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

University of Milan, Milano, Lombardy, Italy
Diabetologia (Impact Factor: 6.67). 12/2006; 49(12):2824-7. DOI: 10.1007/s00125-006-0465-3
Source: PubMed


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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    • "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.
    Full-text · Article · Jul 2014 · The Journal of nutritional biochemistry
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    • "Intestinal pathophysiology is related to the development of T1D, once increased intestinal permeability is detectable even before the clinical onset of the disease [69]. A pioneering study by Brugman and colleagues [70] found in BioBreeding diabetes-prone (BB) rats that progressed into T1D presented reduced variety of bacteria of the phylum Bacteroidetes, as compared to control rats. "
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    ABSTRACT: Diabetes is a condition of multifactorial origin, involving several molecular mechanisms related to the intestinal microbiota for its development. In type 2 diabetes, receptor activation and recognition by microorganisms from the intestinal lumen may trigger inflammatory responses, inducing the phosphorylation of serine residues in insulin receptor substrate-1, reducing insulin sensitivity. In type 1 diabetes, the lowered expression of adhesion proteins within the intestinal epithelium favours a greater immune response that may result in destruction of pancreatic beta cells by CD8+ T-lymphocytes, and increased expression of interleukin-17, related to autoimmunity. Research in animal models and humans has hypothesized whether the administration of probiotics may improve the prognosis of diabetes through modulation of gut microbiota. We have shown in this review that a large body of evidence suggests probiotics reduce the inflammatory response and oxidative stress, as well as increase the expression of adhesion proteins within the intestinal epithelium, reducing intestinal permeability. Such effects increase insulin sensitivity and reduce autoimmune response. However, further investigations are required to clarify whether the administration of probiotics can be efficiently used for the prevention and management of diabetes.
    Full-text · Article · Jun 2014 · Nutrition Journal
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    • "Enteroviruses must enter the epithelial cells of the respiratory or intestinal systems in order to infect the host. Increased gut permeability is found among individuals with IA (31), suggesting that factors leading to a damaged endothelial barrier in the gut, such as gluten exposure, may allow for infection with enteroviruses, which may then damage the pancreatic β-cells. Rotavirus, the most common viral agent causing diarrhea in children, affects gut permeability and intestinal cytokine balance, and so exposure to this virus may have varying effects on immune modulation depending on the concurrent exposure to grain antigens. "
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    ABSTRACT: OBJECTIVE Type 1 diabetes is a common chronic childhood disease, and the incidence is increasing globally. Childhood infections are considered a potential environmental trigger of type 1 diabetes. Alternatively, improved hygiene and reduced childhood infections could explain the increase in type 1 diabetes in developed countries. The association of reported illnesses during infancy and later development of islet autoimmunity (IA) were examined in the Diabetes Autoimmunity Study in the Young.RESEARCH DESIGN AND METHODS Complete illness interviews through 9 months of age were collected for 1,729 children, 1,174 without a family history of type 1 diabetes, and 555 children with a first-degree relative with type 1 diabetes. Persistent IA was defined as positive antibodies to insulin, glutamic acid decarboxylase, or tyrosine phosphatase on at least two consecutive study visits.RESULTSThere were 109 children with persistent IA among the 1,729 children with illness records. A greater number of gastrointestinal illnesses were associated with an increased risk of IA, but only among children who were exposed to gluten-containing grains (wheat or barley) either <4 months of age (hazard ratio 1.37 [95% CI 1.22-1.55]; P < 0.0001) or ≥7 months of age (1.12 [1.05-1.19]; P = 0.0005) compared with 4-6 months of age (P for interaction = 0.02). There were no associations of upper respiratory symptoms, respiratory illnesses, or fevers with IA.CONCLUSIONS Specific pathogens such as enteroviruses or rotavirus may increase the risk of IA in the presence of existing inflammation induced by diet.
    Full-text · Article · Oct 2012 · Diabetes care
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