The “Perfect Storm” for Type 1 Diabetes

Vaarala, Outi; Atkinson, Mark A.; Neu, Josef

doi:10.2337/db08-0331

Cited by 450 publications

(376 citation statements)

References 63 publications

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“…There is mounting evidence suggesting that intrinsic or induced intestinal barrier defects skew the intestinal immune environment or the commensal microbiota to promote type 1 diabetes [14]. For example, type 1 diabetes Per cent of islets with no insulitis (score 0).…”

Section: Discussionmentioning

confidence: 99%

“…Impaired intestinal barrier function has also been detected in rodent models of type 1 diabetes [3][4][5][6][7] and in type 1 diabetes patients and their relatives [8][9][10][11][12]. Changes in the intestine, induced by dietary or enteric antigens, have been proposed as causative factors in the course of type 1 diabetes [13,14]; however, the role of the gut and enteric microbes in type 1 diabetes remains unclear. We thus propose that impaired intestinal barrier function in diabetes-prone individuals may allow commensal or pathogenic enteric bacterial antigens to elicit inflammatory signals that promote type 1 diabetes.…”

Section: Introductionmentioning

confidence: 99%

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Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice

et al. 2009

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Aims/hypothesis Increased exposure to enteric microbes as a result of intestinal barrier disruption is thought to contribute to the development of several intestinal inflammatory diseases; however, it less clear whether such exposure modulates the development of extra-intestinal inflammatory and autoimmune diseases. The goal of this study was to examine the potential role of pathogenic enteric microbes and intestinal barrier dysfunction in the pathogenesis of type 1 diabetes. Methods Using NOD mice, we assessed: (1) intrinsic barrier function in mice at different ages by measuring serum levels of FITC-labelled dextran; and (2) the impact on insulitis development of infection by strains of an enteric bacterial pathogen (Citrobacter rodentium) either capable (wild-type) or incapable (lacking Escherichia coli secreted protein F virulence factor owing to deletion of the gene [ΔespF]) of causing intestinal epithelial barrier disruption. Results Here we demonstrate that prediabetic (12-weekold) NOD mice display increased intestinal permeability compared with non-obese diabetes-resistant and C57BL/6 mice. We also found that young (4-week-old) NOD mice infected with wild-type C. rodentium exhibited accelerated development of insulitis in concert with infection-induced barrier disruption. In contrast, insulitis development was not altered in NOD mice infected with the non-barrier-disrupting ΔespF strain. Moreover, C. rodentium-infected NOD mice demonstrated increased activation and proliferation of pancreatic-draining lymph node T cells, including diabetogenic CD8 + T cells, compared with uninfected NOD mice. Conclusions/interpretation This is the first demonstration that a loss of intestinal barrier integrity caused by an enteric bacterial pathogen results in the activation of diabetogenic CD8 + T cells and modulates insulitis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice

et al. 2009

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“…32,33 Based on available experimental and clinical results, it has been proposed that the pathogenesis of T1D is closely linked to events that take place in the intestinal mucosa, where complex interplay between the intestinal microbiota, gut permeability and mucosal immunity determines autoimmune damage to pancreatic beta cells. 34 In several associations, this has also been demonstrated in CD and other autoimmune diseases. 4,35 Here, we aimed to assess whether differences in intestinal permeability, characterized by TJP1 mRNA expression, and intestinal regulatory T cells, measured by Foxp3 mRNA expression, as well as different serum antibodies levels exist between CD patients with and without accompanying T1D.…”

Section: Introductionmentioning

confidence: 87%

Celiac disease in patients with type 1 diabetes: a condition with distinct changes in intestinal immunity?

et al. 2011

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Two common chronic childhood diseases-celiac disease (CD) and type 1 diabetes (T1D)-result from complex pathological mechanisms where genetic susceptibility, environmental exposure, alterations in intestinal permeability and immune responses play central roles. In this study, we investigated whether these characteristics were universal for CD independently of T1D association. For this purpose, we studied 36 children with normal small-bowel mucosa and 26 children with active CD, including 12 patients with T1D. In samples from the small-bowel mucosa, we detected the lowest expression of tight junction protein 1 (TJP1) mRNA in CD patients with T1D, indicating an increase in intestinal permeability. Furthermore, these samples displayed the highest expression of forkhead box P3 (FoxP3) mRNA, a marker for regulatory T cells, as compared with other patient groups. At the same time, serum levels of IgA antibodies specific for the CD-related antigens deamidated gliadin and tissue transglutaminase (tTG) were the highest in CD patients with T1D. In contrast, no significant differences were found in IgA or IgG antibodies specific for bovine beta-lactoglobulin or Bifidobacterium adolescentis DSM 20083-derived proteins. There were also no differences in the transamidating activity of serum autoantibodies between patients and control individuals. Our results show that patients with T1D and newly detected CD exhibit severely altered intestinal permeability, strong local immune activation and increased immunoregulatory mechanisms in the small bowel. Further study is required to determine whether these extreme changes in this CD subgroup are due to some specific environmental factors (virus infections), unknown genetic effects or autoimmune reactions to antigenic targets in intracellular tight junctions. INTRODUCTIONWith an approximate prevalence of 1.0% in Western countries, celiac disease (CD) is one of the most common lifelong chronic disorders. 1 CD and type 1 diabetes (T1D) form a significant sector of childhood diseases with high rate of co-occurrence. 2 Both diseases are autoimmune in origin and develop as a result of complex pathological mechanisms, involving several common genetic, environmental and immunological factors. Among these, the common susceptibility loci of HLA and other immune system-related genes, 3 permeability changes in the small-bowel mucosa, 4 and association with wheat consumption 4,5 are prominent. Both diseases are increasing in most regions of the world, 6,7 as are several other autoimmune diseases, but the actual cause of the disease remains unknown. However, several recent studies have highlighted the role of environmental and social changes that have taken place over the last several decades. 8,9 The central event in the pathogenesis of CD is damage to the small intestinal mucosa that occurs after ingestion of gluten or related prolamins in genetically susceptible individuals. During this process, several morphological and immunological alterations have been demonstrated in the small-bowel mucos...

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“…Diabetes development is commonly described to result from an interplay between genetic and environmental factors, and several susceptibility genes and environmental or lifestyle factors are known to contribute to both type 1 (T1D) and type 2 diabetes (T2D) 1, 2. In T1D, genetic mutations of human leucocyte antigen (HLA) are the most common variants,3 while also virus infections have been implicated in T1D development 3.…”

Section: Introductionmentioning

confidence: 99%

“…In T1D, genetic mutations of human leucocyte antigen (HLA) are the most common variants,3 while also virus infections have been implicated in T1D development 3. The application of genome‐wide association studies (GWAS) has identified over 50 gene variants associated with T2D 2, 4. The high number of genetic alleles with low odds ratios for disease predictability in T2D confirms that genetic and environmental factors interlink in the development of the disease 5, 6.…”

Section: Introductionmentioning

confidence: 99%

Decreased levels of keratin 8 sensitize mice to streptozotocin‐induced diabetes

et al. 2018

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AimDiabetes is a result of an interplay between genetic, environmental and lifestyle factors. Keratin intermediate filaments are stress proteins in epithelial cells, and keratin mutations predispose to several human diseases. However, the involvement of keratins in diabetes is not well known. K8 and its partner K18 are the main β‐cell keratins, and knockout of K8 (K8−/−) in mice causes mislocalization of glucose transporter 2, mitochondrial defects, reduced insulin content and altered systemic glucose/insulin control. We hypothesize that K8/K18 offer protection during β‐cell stress and that decreased K8 levels contribute to diabetes susceptibility.MethodsK8‐heterozygous knockout (K8+/−) and wild‐type (K8+/+) mice were used to evaluate the influence of keratin levels on endocrine pancreatic function and diabetes development under basal conditions and after T1D streptozotocin (STZ)‐induced β‐cell stress and T2D high‐fat diet (HFD).ResultsMurine K8+/− endocrine islets express ~50% less K8/K18 compared with K8+/+. The decreased keratin levels have little impact on basal systemic glucose/insulin regulation, β‐cell health or insulin levels. Diabetes incidence and blood glucose levels are significantly higher in K8+/− mice after low‐dose/chronic STZ treatment, and STZ causes more β‐cell damage and polyuria in K8+/− compared with K8+/+. K8 appears upregulated 5 weeks after STZ treatment in K8+/+ islets but not in K8+/−. K8+/− mice showed no major susceptibility risk to HFD compared to K8+/+.ConclusionPartial K8 deficiency reduces β‐cell stress tolerance and aggravates diabetes development in response to STZ, while there is no major susceptibility to HFD.

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The “Perfect Storm” for Type 1 Diabetes

Cited by 450 publications

References 63 publications

Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice

Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice

Celiac disease in patients with type 1 diabetes: a condition with distinct changes in intestinal immunity?

Decreased levels of keratin 8 sensitize mice to streptozotocin‐induced diabetes

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