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

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Helena Cucak ◽  
Gitte Hansen ◽  
Niels Vrang ◽  
Torben Skarsfeldt ◽  
Eva Steiness ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cell Function ◽  
Interleukin 1 ◽  
Nod Mice ◽  
Small Peptide ◽  
Nonobese Diabetic ◽  
Onset Of Diabetes ◽  
Diabetes Progression ◽  
Nonobese Diabetic Mice

The cytokine interleukin-1β(IL-1β) is known to stimulate proinflammatory immune responses and impairβ-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-1βreceptor 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-1βactivated pathways.

scholarly journals Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant

2015 ◽  
Vol 308 (12) ◽  
pp. E1043-E1055 ◽  
Author(s):  
Subhadra C. Gunawardana ◽  
David W. Piston
Keyword(s):  
Type 1 Diabetes ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Nod Mice ◽  
Nonobese Diabetic ◽  
Brown Adipose ◽  
Igf I ◽  
Onset Of Diabetes ◽  
Nonobese Diabetic Mice

Traditional therapies for type 1 diabetes (T1D) involve insulin replacement or islet/pancreas transplantation and have numerous limitations. Our previous work demonstrated the ability of embryonic brown adipose tissue (BAT) transplants to establish normoglycemia without insulin in chemically induced models of insulin-deficient diabetes. The current study sought to extend the technique to an autoimmune-mediated T1D model and document the underlying mechanisms. In nonobese diabetic (NOD) mice, BAT transplants result in complete reversal of T1D associated with rapid and long-lasting euglycemia. In addition, BAT transplants placed prior to the onset of diabetes on NOD mice can prevent or significantly delay the onset of diabetes. As with streptozotocin (STZ)-diabetic models, euglycemia is independent of insulin and strongly correlates with decrease of inflammation and increase of adipokines. Plasma insulin-like growth factor-I (IGF-I) is the first hormone to increase following BAT transplants. Adipose tissue of transplant recipients consistently express IGF-I compared with little or no expression in controls, and plasma IGF-I levels show a direct negative correlation with glucose, glucagon, and inflammatory cytokines. Adipogenic and anti-inflammatory properties of IGF-I may stimulate regeneration of new healthy white adipose tissue, which in turn secretes hypoglycemic adipokines that substitute for insulin. IGF-I can also directly decrease blood glucose through activating insulin receptor. These data demonstrate the potential for insulin-independent reversal of autoimmune-induced T1D with BAT transplants and implicate IGF-I as a likely mediator in the resulting equilibrium.

scholarly journals Immunotherapy with Tolerogenic Dendritic Cells Alone or in Combination with Rapamycin Does Not Reverse Diabetes in NOD Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Irma Pujol-Autonell ◽  
Rosa M. Ampudia ◽  
Pau Monge ◽  
Anna M. Lucas ◽  
Jorge Carrascal ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Dendritic Cells ◽  
Insulin Secretion ◽  
Cell Function ◽  
Nod Mice ◽  
Glucose Levels ◽  
Endogenous Insulin ◽  
Nonobese Diabetic ◽  
Tolerogenic Dendritic Cells

Type 1 diabetes is a metabolic disease caused by autoimmunity towards β-cells. Different strategies have been developed to restore β-cell function and to reestablish immune tolerance to prevent and cure the disease. Currently, there is no effective treatment strategy to restore endogenous insulin secretion in patients with type 1 diabetes. This study aims to restore insulin secretion in diabetic mice with experimental antigen-specific immunotherapy alone or in combination with rapamycin, a compound well known for its immunomodulatory effect. Nonobese diabetic (NOD) mice develop spontaneous type 1 diabetes after 12 weeks of age. Autologous tolerogenic dendritic cells—consisting in dendritic cells pulsed with islet apoptotic cells—were administered to diabetic NOD mice alone or in combination with rapamycin. The ability of this therapy to revert type 1 diabetes was determined by assessing the insulitis score and by measuring both blood glucose levels and C-peptide concentration. Our findings indicate that tolerogenic dendritic cells alone or in combination with rapamycin do not ameliorate diabetes in NOD mice. These results suggest that alternative strategies may be considered for the cure of type 1 diabetes.

scholarly journals Rotavirus Infection of Infant and Young Adult Nonobese Diabetic Mice Involves Extraintestinal Spread and Delays Diabetes Onset

2007 ◽  
Vol 81 (12) ◽  
pp. 6446-6458 ◽  
Author(s):  
Kate L. Graham ◽  
Joanne A. O'Donnell ◽  
Yan Tan ◽  
Natalie Sanders ◽  
Emma M. Carrington ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Young Adult ◽  
Infectious Virus ◽  
Nod Mice ◽  
Islet Autoimmunity ◽  
Adult Mice ◽  
Nonobese Diabetic ◽  
Diabetes Development ◽  
Nonobese Diabetic Mice

ABSTRACT Rotaviruses have been implicated as a possible viral trigger for exacerbations in islet autoimmunity, suggesting they might modulate type 1 diabetes development. In this study, the ability of rotavirus strain RRV to infect the pancreas and affect insulitis and diabetes was examined in nonobese diabetic (NOD) mice, an experimental model of type 1 diabetes. Mice were inoculated either orally or intraperitoneally as infants or young adults. In infant mice inoculated orally, rotavirus antigen was detected in pancreatic macrophages outside islets and infectious virus was found in blood cells, pancreas, spleen, and liver. Extraintestinal RRV spread and pancreatic presence of infectious virus also occurred in intraperitoneally inoculated infant and adult mice. The initiation of insulitis was unaltered by infection. The onset of diabetes was delayed in infant mice inoculated orally and infant and adult mice inoculated intraperitoneally. In contrast, adult mice inoculated orally showed no evidence of pancreatic RRV, the lowest rate of detectable RRV replication, and no diabetes modulation. Thus, the ability of RRV infection to modulate diabetes development in infant and young adult NOD mice was related to the overall extent of detectable virus replication and the presence of infectious virus extraintestinally, including in the pancreas. These studies show that RRV infection of infant and young adult NOD mice provides significant protection against diabetes. As these findings do not support the hypothesis that rotavirus triggers autoimmunity related to type 1 diabetes, further research is needed to resolve this issue.

scholarly journals A Defect in Tryptophan Catabolism Impairs Tolerance in Nonobese Diabetic Mice

2003 ◽  
Vol 198 (1) ◽  
pp. 153-160 ◽  
Author(s):  
Ursula Grohmann ◽  
Francesca Fallarino ◽  
Roberta Bianchi ◽  
Ciriana Orabona ◽  
Carmine Vacca ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Cell Function ◽  
Nod Mice ◽  
Central Tolerance ◽  
Nonobese Diabetic ◽  
Tryptophan Catabolism ◽  
Ifn Γ ◽  
Nonobese Diabetic Mice ◽  
Antigen Presenting ◽  
Experimental Autoimmune

The predisposition of nonobese diabetic (NOD) mice to develop autoimmunity reflects deficiencies in both peripheral and central tolerance. Several defects have been described in these mice, among which aberrant antigen-presenting cell function and peroxynitrite formation. Prediabetes and diabetes in NOD mice have been targeted with different outcomes by a variety of immunotherapies, including interferon (IFN)-γ. This cytokine may be instrumental in specific forms of tolerance by virtue of its ability to activate immunosuppressive tryptophan catabolism. Here, we provide evidence that IFN-γ fails to induce tolerizing properties in dendritic cells from highly susceptible female mice early in prediabetes. This effect is associated with impaired tryptophan catabolism, is related to transient blockade of the Stat1 pathway of intracellular signaling by IFN-γ, and is caused by peroxynitrite production. However, the use of a peroxynitrite inhibitor can rescue tryptophan catabolism and tolerance in those mice. This is the first report of an experimental autoimmune disease in which defective tolerance is causally linked to impaired tryptophan catabolism.

scholarly journals Determination of gastric emptying in nonobese diabetic mice

2007 ◽  
Vol 293 (5) ◽  
pp. G1039-G1045 ◽  
Author(s):  
Kyoung Moo Choi ◽  
Jin Zhu ◽  
Gary J. Stoltz ◽  
Steven Vernino ◽  
Michael Camilleri ◽  
...  
Keyword(s):  
Gastric Emptying ◽  
Animal Studies ◽  
Time Course ◽  
Breath Test ◽  
Octanoic Acid ◽  
Nonobese Diabetic ◽  
Onset Of Diabetes ◽  
Nonobese Diabetic Mice

Animal studies on diabetic gastroparesis are limited by inability to follow gastric emptying changes in the same mouse. The study aim was to validate a nonlethal gastric emptying method in nonobese diabetic (NOD) LtJ mice, a model of type 1 diabetes, and study sequential changes with age and early diabetic status. The reliability and responsiveness of a [13C]octanoic acid breath test in NOD LtJ mice was tested, and the test was used to measure solid gastric emptying in NOD LtJ mice and nonobese diabetes resistant (NOR) LtJ mice. The 13C breath test produced results similar to postmortem recovery of a meal. Bethanechol accelerated gastric emptying [control: 92 ± 9 min; bethanechol: 53 ± 3 min, mean half emptying time ( T1/2) ± SE], and atropine slowed gastric emptying (control: 92 ± 9 min; atropine: 184 ± 31 min, mean T1/2 ± SE). Normal gastric emptying ( T1/2) in nondiabetic NOD LtJ mice (8–12 wk) was 91 ± 2 min. Aging had differing effects on gastric emptying in NOD LtJ and NOR LtJ mice. Onset of diabetes was accompanied by accelerated gastric emptying during weeks 1–2 of diabetes. Gastric emptying returned to normal by weeks 3–5 with no delay. The [13C]octanoic acid breath test accurately measures gastric emptying in NOD LtJ mice, is useful to study the time course of changes in gastric emptying in diabetic NOD LtJ mice, and is able to detect acceleration in gastric emptying early in diabetes. Opposing changes in gastric emptying between NOD LtJ and NOR LtJ mice suggest that NOR LtJ mice are not good controls for the study of gastric emptying in NOD LtJ mice.

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