scholarly journals Knockout of the Amino Acid Transporter SLC6A19 and Autoimmune Diabetes Incidence in Female Non-Obese Diabetic (NOD) Mice

Metabolites ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 665
Author(s):  
Matthew F. Waters ◽  
Viviane Delghingaro-Augusto ◽  
Kiran Javed ◽  
Jane E. Dahlstrom ◽  
Gaetan Burgio ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Amino Acid ◽  
Confidence Interval ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Amino Acid Transporter ◽  
Diabetes Incidence ◽  
Amino Acid Availability ◽  
Acid Transporter

High protein feeding has been shown to accelerate the development of type 1 diabetes in female non-obese diabetic (NOD) mice. Here, we investigated whether reducing systemic amino acid availability via knockout of the Slc6a19 gene encoding the system B(0) neutral amino acid transporter AT1 would reduce the incidence or delay the onset of type 1 diabetes in female NOD mice. Slc6a19 gene deficient NOD mice were generated using the CRISPR-Cas9 system which resulted in marked aminoaciduria. The incidence of diabetes by week 30 was 59.5% (22/37) and 69.0% (20/29) in NOD.Slc6a19+/+ and NOD.Slc6a19−/− mice, respectively (hazard ratio 0.77, 95% confidence interval 0.41–1.42; Mantel-Cox log rank test: p = 0.37). The median survival time without diabetes was 28 and 25 weeks for NOD.Slc6a19+/+ and NOD.Slc6a19−/− mice, respectively (ratio 1.1, 95% confidence interval 0.6–2.0). Histological analysis did not show differences in islet number or the degree of insulitis between wild type and Slc6a19 deficient NOD mice. We conclude that Slc6a19 deficiency does not prevent or delay the development of type 1 diabetes in female NOD mice.

scholarly journals Proinsulin peptide promotes autoimmune diabetes in a novel HLA-DR3-DQ2-transgenic murine model of spontaneous disease

Diabetologia ◽  
2019 ◽  
Vol 62 (12) ◽  
pp. 2252-2261 ◽  
Author(s):  
Johan Verhagen ◽  
Norkhairin Yusuf ◽  
Emma L. Smith ◽  
Emily M. Whettlock ◽  
Kerina Naran ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Autoimmune Diabetes ◽  
Diabetes Incidence ◽  
Human Type ◽  
Insulin Promoter ◽  
Human Type 1 Diabetes ◽  
Hla Dr3 ◽  
Peptide Region

Abstract Aims/hypothesis The molecular basis for the pathological impact of specific HLA molecules on autoimmune diseases such as type 1 diabetes remains unclear. Recent natural history studies in children have indicated a link between specific HLA genotypes and the first antigenic target against which immune responses develop. We set out to examine this link in vivo by exploring the diabetogenicity of islet antigens on the background of a common diabetes-associated HLA haplotype. Methods We generated a novel HLA-transgenic mouse model that expresses high-risk genes for type 1 diabetes (DRB1*03:01-DQA1*05:01-DQB1*02:01) as well as human CD80 under the rat insulin promoter and human CD4, on a C57BL/6 background. Adjuvanted antigen priming was used to reveal the diabetogenicity of candidate antigens and peptides. Results HLA-DR3-DQ2+huCD4+IA/IE−/−RIP.B7.1+ mice spontaneously developed autoimmune diabetes (incidence 46% by 35 weeks of age), accompanied by numerous hallmarks of human type 1 diabetes (autoantibodies against GAD65 and proinsulin; pancreatic islet infiltration by CD4+, CD8+ B220+, CD11b+ and CD11c+ immune cells). Disease was markedly accelerated and had deeper penetrance after adjuvanted antigen priming with proinsulin (mean onset 11 weeks and incidence 100% by 20 weeks post challenge). Moreover, the diabetogenic effect of proinsulin located to the 15-residue B29-C11 region. Conclusions/interpretation Our study identifies a proinsulin-derived peptide region that is highly diabetogenic on the HLA-DR3-DQ2 background using an in vivo model. This approach and the peptide region identified may have wider implications for future studies of human type 1 diabetes.

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 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 Soy-dairy protein blend and whey protein ingestion after resistance exercise increases amino acid transport and transporter expression in human skeletal muscle

2014 ◽  
Vol 116 (11) ◽  
pp. 1353-1364 ◽  
Author(s):  
P. T. Reidy ◽  
D. K. Walker ◽  
J. M. Dickinson ◽  
D. M. Gundermann ◽  
M. J. Drummond ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amino Acid ◽  
Whey Protein ◽  
Amino Acid Transport ◽  
Amino Acid Transporter ◽  
Acid Transport ◽  
Amino Acid Availability ◽  
Acid Transporter ◽  
Dairy Protein ◽  
Myofibrillar Protein Synthesis

Increasing amino acid availability (via infusion or ingestion) at rest or postexercise enhances amino acid transport into human skeletal muscle. It is unknown whether alterations in amino acid availability, from ingesting different dietary proteins, can enhance amino acid transport rates and amino acid transporter (AAT) mRNA expression. We hypothesized that the prolonged hyperaminoacidemia from ingesting a blend of proteins with different digestion rates postexercise would enhance amino acid transport into muscle and AAT expression compared with the ingestion of a rapidly digested protein. In a double-blind, randomized clinical trial, we studied 16 young adults at rest and after acute resistance exercise coupled with postexercise (1 h) ingestion of either a (soy-dairy) protein blend or whey protein. Phenylalanine net balance and transport rate into skeletal muscle were measured using stable isotopic methods in combination with femoral arteriovenous blood sampling and muscle biopsies obtained at rest and 3 and 5 h postexercise. Phenylalanine transport into muscle and mRNA expression of select AATs [system L amino acid transporter 1/solute-linked carrier (SLC) 7A5, CD98/SLC3A2, system A amino acid transporter 2/SLC38A2, proton-assisted amino acid transporter 1/SLC36A1, cationic amino acid transporter 1/SLC7A1] increased to a similar extent in both groups ( P < 0.05). However, the ingestion of the protein blend resulted in a prolonged and positive net phenylalanine balance during postexercise recovery compared with whey protein ( P < 0.05). Postexercise myofibrillar protein synthesis increased similarly between groups. We conclude that, while both protein sources enhanced postexercise AAT expression, transport into muscle, and myofibrillar protein synthesis, postexercise ingestion of a protein blend results in a slightly prolonged net amino acid balance across the leg compared with whey protein.

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.

11-Keto-β-Boswellic Acid Inhibits Lymphocyte (CD3) Infiltration Into Pancreatic Islets of Young None Obese Diabetic (NOD) Mice

2017 ◽  
Vol 49 (09) ◽  
pp. 693-700 ◽  
Author(s):  
Ahmed Shehata ◽  
Leticia Quintanilla-Fend ◽  
Sabrina Bettio ◽  
Zahra Kamyabi-Moghaddam ◽  
Ursula Kohlhofer ◽  
...  
Keyword(s):  
Animal Model ◽  
Type 1 Diabetes ◽  
Body Weight ◽  
Pancreatic Islets ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Apoptotic Cells ◽  
Boswellic Acid ◽  
Human Type 1 Diabetes

Abstract11-Keto-β-Boswellic acid (KBA) has been shown to prevent infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by injection of Multiple Low Doses of Streptozotocin (MLD-STZ), which is a chemical compound belonging to the class of nitrososureas. The aim of this work was to study whether or not KBA can also prevent/attenuate infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by genetic dysfunction resembling human type 1 diabetes in several important features. Four weeks old female NOD mice received daily i.p. injections of 7.5 mg/kg of KBA over a period of 3 weeks. Compared to 4 weeks old animals there was significant infiltration of lymphocytes (CD3) into pancreatic islets and appearance of peri-insular apoptotic cells in the period between 4 and 7 weeks. During this time plasma glucose dropped significantly and body weight did not increase. As far as pro-inflammatory cytokines are concerned, except a small increase of IFN-γ, there was no change in the blood. In mice that had been treated with KBA between 4 and 7 weeks after birth no significant infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells was observed, when compared to 4 weeks old mice. Moreover, there was no drop of blood glucose and the animals gained body weight. It is concluded that – similar to the model of MLD-STZ-diabetes – also in the NOD mouse model KBA is able to attenuate or even prevent development of insulitis, suggesting that KBA protects islets from autoimmune reaction regardless whether the signal is provided by a chemical compound or by genetic dysfunction. Whether this also holds for human type 1 diabetes remains to be established.

scholarly journals Effective Destruction of Fas-deficient Insulin-producing β Cells in Type 1 Diabetes

2003 ◽  
Vol 198 (7) ◽  
pp. 1103-1106 ◽  
Author(s):  
Irina Apostolou ◽  
Zhenyue Hao ◽  
Klaus Rajewsky ◽  
Harald von Boehmer
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Type 1 Diabetes ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Β Cells ◽  
Β Cell ◽  
Influenza Hemagglutinin ◽  
Insulin Promoter

In type 1 diabetes, autoimmune T cells cause destruction of pancreatic β cells by largely unknown mechanism. Previous analyses have shown that β cell destruction is delayed but can occur in perforin-deficient nonobese diabetic (NOD) mice and that Fas-deficient NOD mice do not develop diabetes. However, because of possible pleiotropic functions of Fas, it was not clear whether the Fas receptor was an essential mediator of β cell death in type 1 diabetes. To directly test this hypothesis, we have generated a β cell–specific knockout of the Fas gene in a transgenic model of type 1 autoimmune diabetes in which CD4+ T cells with a transgenic TCR specific for influenza hemagglutinin (HA) are causing diabetes in mice that express HA under control of the rat insulin promoter. Here we show that the Fas-deficient mice develop autoimmune diabetes with slightly accelerated kinetics indicating that Fas-dependent apoptosis of β cells is a dispensable mode of cell death in this disease.

scholarly journals Peptidylarginine deiminase inhibition prevents diabetes development in NOD mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Fernanda M. C. Sodré ◽  
Samal Bissenova ◽  
Ylke Bruggeman ◽  
Ronak Tilvawala ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Autoimmune Diseases ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Effector Memory ◽  
Cell Reactivity ◽  
Diabetes Development ◽  
T Cell Reactivity

Protein citrullination plays a role in several autoimmune diseases. Its involvement in murine and human type 1 diabetes has recently been recognized through the discovery of antibodies and T-cell reactivity against citrullinated peptides. In the current study, we demonstrate that systemic inhibition of peptidylarginine deiminases (PADs), the enzymes mediating citrullination, through BB-Cl-amidine treatment, prevents diabetes development in NOD mice. This prevention was associated with reduced levels of citrullination in the pancreas, decreased circulating autoantibody titers against citrullinated GRP78 and reduced spontaneous NETosis of bone marrow-derived neutrophils. Moreover, BB-Cl-amidine treatment induced a shift from Th1 to Th2 cytokines in the serum and an increase in the frequency of regulatory T cells in the blood and spleen. In the pancreas, BB-Cl-amidine treatment preserved insulin production and was associated with a less destructive immune infiltrate, characterized by reduced frequencies of effector memory CD4<sup>+</sup> T cells and a modest reduction in the frequency of IFNγ-producing CD4<sup>+</sup> and CD8<sup>+</sup> T cells. Our results point to a role of citrullination in the pathogenesis of autoimmune diabetes, with PAD inhibition leading to disease prevention through modulation of immune pathways. These findings provide insight in the potential of PAD inhibition for treating autoimmune diseases like type 1 diabetes.

scholarly journals Peripherally-induced regulatory T cells contribute to the control of autoimmune diabetes

2017 ◽  
Author(s):  
Cornelia Schuster ◽  
Fangzhu Zhao ◽  
Stephan Kissler
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Pancreatic Beta Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Beta Cell Autoimmunity ◽  
Autoimmune Destruction ◽  
Treg Function ◽  
Distinct Role

AbstractType 1 diabetes (T1D) results from the autoimmune destruction of pancreatic beta cells and is partly caused by deficiencies in the Foxp3+ regulatory T cell (Treg) compartment. Conversely, therapies that increase Treg function can prevent autoimmune diabetes in animal models. The majority of Tregs develop in the thymus (tTregs), but a proportion of Foxp3+ Tregs is generated in the periphery (pTregs) from Foxp3-CD4+ T cell precursors. Whether pTregs play a distinct role in T1D has not yet been explored. We report here that pTregs are a key modifier of disease in the nonobesed diabetic (NOD) mouse model for T1D. We generated NOD mice deficient for the Foxp3 enhancer CNS1 involved in pTreg induction. We show that CNS1 knockout decreased the frequency of pTregs and increased the risk of diabetes. Our results show that pTregs fulfill an important non-redundant function in the prevention of beta cell autoimmunity that causes T1D.

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