Possible Prevention of Diabetes with a Gluten-Free Diet

Martin Haupt-Jorgensen, Laurits J Holm, Knud Josefsen, Karsten Buschard, Martin Haupt-Jorgensen, Laurits J Holm, Knud Josefsen, Karsten Buschard

Abstract

Gluten seems a potentially important determinant in type 1 diabetes (T1D) and type 2 diabetes (T2D). Intake of gluten, a major component of wheat, rye, and barley, affects the microbiota and increases the intestinal permeability. Moreover, studies have demonstrated that gluten peptides, after crossing the intestinal barrier, lead to a more inflammatory milieu. Gluten peptides enter the pancreas where they affect the morphology and might induce beta-cell stress by enhancing glucose- and palmitate-stimulated insulin secretion. Interestingly, animal studies and a human study have demonstrated that a gluten-free (GF) diet during pregnancy reduces the risk of T1D. Evidence regarding the role of a GF diet in T2D is less clear. Some studies have linked intake of a GF diet to reduced obesity and T2D and suggested a role in reducing leptin- and insulin-resistance and increasing beta-cell volume. The current knowledge indicates that gluten, among many environmental factors, may be an aetiopathogenic factors for development of T1D and T2D. However, human intervention trials are needed to confirm this and the proposed mechanisms.

Keywords: NOD mouse; beta cell; beta-cell stress; celiac disease; gluten-free diet; high-fat diet-induced obesity; intestinal permeability; islet of Langerhans; type 1 diabetes; type 2 diabetes.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Gluten free (GF) diet and the development of type 1 diabetes (T1D)—a hypothesis. (A) A GF diet decreases the intestinal permeability and increases the villus-to-crypt (V:C) ratio, thereby preventing food particles such as gliadin peptides from crossing the intestinal barrier and reacting the pancreas. A GF diet increases the number of Akkermansia bacteria, among other changes, and the amount of short-chain fatty acids (SCFAs) such as butyrate. (B) A GF diet modulates the innate and adaptive immune system resulting in reduced interferon gamma (IFNG) secretion from CD4+ T helper (TH) cells, reduced interleukin (IL)22 secretion from gamma delta T cell receptor (gdTCR)+ T cells, and lower numbers of activated (NKG2D+) natural killer (NK) cells, among other things. TH17 cell numbers are reduced and immunosuppressant M2 macrophage numbers and forkhead box P3 (FOXP3)+ regulatory T cell (Treg) numbers are increased. (C) A GF diet reduces beta-cell stress by reducing the insulin secretion. This may preserve the number of islets, reduce insulitis, and ameliorate T1D.
Figure 2
Figure 2
Gluten-free (GF) diet and the development of type 2 diabetes (T2D)—a hypothesis. A GF diet decreases intestinal permeability thereby preventing food particles such a gliadin from crossing the intestinal barrier and reaching the adipose tissue and pancreas. A GF diet increases the proportion of Lactobacillus and decreases the proportion of Akkermansia, Dorea, Clostridium, and Coriobacteriacae. In the blood, a GF diet decreases the level of proinflammatory cytokines and adipokines and increases the anti-inflammatory adiponectin. A GF diet reduces obesity and improves the regulation of lipid metabolism by upregulating peroxisome proliferator activator receptor alpha (PPARA) and peroxisome proliferator activator receptor gamma (PPARG) in adipose tissue. This, in turn, leads to increased insulin sensitivity and improved glucose tolerance, which is further improved by reduced beta-cell stress and increased beta-cell volume.

References

    1. Vajravelu M.E., Keren R., Weber D.R., Verma R., De Leon D.D., Denburg M.R. Incidence and Risk of Celiac Disease after Type 1 Diabetes: A Population-Based Cohort Study Using the Health Improvement Network Database. Pediatr. Diabetes. 2018 doi: 10.1111/pedi.12770.
    1. Fasano A., Berti I., Gerarduzzi T., Not T., Colletti R.B., Drago S., Elitsur Y., Green P.H., Guandalini S., Hill I.D., et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: A large multicenter study. Arch. Intern. Med. 2003;163:286–292. doi: 10.1001/archinte.163.3.286.
    1. West J., Logan R.F., Hill P.G., Lloyd A., Lewis S., Hubbard R., Reader R., Holmes G.K., Khaw K.T. Seroprevalence, correlates, and characteristics of undetected coeliac disease in England. Gut. 2003;52:960–965. doi: 10.1136/gut.52.7.960.
    1. Maki M., Mustalahti K., Kokkonen J., Kulmala P., Haapalahti M., Karttunen T., Ilonen J., Laurila K., Dahlbom I., Hansson T., et al. Prevalence of Celiac disease among children in Finland. N. Engl. J. Med. 2003;348:2517–2524. doi: 10.1056/NEJMoa021687.
    1. Leonard M.M., Sapone A., Catassi C., Fasano A. Celiac Disease and Nonceliac Gluten Sensitivity: A Review. JAMA. 2017;318:647–656. doi: 10.1001/jama.2017.9730.
    1. NCD Risk Factor Collaboration (NCD-RisC) Worldwide trends in diabetes since 1980: A pooled analysis of 751 population-based studies with 4.4 million participants. Lancet. 2016;387:1513–1530. doi: 10.1016/S0140-6736(16)00618-8.
    1. Awika J.M. Major cereal grains production and use around the world. Adv. Cereal Sci. Implic. Food Process. Health Promot. 2011;1089:1–13.
    1. Shewry P.R., Halford N.G. Cereal seed storage proteins: Structures, properties and role in grain utilization. J. Exp. Bot. 2002;53:947–958. doi: 10.1093/jexbot/53.370.947.
    1. Stern M., Ciclitira P.J., Van Eckert R., Feighery C., Janssen F.W., Mendez E., Mothes T., Troncone R., Wieser H. Analysis and clinical effects of gluten in coeliac disease. Eur. J. Gastroenterol. Hepatol. 2001;13:741–747. doi: 10.1097/00042737-200106000-00023.
    1. Piper J.L., Gray G.M., Khosla C. Effect of prolyl endopeptidase on digestive-resistant gliadin peptides in vivo. J. Pharmacol. Exp. Ther. 2004;311:213–219. doi: 10.1124/jpet.104.068429.
    1. Hausch F., Shan L., Santiago N.A., Gray G.M., Khosla C. Intestinal digestive resistance of immunodominant gliadin peptides. Am. J. Physiol. Gastrointest. Liver Physiol. 2002;283 doi: 10.1152/ajpgi.00136.2002.
    1. Fasano A. Zonulin and its regulation of intestinal barrier function: The biological door to inflammation, autoimmunity, and cancer. Physiol. Rev. 2011;91:151–175. doi: 10.1152/physrev.00003.2008.
    1. Lammers K.M., Lu R., Brownley J., Lu B., Gerard C., Thomas K., Rallabhandi P., Shea-Donohue T., Tamiz A., Alkan S., et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology. 2008;135:194–204.e3. doi: 10.1053/j.gastro.2008.03.023.
    1. Lammers K.M., Khandelwal S., Chaudhry F., Kryszak D., Puppa E.L., Casolaro V., Fasano A. Identification of a novel immunomodulatory gliadin peptide that causes interleukin-8 release in a chemokine receptor CXCR3-dependent manner only in patients with coeliac disease. Immunology. 2011;132:432–440. doi: 10.1111/j.1365-2567.2010.03378.x.
    1. Maiuri L., Troncone R., Mayer M., Coletta S., Picarelli A., De Vincenzi M., Pavone V., Auricchio S. In vitro activities of A-gliadin-related synthetic peptides: Damaging effect on the atrophic coeliac mucosa and activation of mucosal immune response in the treated coeliac mucosa. Scand. J. Gastroenterol. 1996;31:247–253. doi: 10.3109/00365529609004874.
    1. Sollid L.M., Qiao S.W., Anderson R.P., Gianfrani C., Koning F. Nomenclature and listing of celiac disease relevant gluten T-cell epitopes restricted by HLA-DQ molecules. Immunogenetics. 2012;64:455–460. doi: 10.1007/s00251-012-0599-z.
    1. Qiao S.W., Bergseng E., Molberg O., Xia J., Fleckenstein B., Khosla C., Sollid L.M. Antigen presentation to celiac lesion-derived T cells of a 33-mer gliadin peptide naturally formed by gastrointestinal digestion. J. Immunol. 2004;173:1757–1762. doi: 10.4049/jimmunol.173.3.1757.
    1. Shan L., Molberg O., Parrot I., Hausch F., Filiz F., Gray G.M., Sollid L.M., Khosla C. Structural basis for gluten intolerance in celiac sprue. Science. 2002;297:2275–2279. doi: 10.1126/science.1074129.
    1. Shan L., Qiao S.W., Arentz-Hansen H., Molberg O., Gray G.M., Sollid L.M., Khosla C. Identification and analysis of multivalent proteolytically resistant peptides from gluten: Implications for celiac sprue. J. Proteome Res. 2005;4:1732–1741. doi: 10.1021/pr050173t.
    1. Schalk K., Lang C., Wieser H., Koehler P., Scherf K.A. Quantitation of the immunodominant 33-mer peptide from alpha-gliadin in wheat flours by liquid chromatography tandem mass spectrometry. Sci. Rep. 2017;7:45092. doi: 10.1038/srep45092.
    1. Clayton D.G. Prediction and interaction in complex disease genetics: Experience in type 1 diabetes. PLOS Genet. 2009;5:e1000540. doi: 10.1371/journal.pgen.1000540.
    1. Pociot F., Lernmark A. Genetic risk factors for type 1 diabetes. Lancet. 2016;387:2331–2339. doi: 10.1016/S0140-6736(16)30582-7.
    1. Group D.P. Incidence and trends of childhood Type 1 diabetes worldwide 1990–1999. Diabet. Med. 2006;23:857–866. doi: 10.1111/j.1464-5491.2006.01925.x.
    1. Patterson C.C., Dahlquist G.G., Gyurus E., Green A., Soltesz G., Group E.S. Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–20: A multicentre prospective registration study. Lancet. 2009;373:2027–2033. doi: 10.1016/S0140-6736(09)60568-7.
    1. Gorelick J., Yarmolinsky L., Budovsky A., Khalfin B., Klein J.D., Pinchasov Y., Bushuev M.A., Rudchenko T., Ben-Shabat S. The Impact of Diet Wheat Source on the Onset of Type 1 Diabetes Mellitus-Lessons Learned from the Non-Obese Diabetic (NOD) Mouse Model. Nutrients. 2017;9 doi: 10.3390/nu9050482.
    1. Bodansky H.J., Staines A., Stephenson C., Haigh D., Cartwright R. Evidence for an environmental effect in the aetiology of insulin dependent diabetes in a transmigratory population. BMJ. 1992;304:1020–1022. doi: 10.1136/bmj.304.6833.1020.
    1. Kondrashova A., Reunanen A., Romanov A., Karvonen A., Viskari H., Vesikari T., Ilonen J., Knip M., Hyoty H. A six-fold gradient in the incidence of type 1 diabetes at the eastern border of Finland. Ann. Med. 2005;37:67–72. doi: 10.1080/07853890410018952.
    1. Kyvik K.O., Green A., Beck-Nielsen H. Concordance rates of insulin dependent diabetes mellitus: A population based study of young Danish twins. BMJ. 1995;311:913–917. doi: 10.1136/bmj.311.7010.913.
    1. Kaprio J., Tuomilehto J., Koskenvuo M., Romanov K., Reunanen A., Eriksson J., Stengard J., Kesaniemi Y.A. Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia. 1992;35:1060–1067. doi: 10.1007/BF02221682.
    1. Knip M., Veijola R., Virtanen S.M., Hyoty H., Vaarala O., Akerblom H.K. Environmental triggers and determinants of type 1 diabetes. Diabetes. 2005;54:S125–S136. doi: 10.2337/diabetes.54.suppl_2.S125.
    1. Atkinson M.A., Eisenbarth G.S. Type 1 diabetes: New perspectives on disease pathogenesis and treatment. Lancet. 2001;358:221–229. doi: 10.1016/S0140-6736(01)05415-0.
    1. Stene L.C., Oikarinen S., Hyoty H., Barriga K.J., Norris J.M., Klingensmith G., Hutton J.C., Erlich H.A., Eisenbarth G.S., Rewers M. Enterovirus infection and progression from islet autoimmunity to type 1 diabetes: The Diabetes and Autoimmunity Study in the Young (DAISY) Diabetes. 2010;59:3174–3180. doi: 10.2337/db10-0866.
    1. Oikarinen S., Martiskainen M., Tauriainen S., Huhtala H., Ilonen J., Veijola R., Simell O., Knip M., Hyoty H. Enterovirus RNA in blood is linked to the development of type 1 diabetes. Diabetes. 2011;60:276–279. doi: 10.2337/db10-0186.
    1. Buschard K., Hastrup N., Rygaard J. Virus-induced diabetes mellitus in mice and the thymus-dependent immune system. Diabetologia. 1983;24:42–46. doi: 10.1007/BF00275946.
    1. Dotta F., Censini S., van Halteren A.G., Marselli L., Masini M., Dionisi S., Mosca F., Boggi U., Muda A.O., Del Prato S., et al. Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc. Natl. Acad. Sci. USA. 2007;104:5115–5120. doi: 10.1073/pnas.0700442104.
    1. Krogvold L., Edwin B., Buanes T., Frisk G., Skog O., Anagandula M., Korsgren O., Undlien D., Eike M.C., Richardson S.J., et al. Detection of a low-grade enteroviral infection in the islets of langerhans of living patients newly diagnosed with type 1 diabetes. Diabetes. 2015;64:1682–1687. doi: 10.2337/db14-1370.
    1. Hober D., Sauter P. Pathogenesis of type 1 diabetes mellitus: Interplay between enterovirus and host. Nat. Rev. Endocrinol. 2010;6:279–289. doi: 10.1038/nrendo.2010.27.
    1. Hoorfar J., Buschard K., Dagnaes-Hansen F. Prophylactic nutritional modification of the incidence of diabetes in autoimmune non-obese diabetic (NOD) mice. Br. J. Nutr. 1993;69:597–607. doi: 10.1079/BJN19930059.
    1. Scott F.W. Food-induced type 1 diabetes in the BB rat. Diabetes Metab. Rev. 1996;12:341–359. doi: 10.1002/(SICI)1099-0895(199612)12:4<341::AID-DMR173>;2-O.
    1. Funda D.P., Kaas A., Bock T., Tlaskalova-Hogenova H., Buschard K. Gluten-free diet prevents diabetes in NOD mice. Diabetes Metab. Res. Rev. 1999;15:323–327. doi: 10.1002/(SICI)1520-7560(199909/10)15:5<323::AID-DMRR53>;2-P.
    1. Hansen A.K., Ling F., Kaas A., Funda D.P., Farlov H., Buschard K. Diabetes preventive gluten-free diet decreases the number of caecal bacteria in non-obese diabetic mice. Diabetes Metab. Res. Rev. 2006;22:220–225. doi: 10.1002/dmrr.609.
    1. Marietta E.V., Gomez A.M., Yeoman C., Tilahun A.Y., Clark C.R., Luckey D.H., Murray J.A., White B.A., Kudva Y.C., Rajagopalan G. Low incidence of spontaneous type 1 diabetes in non-obese diabetic mice raised on gluten-free diets is associated with changes in the intestinal microbiome. PLoS ONE. 2013;8:e78687. doi: 10.1371/journal.pone.0078687.
    1. Antvorskov J.C., Josefsen K., Haupt-Jorgensen M., Fundova P., Funda D.P., Buschard K. Gluten-Free Diet Only during Pregnancy Efficiently Prevents Diabetes in NOD Mouse Offspring. J. Diabetes Res. 2016;2016:3047574. doi: 10.1155/2016/3047574.
    1. Hansen C.H., Krych L., Buschard K., Metzdorff S.B., Nellemann C., Hansen L.H., Nielsen D.S., Frokiaer H., Skov S., Hansen A.K. A maternal gluten-free diet reduces inflammation and diabetes incidence in the offspring of NOD mice. Diabetes. 2014;63:2821–2832. doi: 10.2337/db13-1612.
    1. Ziegler A.G., Schmid S., Huber D., Hummel M., Bonifacio E. Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA. 2003;290:1721–1728. doi: 10.1001/jama.290.13.1721.
    1. Norris J.M., Barriga K., Klingensmith G., Hoffman M., Eisenbarth G.S., Erlich H.A., Rewers M. Timing of initial cereal exposure in infancy and risk of islet autoimmunity. JAMA. 2003;290:1713–1720. doi: 10.1001/jama.290.13.1713.
    1. Antvorskov J.C., Halldorsson T.I., Josefsen K., Svensson J., Granstrom C., Roep B.O., Olesen T.H., Hrolfsdottir L., Buschard K., Olsen S.F. Association between maternal gluten intake and type 1 diabetes in offspring: National prospective cohort study in Denmark. BMJ. 2018;362:k3547. doi: 10.1136/bmj.k3547.
    1. Lamb M.M., Myers M.A., Barriga K., Zimmet P.Z., Rewers M., Norris J.M. Maternal diet during pregnancy and islet autoimmunity in offspring. Pediatr. Diabetes. 2008;9:135–141. doi: 10.1111/j.1399-5448.2007.00311.x.
    1. Virtanen S.M., Uusitalo L., Kenward M.G., Nevalainen J., Uusitalo U., Kronberg-Kippila C., Ovaskainen M.L., Arkkola T., Niinisto S., Hakulinen T., et al. Maternal food consumption during pregnancy and risk of advanced beta-cell autoimmunity in the offspring. Pediatr. Diabetes. 2011;12:95–99. doi: 10.1111/j.1399-5448.2010.00668.x.
    1. Sildorf S.M., Fredheim S., Svensson J., Buschard K. Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus. BMJ Case Rep. 2012;2012 doi: 10.1136/bcr.02.2012.5878.
    1. Svensson J., Sildorf S.M., Pipper C.B., Kyvsgaard J.N., Bojstrup J., Pociot F.M., Mortensen H.B., Buschard K. Potential beneficial effects of a gluten-free diet in newly diagnosed children with type 1 diabetes: A pilot study. Springerplus. 2016;5:994. doi: 10.1186/s40064-016-2641-3.
    1. Pastore M.R., Bazzigaluppi E., Belloni C., Arcovio C., Bonifacio E., Bosi E. Six months of gluten-free diet do not influence autoantibody titers, but improve insulin secretion in subjects at high risk for type 1 diabetes. J. Clin. Endocrinol. Metab. 2003;88:162–165. doi: 10.1210/jc.2002-021177.
    1. Mooradian A.D., Morley J.E., Levine A.S., Prigge W.F., Gebhard R.L. Abnormal intestinal permeability to sugars in diabetes mellitus. Diabetologia. 1986;29:221–224. doi: 10.1007/BF00454879.
    1. Bosi E., Molteni L., Radaelli M.G., Folini L., Fermo I., Bazzigaluppi E., Piemonti L., Pastore M.R., Paroni R. Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia. 2006;49:2824–2827. doi: 10.1007/s00125-006-0465-3.
    1. Carratu R., Secondulfo M., de Magistris L., Iafusco D., Urio A., Carbone M.G., Pontoni G., Carteni M., Prisco F. Altered intestinal permeability to mannitol in diabetes mellitus type I. J. Pediatr. Gastroenterol. Nutr. 1999;28:264–269. doi: 10.1097/00005176-199903000-00010.
    1. Sapone A., De Magistris L., Pietzak M., Clemente M.G., Tripathi A., Cucca F., Lampis R., Kryszak D., Carteni M., Generoso M., et al. Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes. 2006;55:1443–1449. doi: 10.2337/db05-1593.
    1. Murri M., Leiva I., Gomez-Zumaquero J.M., Tinahones F.J., Cardona F., Soriguer F., Queipo-Ortuno M.I. Gut microbiota in children with type 1 diabetes differs from that in healthy children: A case-control study. BMC Med. 2013;11:46. doi: 10.1186/1741-7015-11-46.
    1. De Goffau M.C., Fuentes S., Dan den Bogert B., Honkanen H., De Vos W.M., Welling G.W., Hyoty H., Harmsen H.J. Aberrant gut microbiota composition at the onset of type 1 diabetes in young children. Diabetologia. 2014;57:1569–1577. doi: 10.1007/s00125-014-3274-0.
    1. Vangay P., Ward T., Gerber J.S., Knights D. Antibiotics, pediatric dysbiosis, and disease. Cell Host Microbe. 2015;17:553–564. doi: 10.1016/j.chom.2015.04.006.
    1. Vaarala O. Gut microbiota and type 1 diabetes. Rev. Diabet. Stud. 2012;9:251–259. doi: 10.1900/RDS.2012.9.251.
    1. Hansen C.H., Krych L., Nielsen D.S., Vogensen F.K., Hansen L.H., Sorensen S.J., Buschard K., Hansen A.K. Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse. Diabetologia. 2012;55:2285–2294. doi: 10.1007/s00125-012-2564-7.
    1. Li J., Lin S., Vanhoutte P.M., Woo C.W., Xu A. Akkermansia Muciniphila Protects Against Atherosclerosis by Preventing Metabolic Endotoxemia-Induced Inflammation in Apoe−/−Mice. Circulation. 2016;133:2434–2446. doi: 10.1161/CIRCULATIONAHA.115.019645.
    1. Endesfelder D., Engel M., Davis-Richardson A.G., Ardissone A.N., Achenbach P., Hummel S., Winkler C., Atkinson M., Schatz D., Triplett E., et al. Towards a functional hypothesis relating anti-islet cell autoimmunity to the dietary impact on microbial communities and butyrate production. Microbiome. 2016;4:17. doi: 10.1186/s40168-016-0163-4.
    1. Ohata A., Usami M., Miyoshi M. Short-chain fatty acids alter tight junction permeability in intestinal monolayer cells via lipoxygenase activation. Nutrition. 2005;21:838–847. doi: 10.1016/j.nut.2004.12.004.
    1. Marino E., Richards J.L., McLeod K.H., Stanley D., Yap Y.A., Knight J., McKenzie C., Kranich J., Oliveira A.C., Rossello F.J., et al. Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes. Nat. Immunol. 2017;18:552–562. doi: 10.1038/ni.3713.
    1. Furusawa Y., Obata Y., Fukuda S., Endo T.A., Nakato G., Takahashi D., Nakanishi Y., Uetake C., Kato K., Kato T., et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T. cells. Nature. 2013;504:446–450. doi: 10.1038/nature12721.
    1. Haupt-Jorgensen M., Larsen J., Josefsen K., Jorgensen T.Z., Antvorskov J.C., Hansen A.K., Buschard K. Gluten-free diet during pregnancy alleviates signs of diabetes and celiac disease in NOD mouse offspring. Diabetes Metab. Res. Rev. 2018;34:e2987. doi: 10.1002/dmrr.2987.
    1. Larsen J., Dall M., Antvorskov J.C., Weile C., Engkilde K., Josefsen K., Buschard K. Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion. Eur. J. Immunol. 2014;44:3056–3067. doi: 10.1002/eji.201344264.
    1. Larsen J., Weile C., Antvorskov J.C., Engkilde K., Nielsen S.M., Josefsen K., Buschard K. Effect of dietary gluten on dendritic cells and innate immune subsets in BALB/c and NOD mice. PLoS ONE. 2015;10:e0118618. doi: 10.1371/journal.pone.0118618.
    1. Alam C., Valkonen S., Palagani V., Jalava J., Eerola E., Hanninen A. Inflammatory tendencies and overproduction of IL-17 in the colon of young NOD mice are counteracted with diet change. Diabetes. 2010;59:2237–2246. doi: 10.2337/db10-0147.
    1. Chakir H., Lefebvre D.E., Wang H., Caraher E., Scott F.W. Wheat protein-induced proinflammatory T helper 1 bias in mesenteric lymph nodes of young diabetes-prone rats. Diabetologia. 2005;48:1576–1584. doi: 10.1007/s00125-005-1842-z.
    1. Antvorskov J.C., Fundova P., Buschard K., Funda D.P. Impact of dietary gluten on regulatory T cells and Th17 cells in BALB/c mice. PLoS ONE. 2012;7:e33315. doi: 10.1371/journal.pone.0033315.
    1. Antvorskov J.C., Fundova P., Buschard K., Funda D.P. Dietary gluten alters the balance of pro-inflammatory and anti-inflammatory cytokines in T cells of BALB/c mice. Immunology. 2013;138:23–33. doi: 10.1111/imm.12007.
    1. Thomas K.E., Sapone A., Fasano A., Vogel S.N. Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: Role of the innate immune response in Celiac disease. J. Immunol. 2006;176:2512–2521. doi: 10.4049/jimmunol.176.4.2512.
    1. Nikulina M., Habich C., Flohe S.B., Scott F.W., Kolb H. Wheat gluten causes dendritic cell maturation and chemokine secretion. J. Immunol. 2004;173:1925–1933. doi: 10.4049/jimmunol.173.3.1925.
    1. Ciccocioppo R., Rossi M., Pesce I., Ricci G., Millimaggi D., Maurano F., Corazza G.R. Effects of gliadin stimulation on bone marrow-derived dendritic cells from HLA-DQ8 transgenic MICE. Dig. Liver Dis. 2008;40:927–935. doi: 10.1016/j.dld.2008.05.005.
    1. Healey D., Ozegbe P., Arden S., Chandler P., Hutton J., Cooke A. In vivo activity and in vitro specificity of CD4+ Th1 and Th2 cells derived from the spleens of diabetic NOD mice. J. Clin. Investig. 1995;95:2979–2985. doi: 10.1172/JCI118006.
    1. Yang X., Zheng S.G. Interleukin-22: A likely target for treatment of autoimmune diseases. Autoimmun. Rev. 2014;13:615–620. doi: 10.1016/j.autrev.2013.11.008.
    1. Catassi C., Guerrieri A., Bartolotta E., Coppa G.V., Giorgi P.L. Antigliadin antibodies at onset of diabetes in children. Lancet. 1987;2:158. doi: 10.1016/S0140-6736(87)92357-9.
    1. Troncone R., Franzese A., Mazzarella G., Paparo F., Auricchio R., Coto I., Mayer M., Greco L. Gluten sensitivity in a subset of children with insulin dependent diabetes mellitus. Am. J. Gastroenterol. 2003;98:590–595. doi: 10.1111/j.1572-0241.2003.07301.x.
    1. Mojibian M., Chakir H., Lefebvre D.E., Crookshank J.A., Sonier B., Keely E., Scott F.W. Diabetes-specific HLA-DR-restricted proinflammatory T-cell response to wheat polypeptides in tissue transglutaminase antibody-negative patients with type 1 diabetes. Diabetes. 2009;58:1789–1796. doi: 10.2337/db08-1579.
    1. Hamari S., Kirveskoski T., Glumoff V., Kulmala P., Simell O., Knip M., Ilonen J., Veijola R. CD4(+) T-cell proliferation responses to wheat polypeptide stimulation in children at different stages of type 1 diabetes autoimmunity. Pediatr. Diabetes. 2015;16:177–188. doi: 10.1111/pedi.12256.
    1. Palova-Jelinkova L., Rozkova D., Pecharova B., Bartova J., Sediva A., Tlaskalova-Hogenova H., Spisek R., Tuckova L. Gliadin fragments induce phenotypic and functional maturation of human dendritic cells. J. Immunol. 2005;175:7038–7045. doi: 10.4049/jimmunol.175.10.7038.
    1. Molberg O., McAdam S., Lundin K.E., Kristiansen C., Arentz-Hansen H., Kett K., Sollid L.M. T cells from celiac disease lesions recognize gliadin epitopes deamidated in situ by endogenous tissue transglutaminase. Eur. J. Immunol. 2001;31:1317–1323. doi: 10.1002/1521-4141(200105)31:5<1317::AID-IMMU1317>;2-I.
    1. Molberg O., McAdam S.N., Korner R., Quarsten H., Kristiansen C., Madsen L., Fugger L., Scott H., Noren O., Roepstorff P., et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat. Med. 1998;4:713–717. doi: 10.1038/nm0698-713.
    1. Serena G., Camhi S., Sturgeon C., Yan S., Fasano A. The Role of Gluten in Celiac Disease and Type 1 Diabetes. Nutrients. 2015;7:7143–7162. doi: 10.3390/nu7095329.
    1. Cosnes J., Cellier C., Viola S., Colombel J.F., Michaud L., Sarles J., Hugot J.P., Ginies J.L., Dabadie A., Mouterde O., et al. Incidence of autoimmune diseases in celiac disease: Protective effect of the gluten-free diet. Clin. Gastroenterol. Hepatol. 2008;6:753–758. doi: 10.1016/j.cgh.2007.12.022.
    1. Barera G., Bonfanti R., Viscardi M., Bazzigaluppi E., Calori G., Meschi F., Bianchi C., Chiumello G. Occurrence of celiac disease after onset of type 1 diabetes: A 6-year prospective longitudinal study. Pediatrics. 2002;109:833–838. doi: 10.1542/peds.109.5.833.
    1. Hansen D., Bennedbaek F.N., Hansen L.K., Hoier-Madsen M., Hegedu L.S., Jacobsen B.B., Husby S. High prevalence of coeliac disease in Danish children with type I. diabetes mellitus. Acta. Paediatr. 2001;90:1238–1243. doi: 10.1111/j.1651-2227.2001.tb01568.x.
    1. Aktay A.N., Lee P.C., Kumar V., Parton E., Wyatt D.T., Werlin S.L. The prevalence and clinical characteristics of celiac disease in juvenile diabetes in Wisconsin. J. Pediatr. Gastroenterol. Nutr. 2001;33:462–465. doi: 10.1097/00005176-200110000-00008.
    1. Not T., Tommasini A., Tonini G., Buratti E., Pocecco M., Tortul C., Valussi M., Crichiutti G., Berti I., Trevisiol C., et al. Undiagnosed coeliac disease and risk of autoimmune disorders in subjects with Type, I. diabetes mellitus. Diabetologia. 2001;44:151–155. doi: 10.1007/s001250051593.
    1. Carlsson A.K., Axelsson I.E., Borulf S.K., Bredberg A.C., Lindberg B.A., Sjoberg K.G., Ivarsson S.A. Prevalence of IgA-antiendomysium and IgA-antigliadin autoantibodies at diagnosis of insulin-dependent diabetes mellitus in Swedish children and adolescents. Pediatrics. 1999;103:1248–1252. doi: 10.1542/peds.103.6.1248.
    1. Sblattero D., Maurano F., Mazzarella G., Rossi M., Auricchio S., Florian F., Ziberna F., Tommasini A., Not T., Ventura A., et al. Characterization of the anti-tissue transglutaminase antibody response in nonobese diabetic mice. J. Immunol. 2005;174:5830–5836. doi: 10.4049/jimmunol.174.9.5830.
    1. Burbelo P.D., Lebovitz E.E., Bren K.E., Bayat A., Paviol S., Wenzlau J.M., Barriga K.J., Rewers M., Harlan D.M., Iadarola M.J. Extrapancreatic autoantibody profiles in type I. diabetes. PLoS ONE. 2012;7:e45216. doi: 10.1371/journal.pone.0045216.
    1. Maurano F., Mazzarella G., Luongo D., Stefanile R., D’Arienzo R., Rossi M., Auricchio S., Troncone R. Small intestinal enteropathy in non-obese diabetic mice fed a diet containing wheat. Diabetologia. 2005;48:931–937. doi: 10.1007/s00125-005-1718-2.
    1. Auricchio R., Paparo F., Maglio M., Franzese A., Lombardi F., Valerio G., Nardone G., Percopo S., Greco L., Troncone R. In vitro-deranged intestinal immune response to gliadin in type 1 diabetes. Diabetes. 2004;53:1680–1683. doi: 10.2337/diabetes.53.7.1680.
    1. Scott F.W., Rowsell P., Wang G.S., Burghardt K., Kolb H., Flohe S. Oral exposure to diabetes-promoting food or immunomodulators in neonates alters gut cytokines and diabetes. Diabetes. 2002;51:73–78. doi: 10.2337/diabetes.51.1.73.
    1. Funda D.P., Kaas A., Tlaskalova-Hogenova H., Buschard K. Gluten-free but also gluten-enriched (gluten+) diet prevent diabetes in NOD mice; the gluten enigma in type 1 diabetes. Diabetes Metab. Res. Rev. 2008;24:59–63. doi: 10.1002/dmrr.748.
    1. Labeta M.O., Durieux J.J., Spagnoli G., Fernandez N., Wijdenes J., Herrmann R. CD14 and tolerance to lipopolysaccharide: Biochemical and functional analysis. Immunology. 1993;80:415–423.
    1. Funda D.P., Fundova P., Hansen A.K., Buschard K. Prevention or early cure of type 1 diabetes by intranasal administration of gliadin in NOD mice. PLoS ONE. 2014;9:e94530. doi: 10.1371/journal.pone.0094530.
    1. Locke N.R., Stankovic S., Funda D.P., Harrison L.C. TCR gamma delta intraepithelial lymphocytes are required for self-tolerance. J. Immunol. 2006;176:6553–6559. doi: 10.4049/jimmunol.176.11.6553.
    1. Lindley S., Dayan C.M., Bishop A., Roep B.O., Peakman M., Tree T.I. Defective suppressor function in CD4(+) CD25(+) T-cells from patients with type 1 diabetes. Diabetes. 2005;54:92–99. doi: 10.2337/diabetes.54.1.92.
    1. Haupt-Jorgensen M., Nielsen E., Engkilde K., Lerche M., Larsen J., Buschard K. Occupation with grain crops is associated with lower type 1 diabetes incidence: Registry-based case-control study. PLoS ONE. 2017;12:e0181143. doi: 10.1371/journal.pone.0181143.
    1. Bruun S.W., Josefsen K., Tanassi J.T., Marek A., Pedersen M.H., Sidenius U., Haupt-Jorgensen M., Antvorskov J.C., Larsen J., Heegaard N.H., et al. Large Gliadin Peptides Detected in the Pancreas of NOD and Healthy Mice following Oral Administration. J. Diabetes Res. 2016;2016:2424306. doi: 10.1155/2016/2424306.
    1. Freire R.H., Fernandes L.R., Silva R.B., Coelho B.S., de Araujo L.P., Ribeiro L.S., Andrade J.M., Lima P.M., Araujo R.S., Santos S.H., et al. Wheat gluten intake increases weight gain and adiposity associated with reduced thermogenesis and energy expenditure in an animal model of obesity. Int. J. Obes. 2016;40:479–486. doi: 10.1038/ijo.2015.204.
    1. Chirdo F.G., Rumbo M., Anon M.C., Fossati C.A. Presence of high levels of non-degraded gliadin in breast milk from healthy mothers. Scand. J. Gastroenterol. 1998;33:1186–1192.
    1. In’t Veld P., Marichal M. Microscopic anatomy of the human islet of Langerhans. Adv. Exp. Med. Biol. 2010;654:1–19. doi: 10.1007/978-90-481-3271-3_1.
    1. Dall M., Calloe K., Haupt-Jorgensen M., Larsen J., Schmitt N., Josefsen K., Buschard K. Gliadin fragments and a specific gliadin 33-mer peptide close KATP channels and induce insulin secretion in INS-1E cells and rat islets of langerhans. PLoS ONE. 2013;8:e66474. doi: 10.1371/journal.pone.0066474.
    1. Aaen K., Rygaard J., Josefsen K., Petersen H., Brogren C.H., Horn T., Buschard K. Dependence of antigen expression on functional state of beta-cells. Diabetes. 1990;39:697–701. doi: 10.2337/diab.39.6.697.
    1. Ientile R., Caccamo D., Griffin M. Tissue transglutaminase and the stress response. Amino Acids. 2007;33:385–394. doi: 10.1007/s00726-007-0517-0.
    1. Van Lummel M., Duinkerken G., van Veelen P.A., De Ru A., Cordfunke R., Zaldumbide A., Gomez-Tourino I., Arif S., Peakman M., Drijfhout J.W., et al. Posttranslational modification of HLA-DQ binding islet autoantigens in type 1 diabetes. Diabetes. 2014;63:237–247. doi: 10.2337/db12-1214.
    1. Shaw J.E., Sicree R.A., Zimmet P.Z. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res. Clin. Pract. 2010;87:4–14. doi: 10.1016/j.diabres.2009.10.007.
    1. Leahy J.L. Natural history of beta-cell dysfunction in NIDDM. Diabetes Care. 1990;13:992–1010. doi: 10.2337/diacare.13.9.992.
    1. Perley M., Kipnis D.M. Plasma insulin responses to glucose and tolbutamide of normal weight and obese diabetic and nondiabetic subjects. Diabetes. 1966;15:867–874. doi: 10.2337/diab.15.12.867.
    1. Kloppel G., Lohr M., Habich K., Oberholzer M., Heitz P.U. Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv. Synth. Pathol. Res. 1985;4:110–125.
    1. Kahn S.E. Clinical review 135: The importance of beta-cell failure in the development and progression of type 2 diabetes. J. Clin. Endocrinol. Metab. 2001;86:4047–4058. doi: 10.1210/jcem.86.9.7713.
    1. Florez J.C., Hirschhorn J., Altshuler D. The inherited basis of diabetes mellitus: Implications for the genetic analysis of complex traits. Annu. Rev. Genomics Hum. Genet. 2003;4:257–291. doi: 10.1146/annurev.genom.4.070802.110436.
    1. Poulsen P., Kyvik K.O., Vaag A., Beck-Nielsen H. Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance--a population-based twin study. Diabetologia. 1999;42:139–145. doi: 10.1007/s001250051131.
    1. Diabetes mellitus in twins: A cooperative study in Japan. Committee on Diabetic Twins, Japan Diabetes Society. Diabetes Res. Clin. Pract. 1988;5:271–280. doi: 10.1016/S0168-8227(88)80062-7.
    1. Romao I., Roth J. Genetic and environmental interactions in obesity and type 2 diabetes. J. Am. Diet. Assoc. 2008;108:S24–S28. doi: 10.1016/j.jada.2008.01.022.
    1. Alberti G., Zimmet P., Shaw J., Bloomgarden Z., Kaufman F., Silink M. Type 2 diabetes in the young: The evolving epidemic: The international diabetes federation consensus workshop. Diabetes Care. 2004;27:1798–1811. doi: 10.2337/diacare.27.7.1798.
    1. Neel J.V. Diabetes mellitus: A ‘thrifty’ genotype rendered detrimental by ’progress’? Am. J. Hum. Genet. 1962;14:353–362.
    1. Tinggaard J., Wohlfahrt-Veje C., Husby S., Christiansen L., Skakkebaek N.E., Jensen T.K., Grandjean P., Main K.M., Andersen H.R. Prenatal pesticide exposure and PON1 genotype associated with adolescent body fat distribution evaluated by dual X-ray absorptiometry (DXA) Andrology. 2016;4:735–744. doi: 10.1111/andr.12194.
    1. Hales C.N., Barker D.J. Type 2 (non-insulin-dependent) diabetes mellitus: The thrifty phenotype hypothesis. Diabetologia. 1992;35:595–601. doi: 10.1007/BF00400248.
    1. Jonsson T., Memon A.A., Sundquist K., Sundquist J., Olsson S., Nalla A., Bauer M., Linse S. Digested wheat gluten inhibits binding between leptin and its receptor. BMC Biochem. 2015;16:3. doi: 10.1186/s12858-015-0032-y.
    1. Pan H., Guo J., Su Z. Advances in understanding the interrelations between leptin resistance and obesity. Physiol. Behav. 2014;130:157–169. doi: 10.1016/j.physbeh.2014.04.003.
    1. Jonsson T., Olsson S., Ahren B., Bog-Hansen T.C., Dole A., Lindeberg S. Agrarian diet and diseases of affluence--do evolutionary novel dietary lectins cause leptin resistance? BMC Endocr. Disord. 2005;5:10. doi: 10.1186/1472-6823-5-10.
    1. Jonsson T., Ahren B., Pacini G., Sundler F., Wierup N., Steen S., Sjoberg T., Ugander M., Frostegard J., Goransson L., et al. A Paleolithic diet confers higher insulin sensitivity, lower C-reactive protein and lower blood pressure than a cereal-based diet in domestic pigs. Nutr. Metab. 2006;3:39. doi: 10.1186/1743-7075-3-39.
    1. Tilg H., Moschen A.R. Microbiota and diabetes: An evolving relationship. Gut. 2014;63:1513–1521. doi: 10.1136/gutjnl-2014-306928.
    1. Ley R.E., Turnbaugh P.J., Klein S., Gordon J.I. Microbial ecology: Human gut microbes associated with obesity. Nature. 2006;444:1022–1023. doi: 10.1038/4441022a.
    1. Turnbaugh P.J., Ley R.E., Mahowald M.A., Magrini V., Mardis E.R., Gordon J.I. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–1031. doi: 10.1038/nature05414.
    1. Karlsson F.H., Tremaroli V., Nookaew I., Bergstrom G., Behre C.J., Fagerberg B., Nielsen J., Backhed F. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498:99–103. doi: 10.1038/nature12198.
    1. Lu Y., Fan C., Li P., Lu Y., Chang X., Qi K. Short Chain Fatty Acids Prevent High-fat-diet-induced Obesity in Mice by Regulating G Protein-coupled Receptors and Gut Microbiota. Sci. Rep. 2016;6:37589. doi: 10.1038/srep37589.
    1. Horton F., Wright J., Smith L., Hinton P.J., Robertson M.D. Increased intestinal permeability to oral chromium (51 Cr) -EDTA in human Type 2 diabetes. Diabet. Med. 2014;31:559–563. doi: 10.1111/dme.12360.
    1. Cox A.J., Zhang P., Bowden D.W., Devereaux B., Davoren P.M., Cripps A.W., West N.P. Increased intestinal permeability as a risk factor for type 2 diabetes. Diabetes Metab. 2017;43:163–166. doi: 10.1016/j.diabet.2016.09.004.
    1. Zhang L., Andersen D., Roager H.M., Bahl M.I., Hansen C.H., Danneskiold-Samsoe N.B., Kristiansen K., Radulescu I.D., Sina C., Frandsen H.L., et al. Effects of Gliadin consumption on the Intestinal Microbiota and Metabolic Homeostasis in Mice Fed a High-fat Diet. Sci. Rep. 2017;7:44613. doi: 10.1038/srep44613.
    1. Rajilic-Stojanovic M., De Vos W.M. The first 1000 cultured species of the human gastrointestinal microbiota. FEMS Microbiol. Rev. 2014;38:996–1047. doi: 10.1111/1574-6976.12075.
    1. Clavel T., Desmarchelier C., Haller D., Gerard P., Rohn S., Lepage P., Daniel H. Intestinal microbiota in metabolic diseases: From bacterial community structure and functions to species of pathophysiological relevance. Gut Microbes. 2014;5:544–551. doi: 10.4161/gmic.29331.
    1. Saulnier D.M., Riehle K., Mistretta T.A., Diaz M.A., Mandal D., Raza S., Weidler E.M., Qin X., Coarfa C., Milosavljevic A., et al. Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome. Gastroenterology. 2011;141:1782–1791. doi: 10.1053/j.gastro.2011.06.072.
    1. Rajilic-Stojanovic M., Biagi E., Heilig H.G., Kajander K., Kekkonen R.A., Tims S., de Vos W.M. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology. 2011;141:1792–1801. doi: 10.1053/j.gastro.2011.07.043.
    1. Everard A., Belzer C., Geurts L., Ouwerkerk J.P., Druart C., Bindels L.B., Guiot Y., Derrien M., Muccioli G.G., Delzenne N.M., et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl. Acad. Sci. USA. 2013;110:9066–9071. doi: 10.1073/pnas.1219451110.
    1. Zhang X., Shen D., Fang Z., Jie Z., Qiu X., Zhang C., Chen Y., Ji L. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS ONE. 2013;8:e71108. doi: 10.1371/journal.pone.0071108.
    1. Amar J., Chabo C., Waget A., Klopp P., Vachoux C., Bermudez-Humaran L.G., Smirnova N., Berge M., Sulpice T., Lahtinen S., et al. Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: Molecular mechanisms and probiotic treatment. EMBO Mol. Med. 2011;3:559–572. doi: 10.1002/emmm.201100159.
    1. Fagerberg L., Hallstrom B.M., Oksvold P., Kampf C., Djureinovic D., Odeberg J., Habuka M., Tahmasebpoor S., Danielsson A., Edlund K., et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol. Cell. Proteom. 2014;13:397–406. doi: 10.1074/mcp.M113.035600.
    1. Shi H., Kokoeva M.V., Inouye K., Tzameli I., Yin H., Flier J.S. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Investig. 2006;116:3015–3025. doi: 10.1172/JCI28898.
    1. Ladefoged M., Buschard K., Hansen A.M. Increased expression of toll-like receptor 4 and inflammatory cytokines, interleukin-6 in particular, in islets from a mouse model of obesity and type 2 diabetes. APMIS. 2013;121:531–538. doi: 10.1111/apm.12018.
    1. Palova-Jelinkova L., Danova K., Drasarova H., Dvorak M., Funda D.P., Fundova P., Kotrbova-Kozak A., Cerna M., Kamanova J., Martin S.F., et al. Pepsin digest of wheat gliadin fraction increases production of IL-1beta via TLR4/MyD88/TRIF/MAPK/NF-kappaB signaling pathway and an NLRP3 inflammasome activation. PLoS ONE. 2013;8:e62426. doi: 10.1371/journal.pone.0062426.
    1. Mokady S., Einav P. Effect of dietary wheat gluten in lipid metabolism in growing rats. Nutr. Metab. 1978;22:181–189. doi: 10.1159/000176214.
    1. Soares F.L., de Oliveira Matoso R., Teixeira L.G., Menezes Z., Pereira S.S., Alves A.C., Batista N.V., De Faria A.M., Cara D.C., Ferreira A.V., et al. Gluten-free diet reduces adiposity, inflammation and insulin resistance associated with the induction of PPAR-alpha and PPAR-gamma expression. J. Nutr. Biochem. 2013;24:1105–1111. doi: 10.1016/j.jnutbio.2012.08.009.
    1. Haupt-Jorgensen M., Buschard K., Hansen A.K., Josefsen K., Antvorskov J.C. Gluten-free diet increases beta-cell volume and improves glucose tolerance in an animal model of type 2 diabetes. Diabetes Metab. Res. Rev. 2016;32:675–684. doi: 10.1002/dmrr.2802.
    1. Rune I., Rolin B., Larsen C., Nielsen D.S., Kanter J.E., Bornfeldt K.E., Lykkesfeldt J., Buschard K., Kirk R.K., Christoffersen B., et al. Modulating the Gut Microbiota Improves Glucose Tolerance, Lipoprotein Profile and Atherosclerotic Plaque Development in ApoE-Deficient Mice. PLoS ONE. 2016;11:e0146439. doi: 10.1371/journal.pone.0146439.
    1. Mortensen L.S., Hartvigsen M.L., Brader L.J., Astrup A., Schrezenmeir J., Holst J.J., Thomsen C., Hermansen K. Differential effects of protein quality on postprandial lipemia in response to a fat-rich meal in type 2 diabetes: Comparison of whey, casein, gluten, and cod protein. Am. J. Clin. Nutr. 2009;90:41–48. doi: 10.3945/ajcn.2008.27281.
    1. Kim H.S., Demyen M.F., Mathew J., Kothari N., Feurdean M., Ahlawat S.K. Obesity, Metabolic Syndrome, and Cardiovascular Risk in Gluten-Free Followers Without Celiac Disease in the United States: Results from the National Health and Nutrition Examination Survey 2009–2014. Dig. Dis. Sci. 2017 doi: 10.1007/s10620-017-4583-1.
    1. Mari-Bauset S., Llopis-Gonzalez A., Zazpe I., Mari-Sanchis A., Suarez-Varela M.M. Nutritional Impact of a Gluten-Free Casein-Free Diet in Children with Autism Spectrum Disorder. J. Autism. Dev. Disord. 2016;46:673–684. doi: 10.1007/s10803-015-2582-7.
    1. Zong G., Lebwohl B., Hu F.B., Sampson L., Dougherty L.W., Willett W.C., Chan A.T., Sun Q. Gluten intake and risk of type 2 diabetes in three large prospective cohort studies of US men and women. Diabetologia. 2018;61:2164–2173. doi: 10.1007/s00125-018-4697-9.

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