Caution is required with interferon alpha as a potential treatment for type I diabetes.
Explore the source record for details and available documents.
Administration, Oral↗
Biomedical subjects
P E Beales
Publications and source records attributed to P E Beales.
Troglitazone exhibits immunomodulatory activity on the cytokine production of activated human lymphocytes.
Troglitazone (TGL), a thiazolidinedione compound that improves the response of peripheral target tissue to insulin, also has anti-inflammatory properties, a potential means of protection from Type 1 (insulin dependent) diabetes. In order to test the ability of TGL to affect cytokine production, peripheral blood mononuclear cells from healthy donors were exposed to TGL in the presence or absence of a polyclonal activator (PHA) and the production of cytokines assayed. TGL enhanced PHA response, promoted secretion of the cytokines granulocyte and macrophage colony-stimulating factor and leukaemia inhibitory factor and inhibited tumour necrosis factor-alpha secretion, consistent with causing Th-2 differentiation in T-cells. These results suggest that TGL is capable of modulating cytokine production and could therefore influence Th1/Th2 differentiation.
Chromans↗
Troglitazone prevents insulin dependent diabetes in the non-obese diabetic mouse.
Troglitazone has recently been introduced in the treatment of Type 2 diabetes. In addition to its anti-diabetic effects it acts as a perixosome proliferator activated receptor-gamma (PPAR-gamma) agonist and has anti-inflammatory properties by inhibiting macrophage tumour necrosis factor-alpha (TNF-alpha) secretion. It also inhibits the production of endothelial selectin (e-selectin). Troglitazone also reduces interleukin-1alpha induced nitric oxide production in pancreatic beta-cells, which may be relevant in preventing nitric oxide mediated damage to these cells in the Type 1 diabetes process. We tested troglitazone in the spontaneous model of autoimmune diabetes, the non-obese diabetic (NOD) mouse, to determine its effect on the disease process. When administered by gavage from weaning at a dose of 400 mg/kg body weight (n = 32), troglitazone reduced the incidence of diabetes by 16 weeks compared to controls (n = 32) in a pattern that was maintained up to the conclusion of the experiment at 31 weeks of age (p < 0.05). Insulitis was unaltered (index = 1.05 +/- 0.71 vs. 1.13 +/- 0.82, treated vs. controls, p = 0.78). The study was repeated using troglitazone in the diet of NOD mice (n = 24) to give a dose of approximately 200 mg/kg body weight in order to provide a more consistent level of troglitazone during the time course of the experiment. There was a reduction of diabetes incidence in this group but it did not reach significance. Insulin levels were reduced in gavage treated mice although such reduction did not reach significance (p < 0.07). We conclude that, in view of its effect on this model of autoimmune diabetes and because of its known function as an insulin sensitiser, troglitazone might be considered for potential use in those patients with Type 1 masquerading as Type 2 diabetes.
Age Factors↗
Problems with inducing tolerance to type 1 diabetes.
Explore the source record for details and available documents.
Animals↗
CD95 and CD95-ligand expression in endocrine pancreas of NOD, NOR and BALB/c mice.
The non-obese diabetic (NOD) mouse is widely used to study the pathogenesis of insulin-dependent diabetes mellitus. However, the mechanisms responsible for beta-cell destruction, in this model, are still poorly defined. The CD95/CD95L system among other effector systems has been implicated in beta-cell death. In this study we investigated in NOD, non-obese resistant (NOR) and Balb/c mice the expression of CD95 and CD95L in alpha and beta pancreatic cells by immunohistochemistry and immunofluorescence. We demonstrate that alpha cells in the islets of Langherans constitutively express CD95L forming a natural shield around beta cells.
Animals↗
Metformin does not alter diabetes incidence in the NOD mouse.
In insulin-dependent (type 1) diabetes mellitus, increasing peripheral insulin sensitivity might be a useful approach in controlling the process leading to beta cell destruction by reducing insulin output and thereby reducing the antigenicity associated with its release. The aim of this study was to investigate whether the use of a biguanide, Metformin, which has been suggested to increase insulin sensitivity, was capable of modifying the natural history of diabetes in a model of type 1 diabetes, the non-obese diabetic (NOD) mouse. Using age-, sex- and litter-matched groups, three groups of 32 animals each were treated with Metformin in their drinking water at a high dose of 200 mg/kg body weight and at a low dose of 20 mg/kg body weight; the third group of mice acted as controls. Diabetes incidence at 30 weeks of age was similar in all groups. No significant differences in the calculated index of insulitis were observed in treated or control animals. We conclude that Metformin does not affect the disease process leading to clinical diabetes in this animal model.
Aging↗
Standardizing experiments with NOD mice.
Explore the source record for details and available documents.
Adoptive Transfer↗
Baclofen, a gamma-aminobutyric acid-b receptor agonist, delays diabetes onset in the non-obese diabetic mouse.
Glutamic acid decarboxylase (GAD) is the enzyme responsible for the synthesis of gamma-aminobutyric acid (GABA). GAD has been identified as a 64-kDa antigen expressed in pancreatic beta-cells, to which autoantibodies are generated prior to the onset of type 1 (insulin-dependent) diabetes mellitus. GAD may therefore be an initiating factor in beta-cell destruction. We administered baclofen, a GABA-B receptor agonist, to non-obese diabetic (NOD) mice in an attempt to down-regulate GAD expression and thereby reduce the incidence of diabetes. Twenty-four female NOD mice were given baclofen in their drinking water at a final dose of 50 mg/kg body weight daily from weaning to 30 weeks of age. Twenty-four sex- and litter-matched mice were used as controls. At 30 weeks there was no difference in the incidence of diabetes in the treated group compared with the controls. However, there was a significant delay in the onset of diabetes in the treated group (P < 0.001, parallelism test). The degree of insulitis and the GAD activity in the pancreas per mg of protein were unchanged by baclofen treatment with respect to controls. These results suggest that baclofen may be effective in delaying diabetes onset in NOD mice by stimulating GABA activity, as this neurotransmitter, localised in the islets, may modulate insulin secretion and the antigen expression associated with it.
Aging↗
Histological study of pancreatic beta-cell loss in relation to the insulitis process in the non-obese diabetic mouse.
Non-obese diabetic (NOD) mice spontaneously develop an autoimmune diabetes with higher incidence in females than in males. In order to elucidate possible factors involved in the different incidence of diabetes between male and female mice, we studied the progression of pancreatic beta-cell loss in relation to mononuclear cell infiltration of the pancreas (insulitis). We examined the pancreas of 76 NOD mice (39 males and 37 females) of different ages. The beta-cell content was assessed by immunoperoxidase staining of sections with an anti-insulin serum and the severity of insulitis was determined by haematoxylin staining of the same sections. A semi-quantitative criterion was used to grade both parameters. The results showed that females have a faster loss of beta-cell mass, which progressively decreases with the increase of severity of insulitis. In males, a medium to severe degree of insulitis is required before initial loss of beta cells occurs. Under the age of 10 weeks there was a significantly lower content of beta cells in females than males (2.84 +/- 0.03 vs 2.67 +/- 0.07; P = 0.02). Since we never observed a significant difference in the degree of mononuclear cell infiltration in age-matched males and females, these data support the hypothesis of weaker beta-cell resistance to immunological attack in female mice. Thus beta-cell sensitivity, in addition to immunological activity, is an important factor in the pathogenesis of insulin dependent diabetes.
Aging↗
Vitamin E delays diabetes onset in the non-obese diabetic mouse.
Vitamin E was administered to non-obese diabetic (NOD) mice to determine if the selective destruction of pancreatic beta cells leading to Type 1 (insulin dependent) diabetes mellitus could be halted by virtue of this vitamin's free oxygen radical scavenger activity. Two groups of NOD mice were treated from 3 weeks of age until 30 weeks of age with either diet supplemented with vitamin E or control diet. Diabetes incidence was recorded as well as the degree of lymphocytic infiltration of the pancreas (insulitis) in animals which did not develop diabetes. Vitamin E did not reduce the incidence of diabetes by 30 weeks of age, however it did significantly delay the onset of the disease (p < 0.01--parallelism test). There were no differences in the degree of insulitis with respect to control mice. We conclude that antioxidant therapy with Vitamin E delays diabetes onset in NOD mice without having an apparent effect on the autoimmune process.
Animals↗
Tolbutamide reduces the incidence of diabetes mellitus, but not insulitis, in the non-obese-diabetic mouse.
The functional state of beta cells may influence the rate of their destruction in Type 1 (insulin-dependent) diabetes mellitus. We examined the effect of diazoxide, which inhibits insulin secretion, or tolbutamide, which stimulates insulin secretion, upon the incidence of diabetes in the non-obese-diabetic (NOD) mouse. Female mice were treated from 3-30 weeks of age with diet containing diazoxide 250 mg.kg-1 or tolbutamide 125 mg.kg-1. The cumulative incidence of diabetes at 35 weeks was similar in the diazoxide (16 of 24) and control (18 of 24) groups, but reduced in the tolbutamide group (10 of 23, p < 0.04 vs control group). In a second experiment, treatment was started from 9 weeks of age, by which time insulitis is already present. The cumulative incidence of diabetes at 35 weeks was 16 of 24 in controls, 15 of 24 on diazoxide and 11 of 24 on tolbutamide (p = NS vs control). A third experiment compared the effect of treatment from 3 weeks with control diet or diet containing tolbutamide 125 mg.kg-1 or 500 mg.kg-1. Diabetes was reduced by tolbutamide treatment, with a cumulative incidence of 25 of 31 in controls, 18 of 30 on tolbutamide 125 mg.kg-1 (p < 0.04) and 14 of 32 on 500 mg.kg-1 (p < 0.002), although the difference between the two treatment groups failed to reach statistical significance. A fourth experiment showed that treatment from 3-12 weeks with diazoxide 1000 mg.kg-1 increased the extent of insulitis compared with controls and animals treated with tolbutamide 500 mg.kg-1.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
NOD mouse colonies around the world--recent facts and figures.
Non-obese diabetic (NOD) mice are commonly used in autoimmune research. However, the diversity of these mice in developing autoimmune disease under different conditions prompted a group of researchers to compile a questionnaire on this subject. Here Paolo Pozzilli and colleagues comment on the results of this survey.
Age Factors↗
The effect of a heparin analogue, ITF-5005, on diabetes incidence and insulitis in the non-obese diabetic mouse.
It has been suggested that heparin and its analogues may have a suppressive effect on the immune response by interfering with T-lymphocyte heparinase activity, thus altering the ability of T-lymphocytes to penetrate the extracellular matrix and migrate to target tissues. We have investigated whether a heparin analogue (ITF-5005) can alter lymphocytic infiltration of the endocrine pancreas (insulitis) and/or diabetes incidence in the non-obese diabetic (NOD) mouse. Sixty-four NOD mice were divided at weaning and injected subcutaneously five times per week with either 18, 36 or 72 micrograms/kg body weight of ITF-5005 or saline as a control. At 12 weeks of age, the animals were culled and their pancreata sectioned, stained and assessed 'blind' for insulitis and insulin containing cells. Insulitis was similar in all groups as was the proportion of insulin-containing cells. To determine the effect on diabetes incidence, two groups of mice were injected with either saline or 140 micrograms/kg body weight of ITF-5005 from weaning until 30 weeks of age. No difference was found in overall diabetes incidence; however, disease onset was significantly accelerated in the treated group. We conclude that ITF-5005, at the doses employed, has no effect on insulitis or the proportion of treated group. We conclude that ITF-5005, at the doses employed, has no effect on insulitis or the proportion of insulin-containing cells found in the pancreas, but that it can accelerate the course of diabetes in the NOD mouse.
Animals↗
Immunotherapy with ciamexon in the non obese diabetic (NOD) mouse.
Ciamexon (CMX), a new immunomodulatory compound acting mainly on B-lymphocytes was given orally to 42 NOD mice divided into three sex and litter matched groups (A: 0.3 mg/mouse/day CMX, B: 1.5 mg/mouse/day CMX, C: control) from 7 weeks of age. Animals were followed up for evaluation of diabetes incidence up to 32 weeks of age. There was a tendency for a delayed onset of hyperglycemia in mice of group B up to 26 weeks of age; however no significant difference in the cumulative incidence of diabetes at 32 weeks of age was observed (A: 57.5%, B: 38.5%, C: 38.5%). No differences were found in the number of infiltrated islets in animals culled at 10 weeks of age treated with CMX from 4 weeks of age. We conclude that CMX does not modify the course of insulitis and diabetes incidence in NOD mice although though the appearance of glycosuria was delayed by this treatment.
Adjuvants, Immunologic↗
Parathyroiditis in the non-obese diabetic mouse--a new finding.
Autoimmune reactions to parathyroid cells have been observed in human autoimmune polyendocrinopathy, but such findings have not been described in animal models of polyendocrine autoimmunity. We report here three cases of lymphocytic infiltrations in 12 parathyroid glands identified in a total of 18 thyroid glands studied in the non-obese diabetic (NOD) mouse. The majority of parathyroid-infiltrating lymphocytes possessed the helper/inducer phenotype as defined by the L3T4 monoclonal antibody. Parathyroiditis was accompanied by lymphocytic thyroiditis only on one occasion, whereas in other cases of thyroiditis, lymphocytic infiltration of the parathyroid was undetectable. We conclude that parathyroiditis in the NOD mouse is part of the wide spectrum of autoimmunity observed in this animal model of diabetes.
Animals↗
Raised temperature reduces the incidence of diabetes in the NOD mouse.
An association between the incidence of childhood Type 1 (insulin-dependent) diabetes mellitus and the average yearly temperature in different countries has been reported, the incidence being higher in countries with a lower mean temperature. We have studied the effect of environmental temperature on the incidence of diabetes in an animal model of Type 1 diabetes, the non-obese diabetic (NOD) mouse. Female NOD mice were divided at weaning, with one group placed at a higher temperature (mean 23.7 +/- 1.7 degrees C) and the other at a lower temperature (21.0 +/- 1.8 degrees C). At 20 weeks of age 6 of 16 mice at lower temperature and 1 of 17 mice at higher temperature had developed diabetes (p less than 0.02); at 30 weeks 10 of 16 and 5 of 17 mice had developed diabetes (p less than 0.05). Non-diabetic animals in the low temperature group had a higher food intake than those in the high temperature group between 13-15 weeks of age (28.0 +/- 1.2 g/week vs 24.8 +/- 0.7 g/week, p less than 0.05). In a parallel experiment, histological examination showed that there were similar degrees of insulitis in the high and low temperature groups at seven weeks of age. We conclude that environmental temperature can affect the incidence of diabetes in the NOD mouse and that this may be related to alterations in food intake.
Animals↗
Effect of Tenidap, a novel anti-inflammatory compound on islet lymphocytic infiltration and diabetes incidence in the non obese diabetic (NOD) mouse.
Tenidap, a novel compound inhibiting cyclooxygenase and lipoxygenase, also possessing an inhibitory effect on interleukin-1 secretion by in vitro activated macrophages, has been administered to the non obese diabetic (NOD) mouse to evaluate its action on the induction and progression of insulitis and the diabetes incidence. Animals were allocated to three groups (group A: control group; group B: 12 mg/kg/day Tenidap; group C: 36 mg/kg/day Tenidap); female animals only were followed up to investigate the effect on diabetes incidence. The administration of Tenidap influenced the natural course of insulitis in male NOD mice; thus, at 60 and 100 days of age the mean percentage of infiltrated islets was significantly reduced compared to control animals (p less than 0.02). Moreover the severity of lymphocytic infiltration at 60 days of age was reduced in male mice of group B and C compared to control mice (p less than 0.004 and p less than 0.0001, respectively) whereas at 100 days of age this difference was not significant. However the progression towards severe insulitis in male animals receiving Tenidap was halted compared to control animals. Tenidap had also a significant dose dependent effect at 60 days on the severity of lymphocytic infiltration (group B vs. group C, p less than 0.01). By contrast, this agent had no effect on the degree of insulitis and diabetes incidence in female NOD mice. In both sexes at the end of follow-up a significant reduction in body weight was observed in animals of Group C compared to control animals (p less than 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗