scholarly journals Dexi disruption depletes gut microbial metabolites and accelerates autoimmune diabetes

2018 ◽  
Author(s):  
LJ Davison ◽  
MD Wallace ◽  
C Preece ◽  
K Hughes ◽  
JA Todd ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Gut Microbiome ◽  
Pancreatic Beta Cell ◽  
Nod Mouse ◽  
Microbial Metabolites ◽  
Beta Cell Destruction ◽  
Cell Destruction ◽  
Autoimmune Attack

AbstractNon-coding genetic variants in the CLEC16A gene on human chromosome 16p13.13 are associated with risk of autoimmune diseases, including type 1 diabetes and multiple sclerosis. In this region, we previously identified DEXI, a candidate causal gene of unknown function, which alters the risk of type 1 diabetes, where the T1D predisposing allele is associated with lower DEXI expression. Here, we demonstrate by CRISPR mutagenesis in vivo and deep phenotyping that disrupted Dexi expression accelerates diabetes in the non-obese diabetic (NOD) mouse, a spontaneous model of autoimmune pancreatic beta-cell destruction. Mutant mice have increased serum IgM and IgA concentrations compared to wild-type NOD mice, as well as changes in both the gut microbiome and molecular metabolites associated with microbial metabolism. These findings suggest that the mechanism by which DEXI alters diabetes risk involves the composition and function of the microbiome and its impact on host metabolites. Such metabolites, including short chain fatty acids such as butyrate, have been shown to alter the activity of the immune cells involved in beta-cell destruction and susceptibility of the beta cells to autoimmune attack.One Sentence Summary: Disruption of the Dexi gene leads to accelerated diabetes in the non-obese diabetic (NOD) mouse, accompanied by changes in serum immunoglobulins, gut microbiome and microbial metabolites.

scholarly journals Beta-cell destruction and preservation in childhood and adult onset type 1 diabetes

Endocrine ◽  
2015 ◽  
Vol 49 (3) ◽  
pp. 693-702 ◽  
Author(s):  
Ananta Poudel ◽  
Omid Savari ◽  
Deborah A. Striegel ◽  
Vipul Periwal ◽  
Jerome Taxy ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Adult Onset ◽  
Onset Type ◽  
Beta Cell Destruction ◽  
Cell Destruction

scholarly journals Islet-Specific CTL Cloned from a Type 1 Diabetes Patient Cause Beta-Cell Destruction after Engraftment into HLA-A2 Transgenic NOD/SCID/IL2RG Null Mice

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e49213 ◽  
Author(s):  
Wendy W. J. Unger ◽  
Todd Pearson ◽  
Joana R. F. Abreu ◽  
Sandra Laban ◽  
Arno R. van der Slik ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Diabetes Patient ◽  
Beta Cell Destruction ◽  
Cell Destruction

scholarly journals Mediators and mechanisms of pancreatic beta-cell death in type 1 diabetes

2008 ◽  
Vol 52 (2) ◽  
pp. 156-165 ◽  
Author(s):  
Pierre Pirot ◽  
Alessandra K. Cardozo ◽  
Décio L. Eizirik
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Map Kinases ◽  
Pancreatic Beta Cell ◽  
Insulin Deficiency ◽  
Beta Cell Destruction ◽  
Pro Inflammatory Cytokines

Type 1 diabetes mellitus (T1D) is characterized by severe insulin deficiency resulting from chronic and progressive destruction of pancreatic beta-cells by the immune system. The triggering of autoimmunity against the beta-cells is probably caused by environmental agent(s) acting in the context of a predisposing genetic background. Once activated, the immune cells invade the islets and mediate their deleterious effects on beta-cells via mechanisms such as Fas/FasL, perforin/granzyme, reactive oxygen and nitrogen species and pro-inflammatory cytokines. Binding of cytokines to their receptors on the beta-cells activates MAP-kinases and the transcription factors STAT-1 and NFkappa-B, provoking functional impairment, endoplasmic reticulum stress and ultimately apoptosis. This review discusses the potential mediators and mechanisms leading to beta-cell destruction in T1D.

scholarly journals Vildagliptin Ameliorates Oxidative Stress and Pancreatic Beta Cell Destruction in Type 1 Diabetic Rats

2013 ◽  
Vol 44 (3) ◽  
pp. 194-202 ◽  
Author(s):  
Danielle de Lima Ávila ◽  
Glaucy Rodrigues de Araújo ◽  
Maisa Silva ◽  
Pedro Henrique de Amorim Miranda ◽  
Mirla Fiuza Diniz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Beta Cell ◽  
Pancreatic Beta Cell ◽  
Diabetic Rats ◽  
Beta Cell Destruction ◽  
Cell Destruction

scholarly journals Is the process of beta-cell destruction in type 1 diabetes at time of diagnosis more extensive in females than in males?

2001 ◽  
pp. 757-761 ◽  
Author(s):  
P Pozzilli ◽  
CA Mesturino ◽  
A Crino ◽  
TM Gross ◽  
LM Jeng ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Insulin Therapy ◽  
Metabolic Control ◽  
Metabolic Parameters ◽  
C Peptide ◽  
Beta Cell Destruction ◽  
Cell Destruction ◽  
Good Metabolic Control

OBJECTIVE: To evaluate sex differences in patients with insulin-dependent diabetes mellitus (type 1 diabetes) by comparing the integrated parameters of metabolic control at the time of clinical diagnosis and 3 months after intensive insulin therapy in pre-pubertal, pubertal and post-pubertal patients. DESIGN: A total of 331 consecutive patients with newly diagnosed type 1 diabetes were studied. The mean age of the group was 15 years (s.d. 8.1; range 5-23 years). Patients were stratified into three groups according to their age at disease onset: pre-pubertal (ages 5-9 years), pubertal (ages 10-18 years) and post-pubertal (ages 19-23 years). METHODS: Glycated haemoglobin (HbA(1c)), insulin dose and both basal and glucagon-stimulated C-peptide were evaluated at diagnosis and after 3 months of insulin therapy. RESULTS: We found that females diagnosed after puberty were those with the lowest basal C-peptide compared with males (P=0.005). No statistically significant differences were observed for other metabolic parameters. When the entire group was evaluated, females at the time of diagnosis showed significant lower body mass index (P=0.001), lower basal C-peptide (P=0.021) and higher HbA(1c) (P=0.023) and required more insulin than males (P<0.001). After 3 months of therapy, only a significantly greater dose of insulin was observed in females compared with males (P=0.001), with similar good metabolic control as assessed by HbA(1c). CONCLUSIONS: We conclude that the process of beta-cell destruction at diagnosis may be more extensive in post-pubertal females than in males. Moreover, after the introduction of insulin therapy, females and males show similar metabolic parameters, although females still require significantly more insulin than males to achieve good metabolic control, 3 months after diagnosis.

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