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      Gluten-Free Diet Only during Pregnancy Efficiently Prevents Diabetes in NOD Mouse Offspring

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          Abstract

          Studies have documented that the pathogenesis of autoimmune diabetes is influenced by the intake of gluten. Aims. To investigate the importance of gluten exposure during pregnancy and the subsequent development of autoimmune diabetes in offspring. Methods. Nonobese diabetic mice were divided into 7 groups to receive combinations of gluten-free and standard diet before, during, or after pregnancy. Diabetes incidence in offspring was followed in each group ( n = 16–27) for 310 days. Insulitis score and intestinal expression of T-cell transcription factors (RT-QPCR) were evaluated in animals from the different diet groups. Results. If mothers were fed a gluten-free diet only during pregnancy, the development of autoimmune diabetes in offspring was almost completely prevented with an incidence reduction from 62.5% in gluten-consuming mice to 8.3% ( p < 0.0001) in the gluten-free group. The islets of Langerhans were less infiltrated ( p < 0.001) and the intestinal expression of ROR γt (Th17) ( p < 0.0001) reduced in mice whose mothers were Gluten-free during pregnancy. Conclusion. A gluten-free diet exclusively during pregnancy efficiently prevents autoimmune diabetes development in offspring and reduces insulitis and intestinal expression of ROR γt (Th17).

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          Most cited references26

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          Timing of initial cereal exposure in infancy and risk of islet autoimmunity.

          Dietary exposures in infancy have been implicated, albeit inconsistently, in the etiology of type 1 diabetes mellitus (DM). To examine the association between cereal exposures in the infant diet and appearance of islet autoimmunity (IA). Birth cohort study conducted from 1994 to 2002 with a mean follow-up of 4 years. Newborn screening for HLA was done at St Joseph's Hospital in Denver, Colo. First-degree relatives of type 1 DM individuals were recruited from the Denver metropolitan area. We enrolled 1183 children at increased type 1 DM risk, defined as either HLA genotype or having a first-degree relative with type 1 DM, at birth and followed them prospectively. We obtained exposure and outcome measures for 76% of enrolled children. Participants had variable lengths of follow-up (9 months to 9 years). Blood draws for the detection of insulin autoantibody, glutamic acid decarboxylase autoantibody, or IA-2 autoantibody were performed at 9, 15, and 24 months and annually thereafter. Children with IA (n = 34) were defined as those testing positive for at least 1 of the autoantibodies on 2 or more consecutive visits and who tested positive or had diabetes on their most recent visit. Children initially exposed to cereals between ages 0 and 3 months (hazard ratio [HR], 4.32; 95% confidence interval [CI], 2.0-9.35) and those who were exposed at 7 months or older (HR, 5.36; 95% CI, 2.08-13.8) had increased hazard of IA compared with those who were exposed during the fourth through sixth month, after adjustment for HLA genotype, family history of type 1 DM, ethnicity, and maternal age. In children who were positive for the HLA-DRB1*03/04,DQB8 genotype, adjusted HRs were 5.55 (95% CI, 1.92-16.03) and 12.53 (95% CI, 3.19-49.23) for initial cereal exposure between ages 0 to 3 months and at 7 months or older, respectively. There may be a window of exposure to cereals in infancy outside which initial exposure increases IA risk in susceptible children.
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            Differences in risk of insulin-dependent diabetes in offspring of diabetic mothers and diabetic fathers.

            To examine the role of heritable factors in insulin-dependent diabetes mellitus (IDDM), we studied the incidence of IDDM in the offspring of patients with the disease who were identified by the medical records of the Joslin Diabetes Center from 1928 to 1939. We found 187 survivors who, after the diagnosis of IDDM, had produced 419 offspring for whom information about diabetes status was available. By the age of 20, 6.1 per cent of the offspring of the 88 men had diabetes; in contrast, only 1.3 per cent of the offspring of the 99 women had the disease by the age of 20 (P less than 0.05). Daughters and sons of the men with IDDM were affected equally (there were insufficient numbers of affected offspring of diabetic women to permit determination of whether the sexes were equally affected). We conclude that IDDM is transmitted less frequently to the offspring of diabetic women than to those of diabetic men. More study is required to determine whether this difference reflects a genetic mechanism or, instead, selective perinatal loss of the affected offspring of diabetic mothers.
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              A maternal gluten-free diet reduces inflammation and diabetes incidence in the offspring of NOD mice.

              Early-life interventions in the intestinal environment have previously been shown to influence diabetes incidence. We therefore hypothesized that a gluten-free (GF) diet, known to decrease the incidence of type 1 diabetes, would protect against the development of diabetes when fed only during the pregnancy and lactation period. Pregnant nonobese diabetic (NOD) mice were fed a GF or standard diet until all pups were weaned to a standard diet. The early-life GF environment dramatically decreased the incidence of diabetes and insulitis. Gut microbiota analysis by 16S rRNA gene sequencing revealed a pronounced difference between both mothers and their offspring on different diets, characterized by increased numbers of Akkermansia, Proteobacteria, and TM7 in the GF diet group. In addition, pancreatic forkhead box P3 regulatory T cells were increased in GF-fed offspring, as were M2 macrophage gene markers and tight junction-related genes in the gut, while intestinal gene expression of proinflammatory cytokines was reduced. An increased proportion of T cells in the pancreas expressing the mucosal integrin α4β7 suggests that the mechanism involves increased trafficking of gut-primed immune cells to the pancreas. In conclusion, a GF diet during fetal and early postnatal life reduces the incidence of diabetes. The mechanism may involve changes in gut microbiota and shifts to a less proinflammatory immunological milieu in the gut and pancreas.
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                Author and article information

                Journal
                J Diabetes Res
                J Diabetes Res
                JDR
                Journal of Diabetes Research
                Hindawi Publishing Corporation
                2314-6745
                2314-6753
                2016
                25 August 2016
                : 2016
                : 3047574
                Affiliations
                1The Bartholin Institute, Rigshospitalet, 2200 Copenhagen, Denmark
                2Laboratory of Specific Cellular Immunity, Institute of Microbiology ASCR, 54922 Prague, Czech Republic
                Author notes

                Academic Editor: Marco Songini

                Author information
                http://orcid.org/0000-0003-2618-6301
                http://orcid.org/0000-0002-5093-2901
                http://orcid.org/0000-0003-4088-5862
                http://orcid.org/0000-0001-5261-6091
                http://orcid.org/0000-0001-8327-6931
                http://orcid.org/0000-0002-0126-7423
                Article
                10.1155/2016/3047574
                5014974
                27642610
                424bade7-4312-4497-975b-1acf46b30086
                Copyright © 2016 Julie C. Antvorskov et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 May 2016
                : 5 July 2016
                : 10 July 2016
                Funding
                Funded by: Kirsten and Freddy Johansens Fond
                Funded by: Institutional Research Concept
                Award ID: RVO 61388971
                Award ID: 15-24487S
                Funded by: Grant Agency of the Czech Republic
                Categories
                Research Article

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