Zincsulphate induced metallothionein in pancreatic islets and protected against the diabetogenic toxin streptozotocin.

In mice, autoimmune diabetes can be induced with multiple low doses of streptozotocin (MLD-STZ). Specific T cell-dependent immune reactions and non-specific inflammatory damage induced by reactive oxygen species (ROS) are involved in the pathogenesis of MLD-STZ diabetes. Metallothionein (MT) can be significantly (P<0.

Prevention of spontaneous and experimentally induced diabetes in mice with zinc sulfate-enriched drinking water is associated with activation and reduction of NF-kappa B and AP-1 in islets, respectively.

Recently, we reported that zinc sulfate-enriched (25 mM) drinking water (Zn(2+)) protected male C57BL/6 mice from diabetes induced by multiple low doses of streptozotocin (MLD-STZ) and that MLD-STZ activates the transcription factors nuclear factor (NF)-kappa B and activator protein (AP)-1 in islets of these mice. Therefore, we studied the effect of Zn(2+) on spontaneous diabetes in female nonobese diabetic (NOD) mice and on the activity of NF-kappa B and AP-1 in islets of NOD and MLD-STZ-injected male C57BL/6 mice. We hypothesized that Zn(2+) may affect NF-kappa B, which may play a key role in immune-mediated diabetogenesis.

Generation of hydrogen peroxide and failure of antioxidative responses in pancreatic islets of male C57BL/6 mice are associated with diabetes induced by multiple low doses of streptozotocin.

Aims/hypothesis: We studied the impact of the reactive oxygen species hydrogen peroxide (H2O2) and antioxidative enzymes on the pathogenesis of diabetes induced by multiple low doses of streptozotocin (MLD-STZ).

Methods: We isolated the islets of C57BL/6 mice. For ex vivo analyses, mice had been injected with MLD-STZ.

Interleukin-11 inhibits NF-kappaB and AP-1 activation in islets and prevents diabetes induced with streptozotocin in mice.

This laboratory has reported that multiple low doses of streptozotocin (MLD-STZ) similarly upregulate the T helper (Th)1-type proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in islets of both the diabetes-susceptible male and the diabetes-resistant female C57BL/6 mice and that MLD-STZ downregulates the anti-inflammatory Th2-type cytokines interleukin (IL)-4 and IL-10, as well as the anti-inflammatory Th3-type cytokine-transforming growth factor (TGF)-ss1 in islets of male, but not female, mice. Thus, diabetes is associated with a relative preponderance of local proinflammatory cytokines. Here, we investigated the effects of MLD-STZ on the anti-inflammatory cytokine IL-11 and the transcription factors nuclear factor (NF)-kappaB and activator protein (AP)-1, which are involved in gene activation of proinflammatory cytokines, and on the cytosolic kinase (IKK-alpha) of NF-kappaB inhibitor (IkappaB).

Differential target molecules for toxicity induced by streptozotocin and alloxan in pancreatic islets of mice in vitro.

Streptozotocin (STZ) and alloxan (ALX) are potent diabetogens in different species of laboratory animals. Here, we describe differential in vitro effects of STZ and ALX on beta-cell molecules that are essential for glucose transport and metabolism, the glucose transporter 2 (GLUT2) and glucokinase (GK), respectively. Incubation of isolated pancreatic islets of C57 BL/6 mice with STZ or ALX for 30 min resulted in a concentration-dependent gradual loss of beta-cell function as determined by basal and D-glucose (D-G)-stimulated insulin release.

Generation of hydroxyl radicals mediated by streptozotocin in pancreatic islets of mice in vitro.

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.

Molecular target structures in alloxan-induced diabetes in mice.

Type 1 diabetes results from irreversible damage of insulin-producing beta-cells. In laboratory animals, diabetes can be induced with alloxan (ALX), a 2,4,5,6-tetraoxopyrimidine. ALX is a potent generator of reactive oxygen species (ROS), which can mediate beta-cell toxicity.

Differential regulation of Th1-type and Th2-type cytokine profiles in pancreatic islets of C57BL/6 and BALB/c mice by multiple low doses of streptozotocin.

In the nonobese diabetic (NOD) mouse, the T helper (Th)1-type inflammatory cytokines interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha play a critical role in the development of type 1 diabetes, whereas the Th2-type anti-inflammatory cytokines interleukin (IL)-4 and IL-10 operate counterregulatory. There are no comprehensive analyses on cytokine profiles in the mouse model of diabetes induced with multiple low doses of streptozotocin (MLD-STZ). Therefore, we used islets to study ex vivo effects of MLD-STZ and in vitro effects of STZ on IFN-gamma, TNF-alpha, IL-4, and IL-10 on both levels of protein-producing cells and the mRNA expression, as well as the mRNA expression of the Th3-type cytokine transforming growth factor TGF-beta1.

Zinc sulphate induces metallothionein in pancreatic islets of mice and protects against diabetes induced by multiple low doses of streptozotocin.

Aims/hypothesis: Diabetes is induced by multiple low doses of streptozotocin (MLD-STZ) in male mice of susceptible strains. In this model beta-cell injury and T-cell-mediated inflammatory reactions are induced. Probably, reactive oxygen species (ROS) participate in the destruction of beta cells.

GLUT2 in pancreatic islets: crucial target molecule in diabetes induced with multiple low doses of streptozotocin in mice.

In mice, diabetes can be induced by multiple low doses of streptozotocin (MLD-STZ), i.e., 40 mg/kg body wt on each of 5 consecutive days.

Comparison of a new anti-glutamic acid decarboxylase (GAD) enzyme-linked immunosorbent assay (ELISA) with radioimmunoassay methods: a multicenter study.

Several methods are available for the measurement of antibodies to glutamic acid decarboxylase (anti GAD). These antibodies are valuable tools for the immunodiagnosis of insulin-dependent (type 1) diabetes mellitus (IDDM) and for the assessment of risk for the future development of IDDM. We here describe a new enzyme-linked immunosorbent assay (ELISA) for the detection of anti-GAD which was tested in a multicenter study.

Experimental benefit of moxonidine on glucose metabolism and insulin secretion in the fructose-fed rat.

Objective: Non-insulin-dependent diabetes mellitus (NIDDM) is often associated with hypertension leading to a specifically high cardiovascular risk in these patients. However, there is evidence that insulin resistance and hyperinsulinaemia are not only characteristic for diabetic patients but also for some non-diabetic populations in which a cluster of cardiovascular risk factors is observed (hypertension, hypertriglyceridaemia, obesity). Therefore, hyperinsulinaemia and insulin resistance have been suggested to be of major pathophysiological importance for the development of this syndrome (syndrome X).

Predictive immunotoxicological test systems: suitability of the popliteal lymph node assay in mice and rats.

This article reviews results obtained with popliteal lymph node assays (PLNAs) in rodents and discusses their ability to detect and analyze immunotoxic effects of drugs and other low molecular weight (LMW) chemicals. In its basic form, the PLNA measures activation of the draining lymph node of the hind paw (i.e.

Glucose transporter 2 expression: prevention of streptozotocin-induced reduction in beta-cells with 5-thio-D-glucose.

The effect of streptozotocin (STZ) on the glucose transporter 2 (GLUT2) expression in beta-cells was investigated in vitro and in vivo. By Western blot analysis, a gradually decreasing GLUT2 expression was found in islets prepared from C57BL/6 male mice that had received multiple low doses of STZ (MD-STZ) for induction of autoimmune diabetes. Reduction of GLUT2 expression correlated with the number of STZ injections administered and preceded development of hyperglycemia.

Metallothionein: in vitro induction with zinc and streptozotocin in pancreatic islets of mice.

Recently, this laboratory reported that the antioxidant metallothionein (MT) is constitutively expressed and significantly (p < 0.001) induced with zinc in pancreatic islets in vivo. Therefore, our aim was to study, whether MT can also be induced in vitro.

Prevention of high- and low-dose STZ-induced diabetes with D-glucose and 5-thio-D-glucose.

To induce hyperglycemia in mice by administration of STZ, two experimental protocols that involve different pathogenic pathways are being used. First, the intraperitoneal injection of a single high dose (HD-STZ) exerts direct toxicity on beta-cells, which results in necrosis within 48-72 h and overt permanent hyperglycemia. Second, injections of multiple low doses of STZ (LD-STZ), administered intraperitoneally on 5 consecutive days, induce both beta-cytotoxic effects and STZ-specific T-cell-dependent immune reactions.

Metallothionein in isolated pancreatic islets of mice: induction by zinc and streptozotocin, a naturally occurring diabetogen.

Metallothionein (MT) concentrations were determined in the cytosol of isolated pancreatic islets of mice, using both the cadmium (Cd)-heme and the Cd-Chelex assay. Both constitutive MT levels and significant MT induction were detected in islet cells. For MT induction, mice were injected intraperitoneally (i.

Assessment of precision, concordance, specificity, and sensitivity of islet cell antibody measurement in 41 assays.

Forty-one assays were analysed at the 3rd International Workshop on the standardisation of islet cell antibodies. Analysis of precision demonstrated assays consistently detecting blind duplicates within one doubling dilution and capable of discriminating one doubling dilution differences in islet cell antibody concentration. Some assays, however, reported duplicates discrepantly by more than seven doubling dilutions, and consequently could not distinguish even large quantities of islet cell antibodies.

Class II MHC antigens in vivo induced by the diabetogen streptozotocin in BALB/c mice.

Immunologic reactions are involved in the pathogenic pathway of hyperglycemia development induced by multiple subdiabetogenic doses of streptozotocin (STZ) in mice. Recently, we have reported that STZ, a nitrosurea derivative, can act in vivo as hapten for T lymphocytes, as assayed by applying the popliteal lymph node assay. In subsequent experiments, induction of Class II major histocompatibility (MHC) antigens by STZ were evaluated in BALB/c mice.

T cell-dependent class II major histocompatibility complex antigen expression in vivo induced by the diabetogen streptozotocin.

Immune reactions are involved in the low-dose streptozotocin (STZ)-model of hyperglycemia (1). By means of the popliteal lymph node assay, we demonstrated that T cell-dependent lymphoproliferation can be evoked by STZ (2). The present report shows that class II MHC antigen expression is readily inducible in multiple organs by a single dose of STZ injected subcutaneously (s.