in vitro analysis of the effect of insulin on cellular zinc status and by analysis of the modulation of insulin signal transduction by intracellular zinc homeostasis. Concerning the expression of hZnT-8 and the SNPs analyzed, we did not observe any differences between diabetic and control subjects. Serum zinc was significantly lower in diabetic patients compared to controls, and intracellular zinc showed the same tendency. Interestingly, type 2 diabetes patients treated with insulin displayed lower serum zinc compared to those not injecting insulin. In vitro analyses showed that insulin leads to an increase in intracellular zinc and that insulin signaling was enhanced by elevated intracellular zinc concentrations. In conclusion, we show that type 1 and type 2 diabetic patients suffer from zinc deficiency, and our results indicate that zinc supplementation may qualify as a potential treatment adjunct in type 2 diabetes by promoting insulin signaling, especially in zinc-deficient subjects.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Cation Transport Proteins; Cells, Cultured; Culture Media; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Gene Expression Regulation; Homeostasis; Humans; Insulin; Leukocytes; Lymphocytes; Male; Metallothionein; Middle Aged; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins c-akt; Signal Transduction; Young Adult; Zinc; Zinc Transporter 8

Background The aim of this study was to investigate the effects of selenium, zinc, insulin, and metallothionein on oxidative damage and metallothionein (MT) gene expression levels in streptozotocin (STZ)-induced type 1 diabetic rats exposed to Cd. Methods Rats were categorized under eight groups (control, STZ, Cd, STZ + Cd, Group 5, Group 6, Group 7, and STZ + Cd + MT [n:8/group]) were used. After diabetes was induced by STZ (55 mg/kg, i.p.), Cd was administered (1 mg/kg CdCl, orally) for 4 weeks. In cadmium-treated groups selenium (Na2SeO3 1.5 mg/kg, i.p.), zinc (ZnSO4 10 mg/kg via oral gavage), insulin (insulin glargine, 2U/day, s.c.), and MT (1mg/kg, every other 10 days, s.c.) were administered. MT gene expression levels, MDA levels, GPx, SOD, and CAT activity levels were determined in liver and kidney tissues. Results MT gene expression and MDA levels increased (p < 0.05) while GPx and SOD activity levels decreased (p < 0.05) in STZ, Cd, and STZ + Cd groups. In Group 5, Group 6, Group 7, and Group 8 groups MT gene expression and MDA levels were decreased while GPx and SOD activity levels were increased (p < 0.05). CAT activity significantly increased (p < 0.05) in STZ + Cd group while there were no significance in other groups (p > 0.05). Compared to the control, Group 5, Group 6, Group 7, and Group 8 groups provided no difference for alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen and creatinine levels (p > 0.05). Conclusions Our results suggest that Se, insulin, Zn and MT may have protective effects against hepatotoxicity and nephrotoxicity caused by Cd exposure in diabetic rats by reducing oxidative stress and MT gene expression levels.

Topics: Animals; Cadmium; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Gene Expression Regulation; Insulin; Kidney Diseases; Liver Diseases; Male; Metallothionein; Oxidative Stress; Rats; Rats, Wistar; Selenium; Streptozocin; Zinc

Cardiac insulin resistance is a key pathogenic factor for diabetic cardiomyopathy (DCM), but the mechanism remains largely unclear. We found that diabetic hearts exhibited decreased phosphorylation of total Akt and isoform Akt2 but not Akt1 in wild-type (WT) male FVB mice, which was accompanied by attenuation of Akt downstream glucose metabolic signal. All of these signal changes were not observed in metallothionein cardiac-specific transgenic (MT-TG) hearts. Furthermore, insulin-induced glucose metabolic signals were attenuated only in WT diabetic hearts. In addition, diabetic hearts exhibited increased Akt-negative regulator tribbles pseudokinase 3 (TRB3) expression only in WT mice, suggesting that MT may preserve Akt2 function via inhibiting TRB3. Moreover, MT prevented tert-butyl hydroperoxide (tBHP)-reduced insulin-stimulated Akt2 phosphorylation in MT-TG cardiomyocytes, which was abolished by specific silencing of Akt2. Specific silencing of TRB3 blocked tBHP inhibition of insulin-stimulated Akt2 phosphorylation in WT cardiomyocytes, whereas overexpression of TRB3 in MT-TG cardiomyocytes and hearts abolished MT preservation of insulin-stimulated Akt2 signals and MT prevention of DCM. Most importantly, supplementation of Zn to induce MT preserved cardiac Akt2 signals and prevented DCM. These results suggest that diabetes-inhibited cardiac Akt2 function via TRB3 upregulation leads to aberrant cardiac glucose metabolism. MT preservation of cardiac Akt2 function by inhibition of TRB3 prevents DCM.

Topics: Animals; Cell Cycle Proteins; Cells, Cultured; Diabetes Mellitus, Type 1; Heart; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipopolysaccharides; Male; Metallothionein; Mice; Mice, Mutant Strains; Mice, Transgenic; Myocardium; Myocytes, Cardiac; Organ Specificity; Oxidants; Oxidative Stress; Phosphorylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; RNA Interference

Whether zinc is able to improve diabetes-induced liver injury remains unknown. Transgenic type 1 diabetic (OVE26) mice develop hyperglycemia at 3 weeks old; therefore therapeutic effect of zinc on diabetes-induced liver injury was investigated in OVE26 mice. Three-month old OVE26 and age-matched wild-type mice were treated by gavage with saline or zinc at 5mg/kg body-weight every other day for 3 months. Hepatic injury was examined by serum alanine aminotransferase (ALT) level with liver histopathological and biochemical changes. OVE26 mice at 6 months old showed significant increases in serum ALT level and hepatic oxidative damage, endoplasmic reticulum stress and associated cell death, mild inflammation, and fibrosis. However, all these hepatic morphological and functional changes were significantly prevented in 3-month zinc-treated OVE26 mice. Mechanistically, zinc treatment significantly increased hepatic metallothionein, a protein with known antioxidant activity, in both wild-type and OVE26 mice. These results suggest that there were significantly functional, structural and biochemical abnormalities in the liver of OVE26 diabetic mice at 6 months old; however, all these changes could be prevented with zinc treatment, which was associated with the upregulation of hepatic metallothionein expression.

Topics: Animals; Apoptosis; Cell Death; Chemical and Drug Induced Liver Injury; Chickens; Collagen; Diabetes Mellitus, Type 1; Endoplasmic Reticulum Stress; Fatty Liver; Liver Function Tests; Metallothionein; Mice; Mice, Transgenic; Oxidative Stress; Rats; Zinc

Cardiovascular diseases remain a leading cause of the mortality world-wide, which is related to several risks, including the life style change and the increased diabetes prevalence. The present study was to explore the preventive effect of zinc on the pathogenic changes in the aorta.. A genetic type 1 diabetic OVE26 mouse model was used with/without zinc supplementation for 3 months. To determine gender difference either for pathogenic changes in the aorta of diabetic mice or for zinc protective effects on diabetes-induced pathogenic changes, both males and females were investigated in parallel by histopathological and immunohistochemical examinations, in combination of real-time PCR assay.. Diabetes induced significant increases in aortic oxidative damage, inflammation, and remodeling (increased fibrosis and wall thickness) without significant difference between genders. Zinc treatment of these diabetic mice for three months completely prevented the above pathogenic changes in the aorta, and also significantly up-regulated the expression and function of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a pivotal regulator of anti-oxidative mechanism, and the expression of metallothionein (MT), a potent antioxidant. There was gender difference for the protective effect of zinc against diabetes-induced pathogenic changes and the up-regulated levels of Nrf2 and MT in the aorta.. These results suggest that zinc supplementation provides a significant protection against diabetes-induced pathogenic changes in the aorta without gender difference in the type 1 diabetic mouse model. The aortic protection by zinc against diabetes-induced pathogenic changes is associated with the up-regulation of both MT and Nrf2 expression.

Topics: Animals; Aorta, Thoracic; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dietary Supplements; Disease Models, Animal; Female; Male; Metallothionein; Mice; Mice, Transgenic; NF-E2-Related Factor 2; Up-Regulation; Zinc

Zinc is an element that under physiological conditions preferentially binds to and is a potent inducer of metallothionein under physiological conditions. The present study was conducted to explore whether zinc supplementation morphologically and biochemically protects against diabetic nephropathy through modulation of kidney metallothionein induction and oxidative stress in streptozotocin-induced diabetic rats. Thirty-two Wistar albino male rats were equally divided into four groups. The first group was used as untreated controls and the second group was supplemented with 30 mg/kg/day zinc as zinc sulfate. The third group was treated with streptozotocin to induce diabetes and the fourth group was treated with streptozotocin and supplemented with zinc as described for group 2. The blood glucose and micro-albuminuria levels, body and kidney weights were measured during the 42-day experimental period. At the end of the experiment, the kidneys were removed from all animals from the four groups. Diabetes resulted in degenerative kidney morphological changes. The metallothionein immunoreactivity level was lower and the kidney lipid peroxidation levels were higher in the diabetes group than in the controls. The metallothionein immunoreactivity levels were higher in the tubules of the zinc-supplemented diabetic rats as compared to the non-supplemented diabetic group. The zinc and metallothionein concentrations in kidney tissue were higher in the supplemented diabetic group compared to the non-supplemented diabetes group. The activity of glutathione peroxidase did not change in any of the four groups. In conclusion, the present study shows that zinc has a protective effect against diabetic damage of kidney tissue through stimulation of metallothionein synthesis and regulation of the oxidative stress.

Topics: Animals; Antioxidants; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Dietary Supplements; Glutathione Peroxidase; Hypoglycemic Agents; Kidney; Kidney Tubules; Lipid Peroxidation; Male; Metallothionein; Oxidative Stress; Rats; Rats, Wistar; Streptozocin; Tissue Distribution; Up-Regulation; Zinc; Zinc Sulfate

Reactive oxygen species are considered an important cause of the death of pancreatic β cells, thereby triggering the development of type 2 diabetes as well as failure of islet transplantation. The biological properties of metallothionein (MT) and superoxide dismutase (SOD) are likely to be related to their antioxidant and free-radical scavenging abilities, but their access across biological membranes is limited.. We investigated whether Tat-MT and Tat-SOD fusion protein could be introduced into islets by a novel protein transduction technology and protect them from oxidative damage. We used 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and Annexin V/propidium iodide assays to analyse cell viability, and assessed expression of apoptosis marker proteins by Western blotting. We examined the protective effect of Tat-MT and Tat-SOD on the development of diabetes and on graft failure after syngeneic islet transplantation into Otsuka Long Evans Tokushima Fatty (OLETF) rats and Imprinting Control Region (ICR) mice, respectively.. Tat-MT and Tat-SOD were successfully delivered into the rat islets, and reactive oxygen species, nitric oxide, glucolipotoxicity-induced cell death, cytokine injury, and DNA fragmentation due to ischaemia-reperfusion in pancreatic β cells were significantly reduced. In addition Tat-MT and Tat-SOD treatment protected OLETF rats from developing diabetes, and enhanced the survival of antioxidant-treated islets transplanted into the renal capsules of diabetic mice.. Transduction of Tat-MT and Tat-SOD proteins offers a new strategy for protecting against the development of diabetes by relieving oxidative stress.

Topics: Animals; Diabetes Mellitus, Type 1; Gene Products, tat; Hep G2 Cells; Humans; Insulin-Secreting Cells; Islets of Langerhans; Male; Metallothionein; Mice; Oxidative Stress; Rats; Reactive Oxygen Species; Recombinant Fusion Proteins; Superoxide Dismutase; Transduction, Genetic

The trigger of juvenile diabetes has been suggested to be an interaction between a virus and trace elements, where enteroviruses, including coxsackievirus B3 (CVB3), have been discussed as potential initiators. The aim of this study was to investigate the effects in the pancreas on gene expressions of metallothionein 1 (MT1), divalent metal transporter 1 (DMT1), and zinc transporter 5 (ZnT-5) and concomitant changes in iron (Fe), copper (Cu), and zinc (Zn) in serum and pancreas of Balb/c mice on days 3, 6, and 9 of CVB3 infection.. Trace elements were measured through inductively coupled plasma-mass spectrometry, and CVB3, MT1, DMT1, and ZnT-5 were measured by reverse transcription-polymerase chain reaction.. Virus was found in the pancreas on all days, with a peak on day 3. Infection tended to increase Fe in both serum and the pancreas. The Cu/Zn ratio in the pancreas increased early in the infection because of a great decrease in Zn. In serum, the Cu/Zn ratio was not increased until day 9 of the disease. In the pancreas, MT1 decreased, whereas DMT1 tended to increase on day 6, and ZnT-5 increased progressively during the course of the disease.. Virus-induced changes in trace elements, MT1, DMT1, and ZnT-5 in the pancreas may reflect early stages of the development of pancreatitis and prestages of diabetic disease.

Topics: Animals; Carrier Proteins; Cation Transport Proteins; Copper; Diabetes Mellitus, Type 1; Disease Progression; Enterovirus B, Human; Enterovirus Infections; Female; Gene Expression Regulation; Iron; Membrane Transport Proteins; Metallothionein; Mice; Mice, Inbred BALB C; Pancreas; Trace Elements; Viremia; Zinc

It is widely proposed that reactive oxygen species (ROS) contribute to beta-cell death in type 1 diabetes. We tested this in nonobese diabetic (NOD) mice using beta-cell-specific overexpression of three antioxidant proteins: metallothionein (MT), catalase (Cat), or manganese superoxide dismutase (MnSOD). Unexpectedly, the cytoplasmic antioxidants, MT and catalase, greatly accelerated diabetes after cyclophosphamide and accelerated spontaneous diabetes in male NOD mice. This occurred despite the fact that they reduced cytokine-induced ROS production and MT reduced streptozotocin diabetes in NOD mice. Accelerated diabetes onset coincided with increased beta-cell death but not with increased immune attack. Islets from MTNOD mice were more sensitive to cytokine injury. In vivo and in vitro studies indicated reduced activation of the Akt/pancreatic duodenal homeobox-1 survival pathway in MTNOD and CatNOD islets. Our study indicates that cytoplasmic ROS may have an important role for protecting the beta-cell from autoimmune destruction.

Topics: Animals; Antioxidants; Apoptosis; Blotting, Western; Catalase; Cyclophosphamide; Cytokines; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Glutathione Peroxidase; Immunohistochemistry; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Male; Metallothionein; Mice; Mice, Inbred NOD; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; Superoxide Dismutase

Cardiomyopathy is a major cause of mortality for both type 1 and 2 diabetic patients. However, experimental analysis of diabetic cardiomyopathy has focused on type 1 diabetes and there are few reports on cardiomyocyte dysfunction in the widely used type 2 diabetic model, db/db. In the current study, we assessed function in isolated ventricular myocytes from type 1 diabetic OVE26 mice and from type 2 diabetic db/db mice. When compared with their respective control strains, both diabetic models showed significant impairment in contractility, as assessed by percent peak shortening, maximal rate of contraction, and maximal rate of relaxation. The calcium decay rate was also significantly reduced in both types of diabetes, but the decrement was much greater in OVE26 myocytes, approx 50% vs only 20% in db/db myocytes. To understand the basis for slow calcium decay in diabetic myocytes and to understand the molecular basis for the quantitative difference between calcium decay in OVE26 and db/db myocytes, we measured cardiac content of the SERCA2a calcium pump. SERCA2a was significantly decreased in OVE26 diabetic myocytes but not reduced at all in db/db myocytes. The reduction of SERCA2a in OVE26 myocytes was completely prevented by overexpression of the antioxidant protein metallothionein, confirming that oxidative stress is an important component of diabetic cardiomyopathy. The current results demonstrate that though contractility is impaired in individual myocytes of db/db hearts and deficits are similar to what is seen in a severe model of type 1 diabetes, impairment in calcium reuptake is less severe, probably as a result of maintenance of normal levels of SERCA2a.

Topics: Animals; Blotting, Western; Calcium Signaling; Calcium-Transporting ATPases; Cell Separation; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Electrophoresis, Polyacrylamide Gel; Female; Fluorescent Dyes; Fura-2; Male; Metallothionein; Mice; Mice, Inbred Strains; Myocardial Contraction; Myocytes, Cardiac; Sarcoplasmic Reticulum Calcium-Transporting ATPases

In order to clarify a possible protective role of metallothionein (MT) in the development of streptozotocin (STZ)-caused insulin-dependent diabetes mellitus (IDDM) and its mechanisms, we studied whether MT is effective for protection against STZ-caused IDDM by utilizing MT-null (isoforms MT-I and II) transgenic mice. It was found that Zn pretreatment (I mg/kg body weight as ZnSO4) has a unique inhibitory effect on IDDM development in MT-null mice in contrast to no marked effect in control (C57BL/6J) mice, suggesting that Zn ions free from MT molecules exerted this protective effect. The highest Zn dose (10 mg/kg body weight) fully suppressed development of hyperglycaemia in both types of mice. Pretreatment with Zn partially led to recovery of superoxide dismutase activities in the liver and pancreas in which STZ administration suppressed superoxide dismutase activity in both types of mice. The present study suggests that Zn plays an important role in the pathogenesis of IDDM, although a possible involvement of MT in the protection of STZ-caused IDDM cannot be completely negated.

Topics: Analysis of Variance; Animals; Blood Glucose; Crosses, Genetic; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Female; Glucagon; Insulin; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Mice, Transgenic; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Zinc

Hyperzincuria and low Zn absorption in diabetic animals and humans have prompted speculation that diabetics are more susceptible to Zn deficiency. There is little information, however, describing the effects of diabetes on the biochemical mechanisms of intestinal Zn transport. We evaluated Zn absorption in streptozotocin-induced diabetic rats based on a model of Zn transport in which cysteine-rich intestinal protein serves as an intracellular carrier that is inhibited by metallothionein (MT). Apparent absorption and retention of Zn and Cu in rats fed a purified diet were measured in a balance study 15-17 d after induction of diabetes. The rate of 65Zn absorption from isolated intestinal segments, molecular distribution of 65Zn in mucosal cytosol, and tissue MT levels were measured on d 20-22. Food consumption, and thus Zn and Cu intake, by diabetic rats was twice that of controls. Although fractional absorption (percent) of Zn and Cu was lower in the diabetic rats, net absorption (micrograms/100 g body weight/d) was higher. The higher net absorption in the diabetic group was offset, however, by higher urinary excretion, so that Zn and Cu retention was similar in both groups of animals. Low fractional absorption is attributable to the down-regulation of intestinal Zn transport, as indicated by the lower rate of 65Zn absorption from isolated intestinal segments in the diabetic rats. Down-regulation of intestinal transport is in turn attributable to higher concentrations of intestinal MT, which resulted in more 65Zn in the mucosal cytosol bound to MT, an inhibitor of Zn transport, and less to cysteine-rich intestinal protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Glucose; Carrier Proteins; Copper; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Intestinal Absorption; LIM Domain Proteins; Male; Metallothionein; Rats; Rats, Sprague-Dawley; Streptozocin; Zinc