Bosi E, Molteni L, Radaelli MG, et al. Increased intestinal permeability precedes clinical onset of type 1 diabetes

General Medicine, Diabetes and Endocrinology Unit, San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Via Olgettina 60, 20132, Milan, Italy.
Diabetologia (Impact Factor: 6.88). 12/2006; 49(12):2824-7. DOI: 10.1007/s00125-006-0465-3
Source: PubMed

ABSTRACT Recent observations have shown subclinical intestinal abnormalities in human type 1 diabetes. Whether these are related to the pathogenetic process or secondary to the diabetes remains to be clarified. The aim of this study was to investigate this issue by examining intestinal permeability to sugars in subjects at different stages of type 1 diabetes: preclinical, new-onset and long-term established disease.
Eighty-one subjects with islet autoimmunity (18 preclinical, 28 new-onset and 35 long-term type 1 diabetes) and 40 healthy control subjects were investigated by a lactulose-mannitol test, consisting of oral administration of the two sugars and measurement of their urinary excretion.
All groups of subjects with islet autoimmunity showed an increase in intestinal permeability (p < or = 0.009 vs controls) to the disaccharide lactulose, indicative of a damaged barrier, but a similar permeability to the monosaccharide mannitol (NS vs controls), indicative of an integral surface mucosa; consequently there was an increase in the lactulose:mannitol excretion ratio (p < or = 0.025 vs controls).
These findings indicate the presence of a subclinical enteropathy associated with type 1 diabetes that is already detectable before clinical onset of the disease, and suggest that the small intestine is an organ participating in the pathogenetic process of type 1 diabetes.

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Available from: Lorenzo Piemonti, Aug 17, 2015
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    • "Impaired gut epithelial integrity and barrier function are the central predisposing factors to autoimmune T1D, inflammatory bowel disease (IBD) and related allergic diseases [7] [8] [9]. Indeed, enhanced gut permeability is observed in patients with T1D and IBD [10] [11]. Gut inflammation is known to enhance epithelial permeability [12]. "
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    ABSTRACT: Impairment of gut epithelial barrier function is a key predisposing factor for inflammatory bowel disease, type 1 diabetes (T1D), and related autoimmune diseases. We hypothesized that maternal obesity induces gut inflammation and impairs epithelial barrier function in the offspring of non-obese diabetic (NOD) mice. 4-week-old female NOD/ShiLtJ mice were fed with a control diet (CON, 10% energy from fat) or a high fat diet (HFD, 60% energy from fat) for 8 weeks to induce obesity and then mated. During pregnancy and lactation, mice were maintained in their respective diets. After weaning, all offspring were fed the CON diet. At 16 weeks of age, female offspring were subjected to in vivo intestinal permeability test and, then, ileum was sampled for biochemical analyses. Inflammasome mediators, activated caspase-1 as well as mature forms of interleukin (IL) -1β and IL-18 were enhanced in offspring of obese mothers, which was associated with elevated serum tumor necrosis factor (TNF)α level and inflammatory mediators. Consistently, abundance of oxidative stress markers including catalase, peroxiredoxin-4 and superoxide dismutase 1 were heightened in offspring ileum (P < 0.05). Furthermore, offspring from obese mothers had a higher intestinal permeability. Morphologically, maternal obesity reduced villi/crypt ratio in the ileum of offspring gut. In conclusion, maternal obesity induced inflammation and impaired gut barrier function in offspring of NOD mice. The enhanced gut permeability in HFD offspring might pre-dispose them to the development of T1D and other gut permeability associated diseases.
    The Journal of nutritional biochemistry 07/2014; 25(7). DOI:10.1016/j.jnutbio.2014.03.009 · 4.59 Impact Factor
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    ABSTRACT: Type 1 diabetes (T1D) is considered to be an autoimmune disease. In T1D insulin producing pancreatic β cells are destroyed. The disease process begins years before the clinical diagnosis of T1D. During the pathogenesis of T1D, pancreatic islets are infiltrated by cells of the immune system and T-lymphocytes are considered to be the main mediators of the β-cell destruction. In children with an active β-cell destruction process, autoantibodies against β-cell antigens appear in the blood. Individuals at increased risk of developing T1D can often be identified by detecting serum autoantibodies against β-cell antigens. Immunological aberrancies associated with T1D are related to defects in the polarization of T cells and in the function of regulatory mechanisms. T1D has been considered as an organ-specific autoimmune disease mediated by uncontrolled Th1-responses. In human T1D, the evidence for the role of over-expression of cytokines promoting cytotoxicity is controversial. For the past 15 years, regulatory T cells (Tregs) have been recognized as having a key role in the initiation and maintenance of tolerance, limiting harmful autoantigen-specific inflammation processes. It is possible that, if regulatory mechanisms fail to be initiated, the subtle inflammation targeting β cells lead to insulitis and eventually to overt T1D in some individuals. In the present thesis, we studied the induction of Tregs during the generation of T-cell responses in T1D. The results suggest that the generation of regulatory mechanisms and effector mechanisms upon T-cell activation is aberrant in children with T1D. In our studies, an in vitro cytotoxic environment inhibited the induction of genes associated with regulatory functions upon T-cell activation. We also found T1D patients to have an impaired cytotoxic response against coxsackievirus B4. Ineffective virus clearance may increase the apoptosis of β cells, and thus the risk of β-cell specific autoimmunity, due to the increased presentation of β-cell-derived peptides by APCs to T cells in pancreatic lymph nodes. Recently, a novel T helper cell subset called Th17 has been discovered. Animal models have associated Th17 cells and especially co-producers of IL-17 and IFN-γ with the pathogenesis of T1D. We aimed to characterize the role of Th17 immunity in human T1D. We demonstrated IL-17 activation to be a major alteration in T1D patients in comparison to healthy children. Moreover, alterations related to the FOXP3-mediated regulatory mechanisms were associated with the IL-17 up-regulation seen in T1D patients. These findings may have therapeutic implications for the treatment and prevention of T1D. Tyypin 1 diabetes (T1D) on elinikäinen insuliinihoitoa vaativa autoimmuunisairaus, johon ei toistaiseksi ole parannuskeinoa. T1D:een johtava tautiprosessi, ja sen perimmäiset syyt ovat heikosti tunnettuja. T1D:ssa elimistön immuunijärjestelmä tuhoaa haiman insuliinia tuottavat β-solut. Valkosolujen poikkeava toiminta on liitetty T1D:n tautiprosessin käynnistymiseen, ja β-solukuoleman aiheuttajana ovatkin todennäköisesti kehon omia β-solurakenteita tunnistavat immuunijärjestelmän valkosolut. T1D:een liitetyt immunologiset häiriöt ovat valkosolujen poikkeava toiminnallinen erilaistuminen ja poikkeava immuunivasteen säätelykyky. Lääketieteellinen tutkimus on tuonut viime aikoina runsaasti uutta tietoa, ja mm. uusia valkosolujen toimintamalleja ja toiminnallisia valkosoluluokkia on kuvattu. Uuden tutkimustiedon perusteella ihmisen immuunijärjestelmän valkosolujen toiminta ja immuunivasteen säätely näyttäisi olevan monipuolisempaa ja muuntuvampaa, kuin mitä aiemmin on tiedetty. Erityisesti säätelevien valkosolujen toiminnasta immuunivasteen synnyssä ja sen rajoittamisessa on saatu uutta tietoa. Tämä tieto avaa uusia näköaloja autoimmuunisairauksien syntymekanismeihin. Tässä väitoskirjassa tutkittiin immuunivasteen käynnistymistä ja valkosolujen säätelymekanismien aktivaatiota immuunivasteen käynnistymisen aikana T1D potilailla. Tulostemme mukaan virusten häätömekanismien käynnistyminen häiritsee säätelevien valkosolujen aktivaatiota T1D potilailla. Lisäksi havaitsimme että T1D:een liitettyjen coxsackievirusten häätömekanismit ovat vaillinaiset T1D potilailla. Tämä puolestaan saattaa johtaa heikkoon coxsackievirusten (CVB) häätöön ja siten pitkittyneisiin ja tihentyneisiin CVB -infektioihin T1D potilailla. Toistuvat ja pitkittyvät CVB -infektiot saattavat lisätä haiman saarekkeissa tapahtuvaa, virusten aiheuttamaa solukuolemaa. Tämä saattaa edelleen johtaa β-solujen rakenteita tunnistavien valkosolujen kehittymiseen T1D potilailla. Hiljattain löydetty uusi toiminnallinen valkosoluluokka, Th17-solut on liitetty eläinmalleissa T1D tautiprosessiin. Tulostemme mukaan liiallinen Th17-solujen aktivaatio näyttää liittyvän myös ihmisen T1D:een. Lisäksi havaitsimme että T1D potilailla aktivoituneiden valkosolujen joukossa oli soluja, jotka ilmensivät merkkiaineita IFN-γ ja IL-17, ja joita aiemmin on pidetty erillisten valkosoluluokkien merkkiaineina Tulokset osoittavat että T1D potilailla valkosolujen toiminnallinen vakaus on heikko, mikä saattaa johtaa virheelliseen, omaa kudosta kohtaan tuotettuun immuunivasteeseen. Tutkimustuloksemme auttavat ymmärtämään T1D tautiprosessia paremmin, mikä on edellytys hoitokeinojen kehittämiseksi T1D:een.
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    ABSTRACT: The influence of different food components on autoimmune diabetes development was tested in three subsequent trials. In a 36 week nutrition trial with NOD mice the influence of basal diets, varying in only one specific compound (casein, wheat in different concentrations, wheat gluten, wheat globulin, wheat albumin, potato, corn, apple, and carrot) on diabetes onset was studied. The combination of wheat and casein led to an earlier diabetes onset. High concentrations of wheat and corresponding concentrations of wheat proteins reduced diabetes rate, whereas the addition of corn accelerated diabetes onset in particular in the first weeks. In the second trial sera of IAA positive children were examined regarding IgA-IAA concentration and IAA binding molecules other than human insulin (here chicken insulin). In some sera IgA-IAA was the predominant IAA compound. Diabetes relevant high affinity IAA bound poorly to chicken insulin whereas low affinity IAA bound strongly to chicken insulin. These findings suggest that some IAA may originate from immunization against molecules other than human insulin at mucosal sites. In the third trial IAA in sera were tested regarding their cross reactivity towards food components relevant to infant nutrition. IAA binding of some sera with insulin could be inhibited by addition of milk powder extract. Testing single cow`s milk proteins showed that IAA binding of milk reactive IAA to human insulin could be strongly inhibited by α- and β-casein, but not by lactoglobuline or BSA. These results suggest that IAA with high affinity to casein or other food components may only secondarily target human insulin. The subsequent immune cascade, leading to the development of further antibodies and eventually to diabetes may in these cases not be triggered.
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