scholarly journals TLR4 regulates cardiac lipid accumulation and diabetic heart disease in the nonobese diabetic mouse model of type 1 diabetes

2012 ◽  
Vol 303 (6) ◽  
pp. H732-H742 ◽  
Author(s):  
Baojun Dong ◽  
Dake Qi ◽  
Long Yang ◽  
Yan Huang ◽  
Xiaoyan Xiao ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Heart Disease ◽  
Lipid Accumulation ◽  
Nod Mice ◽  
Left Ventricular ◽  
Diabetic Heart ◽  
Early Stages ◽  
Nonobese Diabetic ◽  
Diabetic Heart Disease

Toll-like receptor (TLR)4 regulates inflammation and metabolism and has been linked to the pathogenesis of heart disease. TLR4 is upregulated in diabetic cardiomyocytes, and we examined the role of TLR4 in modulating cardiac fatty acid (FA) metabolism and the pathogenesis of diabetic heart disease in nonobese diabetic (NOD) mice. Both wild-type (WT) NOD and TLR4-deficient NOD animals had increased plasma triglyceride levels after the onset of diabetes. However, by comparison, TLR4-deficient NOD mouse hearts had lower triglyceride accumulation in the early stages of diabetes, which was associated with a reduction in myeloid differentiation primary response gene (88) (MyD88), phosphorylation of p38 MAPK (phospho-p38), lipoprotein lipase (LPL), and JNK levels but increased phospho-AMP-activated protein kinase (AMPK). Oleic acid treatment in H9C2 cardiomyocytes also led to cellular lipid accumulation, which was attenuated by TLR4 small interfering RNA. TLR4 deficiency in the cells decreased FA-induced augmentation of MyD88, phospho-p38, and LPL, suggesting that TLR4 may modulate FA-induced lipid metabolism in cardiomyocytes. In addition, although cardiac function was impaired in both diabetic WT NOD and TLR4-deficient NOD animals compared with control nondiabetic mice, this deficit was less in the diabetic TLR4-deficient NOD mice, which had greater ejection fraction, greater fractional shortening, and increased left ventricular developed pressure in the early stages after the development of diabetes compared with their diabetic WT NOD counterparts. Thus, we conclude that TLR4 plays a role in regulating lipid accumulation in cardiac muscle after the onset of type 1 diabetes, which may contribute to cardiac dysfunction.

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 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 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.

P2487Echocardiography and NT-ProBNP both provide independent and improved prediction of prognosis in a type 1 diabetes population without heart disease and with preserved ejection fraction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
R Roerth ◽  
P G Jorgensen ◽  
H U Andersen ◽  
J P Goetze ◽  
P Rossing ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Heart Disease ◽  
Ejection Fraction ◽  
Risk Prediction ◽  
Cardiovascular Events ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Risk Engine

Abstract Background Cardiovascular disease is the most common comorbidity in type 1 diabetes (T1D). Current guidelines, however, do not include routine echocardiography or cardiac biomarkers in T1D. Objectives To investigate if echocardiography and NT-proBNP provide incremental prognostic information in individuals with T1D without heart disease and with preserved left ventricular ejection fraction (LVEF). Methods A prospective cohort of individuals with T1D without heart disease and with preserved LVEF (≥45%) from the outpatient clinic were included. Follow-up was performed through Danish national registers. The association between E/e', a marker of diastolic function, from echocardiography and NT-proBNP with major adverse cardiovascular events (MACE) was tested. MACE was defined as death from all-causes, acute coronary syndromes, cardiac revascularization, incident heart failure, or stroke. Additionally, the incremental prognostic value when adding E/e' and NT-proBNP to the clinical Steno T1D Risk Engine score (including age, sex, duration of diabetes, systolic blood pressure, LDL, HbA1c, presence of albuminuria (micro-or macroalbuminuria), eGFR, smoking status, and physical activity [low, medium, high]), was examined. Follow-up was 100% complete. Results Of 964 individuals (mean (SD)) age 49.7 (14.5) years, 51% men, HbA1c 66 (14) mmol/mol, BMI 25.6 (4.0) kg/m2, and diabetes duration 26.1 (14.5) years), 121 (12.6%) experienced MACE during 7.5 years of follow-up. In the full multivariable model, E/e' significantly and independently predicted MACE: (HR (95%)) E/'e <8 (n=639) vs. 8–12 (n=248): 2.00 (1.23; 3.25), p=0.005, E/'e <8 vs E/e'≥12 (n=77): 3.36 (1.8; 6.1), p<0.001. Also, NT-proBNP significantly predicted outcome: NT-proBNP <150 pg/ml (n=435) vs. 150–450 pg/ml (n=386): 1.52 (0.9; 2.5), p=0.11, NT-proBNP <150 pg/ml vs NT-proBNP >450 pg/ml (n=143): 2.78 (1.6; 4.9), p<0.001. Adding both (log)E/e' and (log)NT-proBNP to the Steno T1D Risk Engine score significantly and incrementally improved risk prediction: Harrell's C-index: Steno T1D Risk Engine (AUC 0.783 (0.747; 0.818)) vs. Steno T1D Risk Engine + (log)E/e' (AUC 0.805 (0.773; 0.837)): p<0.001 and Steno T1D Risk Engine + (log)E/e' + (log) NT-proBNP (AUC 0.816 (0.783; 0.848)): p=0.002. The risk of MACE by groups of E/e' and NT-proBNP is shown in the figure. Figure 1 Conclusion In individuals with T1D without heart disease and with preserved LVEF, E/e' and NT-proBNP significantly improved risk prediction of cardiovascular events beyond clinical risk factors alone. Echocardiography and NT-proBNP could have a role in clinical care.

scholarly journals Systemic Delivery of TNF-Related Apoptosis-Inducing Ligand (TRAIL) Elevates Levels of Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) and Prevents Type 1 Diabetes in Nonobese Diabetic Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5638-5646 ◽  
Author(s):  
Soojeong Kang ◽  
Eun-Jin Park ◽  
Yeonsoo Joe ◽  
Eunhui Seo ◽  
Mi-Kyoung Park ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Blood Glucose ◽  
Gelatin Zymography ◽  
Nod Mice ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitor ◽  
Nonobese Diabetic ◽  
Induced Apoptosis

Recent studies have demonstrated that TNF-related apoptosis-inducing ligand (TRAIL) is a modulator of the immune response. The relation between TRAIL and type 1 diabetes (T1D) as an autoimmune inflammatory disease in vivo is relatively unknown. To explore the potential role of TRAIL in the development of T1D, we examined its in vivo effects in nonobese diabetic (NOD) mice. NOD mice at 7 wk of age were iv injected with an adenovirus carrying either human TRAIL (Ad.hTRAIL) or β-galactosidase genes. Blood glucose was monitored weekly, and the expression of hTRAIL was evaluated in plasma and liver of mice. To investigate whether hTRAIL elicits its effect through the induction of tissue inhibitor of metalloproteinase-1 (TIMP-1), we examined the concentration of plasma TIMP-1 by ELISA and the inhibition of matrix metalloproteinase (MMP) by gelatin zymography. Here, we show that Ad.hTRAIL-transduced mice had significantly reduced blood glucose levels and markedly increased production of TIMP-1 compared with control β-galactosidase animals. Pancreatic tissue isolated from Ad.hTRAIL-treated NOD mice showed reduced MMP activities associated with significantly improved insulitis. In addition, TIMP-1 in vitro suppressed cytokine-induced apoptosis in insulin-producing INS-1 cells. These results indicate that T1D can be prevented by TRAIL overexpression through enhancement of TIMP-1 function. Elevated TIMP-1 production inhibits the activity of MMPs, which may contribute to suppress the transmigration of diabetogenic T cells into the pancreatic islets and protects pancreatic β-cells from cytokine-induced apoptosis. Therefore, TRAIL and TIMP-1 induction may be potential targets to prevent development of T1D.

scholarly journals Prevention of type 1 diabetes in mice by tolerogenic vaccination with a strong agonist insulin mimetope

2011 ◽  
Vol 208 (7) ◽  
pp. 1501-1510 ◽  
Author(s):  
Carolin Daniel ◽  
Benno Weigmann ◽  
Roderick Bronson ◽  
Harald von Boehmer
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Nod Mice ◽  
Nonobese Diabetic ◽  
Cell Clones ◽  
Autoimmune Attack ◽  
Agonistic Activity ◽  
Novel Strategy

Type 1 diabetes (T1D) results from the destruction of insulin-secreting pancreatic β cells by autoreactive T cells. Insulin is an essential target of the autoimmune attack. Insulin epitopes recognized by diabetogenic T cell clones bind poorly to the class II I-Ag7 molecules of nonobese diabetic (NOD) mice, which results in weak agonistic activity of the peptide MHC complex. Here, we describe a strongly agonistic insulin mimetope that effectively converts naive T cells into Foxp3+ regulatory T cells in vivo, thereby completely preventing T1D in NOD mice. In contrast, natural insulin epitopes are ineffective. Subimmunogenic vaccination with strongly agonistic insulin mimetopes might represent a novel strategy to prevent T1D in humans at risk for the disease.

scholarly journals Human Cord Blood Stem Cell-Modulated Regulatory T Lymphocytes Reverse the Autoimmune-Caused Type 1 Diabetes in Nonobese Diabetic (NOD) Mice

PLoS ONE ◽  
2009 ◽  
Vol 4 (1) ◽  
pp. e4226 ◽  
Author(s):  
Yong Zhao ◽  
Brian Lin ◽  
Robert Darflinger ◽  
Yongkang Zhang ◽  
Mark J. Holterman ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Stem Cell ◽  
T Lymphocytes ◽  
Cord Blood ◽  
Nod Mice ◽  
Human Cord Blood ◽  
Regulatory T Lymphocytes ◽  
Nonobese Diabetic ◽  
Cord Blood Stem Cell

scholarly journals N-Acetyl-l-Cysteine Supplement in Early Life or Adulthood Reduces Progression of Diabetes in Nonobese Diabetic Mice

2018 ◽  
Vol 3 (4) ◽  
Author(s):  
Lital Argaev Frenkel ◽  
Hava Rozenfeld ◽  
Konstantin Rozenberg ◽  
Sanford R Sampson ◽  
Tovit Rosenzweig
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Type 1 Diabetes ◽  
Antioxidant Enzymes ◽  
Early Life ◽  
Nod Mice ◽  
Morbidity Rate ◽  
Nonobese Diabetic ◽  
Total Antioxidant

ABSTRACT Background Oxidative stress contributes to the pathologic process leading to the development, progression, and complications of type 1 diabetes (T1D). Objective The aim of this study was to investigate the effect of the antioxidant N-acetyl-l-cysteine (NAC), supplemented during early life or adulthood on the development of T1D. Methods NAC was administered to nonobese diabetic (NOD) female mice during pregnancy and lactation, and the development of diabetes was followed in offspring. In an additional set of experiments, offspring of untreated mice were given NAC during adulthood, and the development of T1D was followed. Morbidity rate, insulitis and serum cytokines were measured in the 2 sets of experiments. In addition, markers of oxidative stress, glutathione, lipid peroxidation, total antioxidant capacity and activity of antioxidant enzymes, were followed. Results Morbidity rate was reduced in both treatment protocols. A decrease in interferon γ, tumor necrosis factor α, interleukin 1α, and other type 1 diabetes-associated proinflammatory cytokines was found in mice supplemented with NAC in adulthood or during early life compared with control NOD mice. The severity of insulitis was higher in control NOD mice than in treated groups. NAC administration significantly reduced oxidative stress, as determined by reduced lipid peroxidation and increased total antioxidant capacity in serum and pancreas of mice treated in early life or in adulthood and increased pancreatic glutathione when administrated in adulthood. The activity of antioxidant enzymes was not affected in mice given NAC in adulthood, whereas an increase in the activity of superoxide dismutase and catalase was demonstrated in the pancreas of their offspring. Conclusion NAC decreased morbidity of NOD mice by attenuating the immune response, presumably by eliminating oxidative stress, and might be beneficial in reducing morbidity rates of T1D in high-risk individuals.

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