Accelerated diabetes in non-obese diabetic (NOD) mice differing in incidence of spontaneous disease

Baxter, Alan G.; Mandel, T. E.

doi:10.1111/j.1365-2249.1991.tb05750.x

Cited by 13 publications

(6 citation statements)

References 25 publications

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“…We selected the well-characterized accelerated model of autoimmune diabetes in the NOD mouse following a single bolus of cyclophosphamide (Cy), which synchronizes progression of T1D. In this widely used animal model of human Type 1 diabetes, two to four days following Cy injection a peak pro-inflammatory cytokine response is reported, which is followed by development of overt autoimmune diabetes in 2–4 weeks [41] , [42] , [43] , [44] . Therefore, we challenged 10-week old female NOD mice with Cy in two groups of seven.…”

Section: Resultsmentioning

confidence: 99%

In Vivo Islet Protection by a Nuclear Import Inhibitor in a Mouse Model of Type 1 Diabetes

et al. 2010

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BackgroundInsulin-dependent Type 1 diabetes (T1D) is a devastating autoimmune disease that destroys beta cells within the pancreatic islets and afflicts over 10 million people worldwide. These patients face life-long risks for blindness, cardiovascular and renal diseases, and complications of insulin treatment. New therapies that protect islets from autoimmune destruction and allow continuing insulin production are needed. Increasing evidence regarding the pathomechanism of T1D indicates that islets are destroyed by the relentless attack by autoreactive immune cells evolving from an aberrant action of the innate, in addition to adaptive, immune system that produces islet-toxic cytokines, chemokines, and other effectors of islet inflammation. We tested the hypothesis that targeting nuclear import of stress-responsive transcription factors evoked by agonist-stimulated innate and adaptive immunity receptors would protect islets from autoimmune destruction.Principal FindingsHere we show that a first-in-class inhibitor of nuclear import, cSN50 peptide, affords in vivo islet protection following a 2-day course of intense treatment in NOD mice, which resulted in a diabetes-free state for one year without apparent toxicity. This nuclear import inhibitor precipitously reduces the accumulation of islet-destructive autoreactive lymphocytes while enhancing activation-induced cell death of T and B lymphocytes derived from autoimmune diabetes-prone, non-obese diabetic (NOD) mice that develop T1D. Moreover, in this widely used model of human T1D we noted attenuation of pro-inflammatory cytokine and chemokine production in immune cells.ConclusionsThese results indicate that a novel form of immunotherapy that targets nuclear import can arrest inflammation-driven destruction of insulin-producing beta cells at the site of autoimmune attack within pancreatic islets during the progression of T1D.

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Section: Resultsmentioning

confidence: 99%

In Vivo Islet Protection by a Nuclear Import Inhibitor in a Mouse Model of Type 1 Diabetes

et al. 2010

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“…However, not all the NOD mouse are destinated to developed the diabetes. Some laboratory try to increase the by using cytotoxic agent [10,11]. So, in our experiment, we attenuate the injury of pancreas by way of injection of STZ intermittently, which obviously accentuated the immune injury of pancrease.…”

Section: Discussionmentioning

confidence: 92%

Beneficial Effect of Rhein on the Treatment of Diabetic Nephropathy in Nonobese Diabetic (NOD) Mice

Jia¹,

Guo²,

Wang³

et al. 2012

J Nephrol Therapeutic

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Objective: Rhein has been discovered early to have the function of inhibiting both electron transfer and ADPdriven H + uptake in mitochondria. It has been also found that rhein can inhibit the up regulation of GLUT1 (glucose transporting protein-1) function and the activity of hexosamine biosynthetic pathway in mesangial cells in vitro. Futhermore, we have showed the renal protective effect of rhein on STZ-induced diabetic rats. So we try to explore the therapeutic effects of rhein on diabetic nephropathy (DN) in another diabetic model of NOD mice. Methods: In our study, NOD mice of eight weeks of age were injected intraperitoneally four times with STZ (50 mg/kg) at 7-day interval. Mice with glycosuria and plasma glucose level above 14.0 mmol/L were verified for diabetes. Diabetic NOD mice were subdivided into control and rhein treatment groups. Mice in rhein treatment group were continuously administraed with rhein (150 mg/kg/d) for 15 weeks after diabetes was developed. Plasma parameters (including plasma glucose and lipid level), urinary protein level and histopathology of kidneys were all observed at the end of the experiment. Results: We demonstrate that rhein not only reduced the urinary protein excretion (0.37 ± 0.17 vs 3.32 ± 0.68 mg/24h, P<0.05), but also prevent the elevation of serum creatinine in diabetic mice after treatment of 15 weeks. In addition, rhein led to a marked decrease of plasma glucose level in experimental model, this effect reached its peak at 15 weeks (7.8 ± 3.80 vs 31.9 ± 4.77 mmol/L, P<0.01), accompanied with decrease of plasma triglyceride (0.74 ± 0.13 vs 2.16 ± 0.73 mmol/L, P<0.01) and cholesterols (1.84 ± 0.55 vs 6.53 ± 5.27 mmol/L, P<0.01). The morphologic studies showed the diabetic NOD mice present glomerular hypertrophy, mesangial expansion and diffuse sclerosis. The accumulation of fibronectin and deposition of immunoglobulin examined by immunostaining in glomeruli were found decreased in rhein-treated NOD mice. Examinition of pancreatic islet sections from NOD mice revealed peri-islet and intraislet mononuclear cells filtration. Treatment with rhein ameliorated cellular aggregation. Stain with Gomori aldehyde fuchsine method showed that loss of β-cells was reduced in rhein-treated mice. Conclusions: Taken together, these results indicate that rhein is able to ameliorate hyperglycemia and halt the progression of diabetic nephropathy in NOD mice, which possesses potential foreground on the management of human diabetes and its complications.

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“…Hence, β -cell mass may be an inadequate determinant of overall β -cell function in this model. In addition, it is well known that some aging female NOD mice never progress to develop diabetes [ 30 ]. The compensatory capacity of a minor residual β -cell mass combined with the heterogeneity of disease penetrance in the NOD mice could be the explanation for the lack of statistical significance in the effect on β -cell mass upon SER140 treatment.…”

Section: Discussionmentioning

confidence: 99%

The IL-1βReceptor Antagonist SER140 Postpones the Onset of Diabetes in Female Nonobese Diabetic Mice

Cucak

Hansen

Vrang

et al. 2016

Journal of Diabetes Research

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The cytokine interleukin-1β (IL-1β) is known to stimulate proinflammatory immune responses and impair β-cell function and viability, all critical events in the pathogenesis of type 1 diabetes (T1D). Here we evaluate the effect of SER140, a small peptide IL-1β receptor antagonist, on diabetes progression and cellular pancreatic changes in female nonobese diabetic (NOD) mice. Eight weeks of treatment with SER140 reduced the incidence of diabetes by more than 50% compared with vehicle, decreased blood glucose, and increased plasma insulin. Additionally, SER140 changed the endocrine and immune cells dynamics in the NOD mouse pancreas. Together, the data suggest that SER140 treatment postpones the onset of diabetes in female NOD mice by interfering with IL-1β activated pathways.

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Accelerated diabetes in non-obese diabetic (NOD) mice differing in incidence of spontaneous disease

Cited by 13 publications

References 25 publications

In Vivo Islet Protection by a Nuclear Import Inhibitor in a Mouse Model of Type 1 Diabetes

In Vivo Islet Protection by a Nuclear Import Inhibitor in a Mouse Model of Type 1 Diabetes

Beneficial Effect of Rhein on the Treatment of Diabetic Nephropathy in Nonobese Diabetic (NOD) Mice

The IL-1βReceptor Antagonist SER140 Postpones the Onset of Diabetes in Female Nonobese Diabetic Mice

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