In type 1 diabetes, insulin-producing beta-cells in the pancreas are destroyed by immune-mediated mechanisms. The manifestation of the disease is preceded by the so-called pre-diabetic period that may last several years and is characterized by the appearance of circulating autoantibodies against beta-cell antigens. The role of the gut as a regulator of type 1 diabetes was suggested in animal studies, in which changes affecting the gut immune system modulated the incidence of diabetes. Dietary interventions, alterations in the intestinal microbiota and exposure to enteric pathogens, regulate the development of autoimmune diabetes in animal models. It has been demonstrated that these modulations affect the gut barrier mechanisms and intestinal immunity. Because the pancreas and the gut belong to the same intestinal immune system, the link between autoimmune diabetes and the gut is not unexpected. The gut hypothesis in the development of type 1 diabetes is also supported by the observations made in human type 1 diabetes. Early diet could modulate the development of beta-cell autoimmunity; weaning to hydrolysed casein formula decreased the risk of beta-cell autoimmunity by age 10 in the infants at genetic risk. Increased gut permeability, intestinal inflammation with impaired regulatory mechanisms and dysregulated oral tolerance have been observed in children with type 1 diabetes. The factors that contribute to these intestinal alterations are not known, but interest is focused on the microbial stimuli and function of innate immunity. It is likely that our microbial environment does not support the healthy maturation of the gut and tolerance in the gut, and this leads to the increasing type 1 diabetes as well as other immune-mediated diseases regulated by intestinal immune system. Thus, the interventions, aiming to prevent or treat type 1 diabetes in humans, should be targeting the gut immune system.
"This could imply some relationship between immune responses in the small intestine and activation of isletreactive T-cell clones. The involvement of environmental factors mostly associated with gut homeostasis and gut immune system in the pathogenesis of type 1 diabetes (Knip and Simell, 2012; Vaarala, 2012) gives rise to the possibility that such islet-clones could originate from immune responses in the small intestine. Following expansion there, they could thereafter probably home also to pancreatic islets (Hanninen et al., 2007, 1996b). "
[Show abstract][Hide abstract] ABSTRACT: Autoimmune destruction of pancreatic islets in the nonobese diabetic (NOD) mouse is driven by T cells recognizing various autoantigens mostly in insulin-producing beta-cells. To investigate if T-cell accumulation in islets during early insulitis is clonally predetermined, we compared the complementarity determining regions (CDR3) of T-cell receptor (TCR)β-chains present in islet-infiltrating T cells in young prediabetic NOD mice. High-throughput sequencing of TCRβ-chain DNA extracted from islets of 7-wk old NOD mice revealed a biased TCRβ-chain repertoire in all mice, as a restricted number of clones (17–36 clones) was highly overrepresented and made over 20% of total islet repertoire in each mouse. Among these clones, various Vβ and Jβ families were present but certain VβJβ combinations such as TRBV19-0-TRBJ2-7 and TRBV13-3-TRBJ2-5 were highly shared between individual mice. On TCRβ-chain CDR sequence level, many islet clones (72–146) were shared between at least two individual mice. None of them was among expanded clones in both, suggesting considerable stochasticity in the interactions between TCR and peptide-MHC, even with a limited range of autoantigens. A comparison of islet-CDR3-sequences with CRD-sequences from other tissues revealed clonal overlap with pancreatic lymph node and gut, but these repertoires did not overlap together. Our results suggest that antigen-specific T cells are expanded in pancreatic lymph node and islets, but different specificities expand in individual mice. Some islet-infiltrating T-cell specificities may have a distinct origin shared with gut-infiltrating T cells.
"However, little is known about mechanisms mediating the link between MO and offspring T1D. Impaired gut epithelial integrity and barrier function are the central predisposing factors to autoimmune T1D, inflammatory bowel disease (IBD) and related allergic diseases   . Indeed, enhanced gut permeability is observed in patients with T1D and IBD  . "
[Show abstract][Hide abstract] 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 · 3.79 Impact Factor
"Patients with type 1 diabetes display an increased gut permeability and decreased gastro-intestinal motility [9,10], and children who develop type 1 diabetes have an altered gut microbiota . Importantly, these factors can directly affect the translocation of LPS through the intestinal epithelium. "
[Show abstract][Hide abstract] ABSTRACT: Background
A high-fat diet promotes postprandial systemic inflammation and metabolic endotoxemia. We investigated the effects of three consecutive high-fat meals on endotoxemia, inflammation, vascular function, and postprandial lipid metabolism in patients with type 1 diabetes.
Non-diabetic controls (n = 34) and patients with type 1 diabetes (n = 37) were given three high-caloric, fat-containing meals during one day. Blood samples were drawn at fasting (8:00) and every two hours thereafter until 18:00. Applanation tonometry was used to assess changes in the augmentation index during the investigation day.
Three consecutive high-fat meals had only a modest effect on serum LPS-activity levels and inflammatory markers throughout the day in both groups. Of note, patients with type 1 diabetes were unable decrease the augmentation index in response to the high-fat meals. The most profound effects of the consecutive fat loads were seen in chylomicron and HDL-metabolism. The triglyceride-rich lipoprotein remnant marker, apoB-48, was elevated in patients compared to controls both at fasting (p = 0.014) and postprandially (p = 0.035). The activities of the HDL-associated enzymes PLTP (p < 0.001), and CETP (p = 0.007) were higher and paraoxonase (PON-1) activity, an anti-oxidative enzyme bound to HDL, decreased in patients with type 1 diabetes (p = 0.027).
In response to high-fat meals, early signs of vascular dysfunction alongside accumulation of chylomicron remnants, higher augmentation index, and decreased PON-1 activity were observed in patients with type 1 diabetes. The high-fat meals had no significant impact on postprandial LPS-activity in non-diabetic subjects or patients with type 1 diabetes suggesting that metabolic endotoxemia may be more central in patients with chronic metabolic disturbances such as obesity, type 2 diabetes, or diabetic kidney disease.
Nutrition and metabolism 06/2014; 11(28). DOI:10.1186/1743-7075-11-28
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