scholarly journals Glucagon-Like Peptide-2 Reduces Intestinal Permeability But Does Not Modify the Onset of Type 1 Diabetes in the Nonobese Diabetic Mouse

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 592-599 ◽  
Author(s):  
Irene Hadjiyanni ◽  
Kunmin Karen Li ◽  
Daniel J. Drucker
Keyword(s):  
Type 1 Diabetes ◽  
Intestinal Permeability ◽  
Barrier Function ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Gut Barrier ◽  
Nonobese Diabetic ◽  
Gut Barrier Function ◽  
Glucagon Like Peptide

The development of type 1 diabetes (T1D) has been linked to environmental factors and dietary components. Increasing evidence indicates that the integrity of the gut mucosa plays a role in the development of autoimmune diseases, and evidence from both preclinical and clinical studies demonstrates that increased leakiness of the intestinal epithelium precedes the development of type 1 diabetes. However, there is limited information on modulation of gut barrier function and its relationship to diabetes development. Here we show that the nonobese diabetic (NOD) mouse, a model of T1D, exhibits enhanced intestinal transcellular permeability before the development of autoimmune diabetes. Treatment of NOD mice with a glucagon-like peptide 2 (GLP-2) analog, synthetic human [Gly2] glucagon-like peptide-2 (h[Gly2]GLP-2, increased the length and weight of the small bowel and significantly improved jejunal transepithelial resistance. However, chronic administration of once daily h[Gly2]GLP-2 failed to delay or reverse the onset of T1D when treatment was initiated in young, normoglycemic female NOD mice. Furthermore, h[Gly2]GLP-2 administration had no significant effect on lymphocyte subpopulations in NOD mice. These findings demonstrate that h[Gly2]GLP-2-mediated enhancement of gut barrier function in normoglycemic NOD mice disease is not sufficient to prevent or delay the development of experimental T1D. Increased intestinal permeability often precedes the clinical appearance of autoimmune disorders such as celiac disease or type 1 diabetes. These studies show that glucagon-like peptide 2 reduces gut permeability, but not the onset of diabetes in NOD mice.

scholarly journals Foxp3+Regulatory T Cells in Mouse Models of Type 1 Diabetes

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Cathleen Petzold ◽  
Julia Riewaldt ◽  
Deepika Watts ◽  
Tim Sparwasser ◽  
Sonja Schallenberg ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Mouse Models ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Treg Cells ◽  
Genetically Engineered ◽  
Genetically Engineered Mouse Models ◽  
Nonobese Diabetic ◽  
Human Type 1 Diabetes

Studies on human type 1 diabetes (T1D) are facilitated by the availability of animal models such as nonobese diabetic (NOD) mice that spontaneously develop autoimmune diabetes, as well as a variety of genetically engineered mouse models with reduced genetic and pathogenic complexity, as compared to the spontaneous NOD model. In recent years, increasing evidence has implicated CD4+CD25+regulatory T (Treg) cells expressing the transcription factor Foxp3 in both the breakdown of self-tolerance and the restoration of immune homeostasis in T1D. In this paper, we provide an overview of currently available mouse models to study the role of Foxp3+Treg cells in the control of destructiveβcell autoimmunity, including a novel NOD model that allows specific and temporally controlled deletion of Foxp3+Treg cells.

scholarly journals Replacing murine insulin 1 with human insulin protects NOD mice from diabetes

2019 ◽  
Author(s):  
Colleen M. Elso ◽  
Nicholas A. Scott ◽  
Lina Mariana ◽  
Emma I. Masterman ◽  
Andrew P.R. Sutherland ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cells ◽  
Mouse Models ◽  
Human Insulin ◽  
Murine Model ◽  
Pancreatic Beta Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Human Type 1 Diabetes

AbstractType 1, or autoimmune, diabetes is caused by the T-cell mediated destruction of the insulin-producing pancreatic beta cells. Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes akin to human type 1 diabetes. For this reason, the NOD mouse has been the preeminent murine model for human type 1 diabetes research for several decades. However, humanized mouse models are highly sought after because they offer both the experimental tractability of a mouse model and the clinical relevance of human-based research. Autoimmune T-cell responses against insulin, and its precursor proinsulin, play central roles in the autoimmune responses against pancreatic beta cells in both humans and NOD mice. As a first step towards developing a murine model of the human autoimmune response against pancreatic beta cells we set out to replace the murine insulin 1 gene (Ins1) with the human insulin gene (INS) using CRISPR/Cas9. Here we describe a NOD mouse strain that expresses human insulin in place of murine insulin 1, referred to as HuPI. HuPI mice express human insulin, and C-peptide, in their serum and pancreata and have normal glucose tolerance. Compared with wild type NOD mice, the incidence of diabetes is much lower in HuPI mice. Only 15-20% of HuPI mice developed diabetes after 300 days, compared to more than 60% of unmodified NOD mice. Immune-cell infiltration into the pancreatic islets of HuPI mice was not detectable at 100 days but was clearly evident by 300 days. This work highlights the feasibility of using CRISPR/Cas9 to create mouse models of human diseases that express proteins pivotal to the human disease. Furthermore, it reveals that even subtle changes in proinsulin protect NOD mice from diabetes.

scholarly journals Rodent Models for Investigating the Dysregulation of Immune Responses in Type 1 Diabetes

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Feng-Cheng Chou ◽  
Heng-Yi Chen ◽  
Shyi-Jou Chen ◽  
Mei-Cho Fang ◽  
Huey-Kang Sytwu
Keyword(s):  
Type 1 Diabetes ◽  
Animal Studies ◽  
Genetic Manipulation ◽  
Nod Mice ◽  
Environmental Parameters ◽  
Conditional Knockout ◽  
Therapeutic Approaches ◽  
Nonobese Diabetic ◽  
Genetically Manipulated

Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells that selectively destroy the insulin-producingβcells. Previous reports based on epidemiological and animal studies have demonstrated that both genetic factors and environmental parameters can either promote or attenuate the progression of autoimmunity. In recent decades, several inbred rodent strains that spontaneously develop diabetes have been applied to the investigation of the pathogenesis of T1D. Because the genetic manipulation of mice is well developed (transgenic, knockout, and conditional knockout/transgenic), most studies are performed using the nonobese diabetic (NOD) mouse model. This paper will focus on the use of genetically manipulated NOD mice to explore the pathogenesis of T1D and to develop potential therapeutic approaches.

scholarly journals Histidine Decarboxylase Deficiency Prevents Autoimmune Diabetes in NOD Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Manal Alkan ◽  
François Machavoine ◽  
Rachel Rignault ◽  
Julie Dam ◽  
Michel Dy ◽  
...  
Keyword(s):  
Histidine Decarboxylase ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Wild Type ◽  
Gene Encoding ◽  
Nonobese Diabetic ◽  
Endogenous Histamine ◽  
Wild Type Counterpart

Recent evidence has highlighted the role of histamine in inflammation. Since this monoamine has also been strongly implicated in the pathogenesis of type-1 diabetes, we assessed its effect in the nonobese diabetic (NOD) mouse model. To this end, we used mice (inactivated) knocked out for the gene encoding histidine decarboxylase, the unique histamine-forming enzyme, backcrossed on a NOD genetic background. We found that the lack of endogenous histamine in NOD HDC−/−mice decreased the incidence of diabetes in relation to their wild-type counterpart. Whereas the proportion of regulatory T and myeloid-derived suppressive cells was similar in both strains, histamine deficiency was associated with increased levels of immature macrophages, as compared with wild-type NOD mice. Concerning the cytokine pattern, we found a decrease in circulating IL-12 and IFN-γin HDC−/−mice, while IL-6 or leptin remained unchanged, suggesting that histamine primarily modulates the inflammatory environment. Paradoxically, exogenous histamine given to NOD HDC−/−mice provided also protection against T1D. Our study supports the notion that histamine is involved in the pathogenesis of diabetes, thus providing additional evidence for its role in the regulation of the immune response.

scholarly journals Genetic and functional data identifying Cd101 as a type 1 diabetes (T1D) susceptibility gene in nonobese diabetic (NOD) mice

PLoS Genetics ◽  
2019 ◽  
Vol 15 (6) ◽  
pp. e1008178 ◽  
Author(s):  
Jochen Mattner ◽  
Javid P. Mohammed ◽  
Michael E. Fusakio ◽  
Claudia Giessler ◽  
Carl-Philipp Hackstein ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Functional Data ◽  
Susceptibility Gene ◽  
Nod Mice ◽  
Nonobese Diabetic

scholarly journals 2’-fucosyllactose (2’-FL) Supplementation Improves Gut Barrier Function and Lipid Metabolism in HF-fed Mice

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 425-425
Author(s):  
Sunhye Lee ◽  
Michael Goodson ◽  
Wendie Vang ◽  
Karen Kalanetra ◽  
Daniela Barile ◽  
...  
Keyword(s):  
Body Weight ◽  
Lipid Metabolism ◽  
Intestinal Permeability ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Gut Barrier ◽  
Low Fat ◽  
Barrier Integrity ◽  
Gut Barrier Function

Abstract Objectives 2’-fucosyllactose (2’-FL), the most predominant oligosaccharide found in human milk, acts as a prebiotic with beneficial effects on the host. The aim of this study was to determine the beneficial effect of 2’-FL on intestinal barrier integrity and metabolic functions in low-fat (LF)- and high-fat (HF)-fed mice. Methods Male C57/BL6 mice (n = 32, 8/group; 6 weeks old, JAX, CA) were counter-balanced into four weight-matched groups and fed either a low-fat (LF; 10% kcal fat with 7% kcal sucrose) or HF (45% kcal fat with 17% kcal sucrose) with or without supplementation of 2’-FL in the diet [10% (w/w), 8 weeks; LF/2’-FL or HF/2’-FL; BASF, Germany]. General phenotypes (body weight, energy intake, fat and lean mass), intestinal permeability (ex vivo in Ussing chambers), lipid profiles, and microbial metabolites were assessed. Results 2’-FL significantly attenuated the HF-induced increase in body fat mass with a trend to decrease body weight gain. 2’-FL significantly decreased intestinal permeability in LF-fed mice with a trend for a decrease in HF-fed mice. This was associated with a significant increase in interleukin-22, a cytokine known to have a protective role in intestinal barrier function. Visceral adipocyte size was significantly decreased by 2’-FL in both LF- and HF-fed mice. 2’-FL suppressed HF-induced upregulation of adipogenic transcription factors peroxisome proliferator-activated receptor gamma and sterol regulatory element binding protein-1c in the liver. Lastly, 2’-FL supplementation led to a significant elevation of lactic acid concentration in the cecum of HF-fed mice, which is known to be a product from beneficial microbes. Conclusions 2’-FL supplementation improved gut barrier integrity and lipid metabolism in mice with and without the metabolic challenge of HF feeding. These findings support the use of 2’-FL in the control of gut barrier function and metabolic homeostasis under normal and abnormal physiological conditions. Funding Sources BASF (Germany).

scholarly journals Comparative Pathogenesis of Autoimmune Diabetes in Humans, NOD Mice, and Canines: Has a Valuable Animal Model of Type 1 Diabetes Been Overlooked?

Diabetes ◽  
2017 ◽  
Vol 66 (6) ◽  
pp. 1443-1452 ◽  
Author(s):  
Allison L. O’Kell ◽  
Clive Wasserfall ◽  
Brian Catchpole ◽  
Lucy J. Davison ◽  
Rebecka S. Hess ◽  
...  
Keyword(s):  
Animal Model ◽  
Type 1 Diabetes ◽  
Autoimmune Diabetes ◽  
Nod Mice

scholarly journals Large Gliadin Peptides Detected in the Pancreas of NOD and Healthy Mice following Oral Administration

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Susanne W. Bruun ◽  
Knud Josefsen ◽  
Julia T. Tanassi ◽  
Aleš Marek ◽  
Martin H. F. Pedersen ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cells ◽  
Degradation Products ◽  
Intestinal Barrier ◽  
Nod Mice ◽  
Radioactive Label ◽  
Nonobese Diabetic ◽  
Gliadin Peptide ◽  
Gliadin Peptides

Gluten promotes type 1 diabetes in nonobese diabetic (NOD) mice and likely also in humans. In NOD mice and in non-diabetes-prone mice, it induces inflammation in the pancreatic lymph nodes, suggesting that gluten can initiate inflammation locally. Further, gliadin fragments stimulate insulin secretion from beta cells directly. We hypothesized that gluten fragments may cross the intestinal barrier to be distributed to organs other than the gut. If present in pancreas, gliadin could interact directly with the immune system and the beta cells to initiate diabetes development. We orally and intravenously administered 33-mer and 19-mer gliadin peptide to NOD, BALB/c, and C57BL/6 mice and found that the peptides readily crossed the intestinal barrier in all strains. Several degradation products were found in the pancreas by mass spectroscopy. Notably, the exocrine pancreas incorporated large amounts of radioactive label shortly after administration of the peptides. The study demonstrates that, even in normal animals, large gliadin fragments can reach the pancreas. If applicable to humans, the increased gut permeability in prediabetes and type 1 diabetes patients could expose beta cells directly to gliadin fragments. Here they could initiate inflammation and induce beta cell stress and thus contribute to the development of type 1 diabetes.

scholarly journals The Intestinal Epithelial Insulin-Like Growth Factor-1 Receptor Links Glucagon-Like Peptide-2 Action to Gut Barrier Function

Endocrinology ◽  
2014 ◽  
Vol 155 (2) ◽  
pp. 370-379 ◽  
Author(s):  
Charlotte X. Dong ◽  
Wen Zhao ◽  
Chloe Solomon ◽  
Katherine J. Rowland ◽  
Cameron Ackerley ◽  
...  
Keyword(s):  
Growth Factor ◽  
Barrier Function ◽  
Insulin Like Growth Factor ◽  
Intestinal Epithelial ◽  
Gut Barrier ◽  
Gut Barrier Function ◽  
Glucagon Like Peptide

scholarly journals Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type-1 diabetes

2020 ◽  
Author(s):  
Heejoo Kim ◽  
Jelena Perovanovic ◽  
Arvind Shakya ◽  
Zuolian Shen ◽  
Cody N. German ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Target Genes ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Glucose Levels ◽  
Transcriptional Coregulator

AbstractThe transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell-specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell-specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8+ T cell receptor specificities associated with diabetes pathogenesis. CD4+ clones associated with diabetes were present, but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice, but diminished in monoclonal models specific to artificial or neoantigens. Rationally-designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels, and reduced T cell infiltration and proinflammatory cytokine expression in newly-diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition.~40-word summary statement for the online JEM table of contents and alertsKim and colleagues show that OCA-B in T cells is essential for the generation of type-1 diabetes. OCA-B loss leaves the pancreatic lymph nodes largely undisturbed, but associates autoreactive CD4+ T cells in the pancreas with anergy while deleting potentially autoreactive CD8+ T cells.SummaryKim et al. show that loss or inhibition of OCA-B in T cells protects mice from type-1 diabetes.

Sign in / Sign up

Export Citation Format

Share Document