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DOI: 10.18544/PEDM-21.04.0042

Role of gluten-free diet in pathogenesis of type 1 diabetes – what new?

Artur Chwalba, Ewa Otto-Buczkowska

Key words: 

gluten, gluten-free diet, prevention of type 1 diabetes


Over the last decades, the association between coeliac disease and other autoimmune disorders, such as autoimmune thyroid diseases or diabetes mellitus type 1 has been well established through many studies, and to this day is subject to an on-going clinical and scientific investigation worldwide. Type 1 diabetes (T1D) and coeliac disease (CD) share a similar genetic background, with high susceptibility associated with the HLA-DQ2/DQ8 genotype. Interplay between ingested gluten and the subsequent development of type 1 diabetes has been revealed by studies in humans and animals. The study shows that a diet without gluten reduces the level of NKG2D receptor and its ligand expression in mice on a gluten-free (GF) diets. Thus, gluten may affect diabetes development by influencing proportional changes in immune cell populations or by modifying the cytokine/chemokine pattern towards an inflammatory profile. This supports an important role for gluten intake in the pathogenesis of type 1 diabetes. It is reasonable to conduct further researchto clarify whether a gluten-free dietcould prevent disease in susceptible individuals or be used with newly diagnosed patients to stop the disease. These observations may be important for the primary prevention of diabetes.


Type 1 diabetes is an autoimmune disease that is frequently accompanied by other illnesses, ex.: autoimmune thyroid disease, celiac disease, gastroenteritis, malignant anaemia, albinism [1–3]. 

Higher incidence of celiac disease in type 1 diabetes in comparison with the general population is known and appointed for a long time. The tissue infiltrations from immunocompetent cells, tissues destruction and specific organ hormonal reaction are observed in cell characterized autoimmune diseases, like type 1 diabetes as well as celiac disease. Concomitance of these two illnesses may be connected with an association between genetic (HLA system alleles DRB1*04 DQB1*0302, DRB1*03 DQB1*0201), immune (lymphocyte T, cytokines production) and environment factor (including infections) [4,5].

In the opinion of many authors bacterial flora of bowels plays an essential role in the progress of autoimmune disorders, including celiac disease and type 1 diabetes [6,7].

The incidence of genotype HLA DQ varies in patients that suffer from celiac disease and type 1 diabetes in comparison with patients with just one of these illnesses.

HLA system genes play a significant role, the contribution of other factorsfrom beyond the HLA system stays unknown [8,9].

Another factor that may signalize the pathogenic correlation between these two diseases is a higher activity of zonulin – the protein responsible for loosening of epithelium cells tight joints and for the increase of epithelium permeability. The high concentration of zonulin leads to intestinal barrier function disorder so the antigenes involved in appearance and progression of celiac disease and related autoimmune disorders, eg. type 1 diabetes enter the organism [10].

It seems that significantly higher incidence of celiac disease in type 1 diabetes can be linked to genetic factor in HLA system as well as antygene mimicry phenomena. The islands of pancreas disorder in the initial progression phase of type 1 diabetes may lead to transglutaminase C release from β cells of the pancreas and induction of autoimmune response that initiate celiac disease development [11–13].

Gluten role as a factor stimulating autoimmunization process

Recently, more and more attention has been focused on gluten role as a factor stimulating autoimmunization process in bowels mucosa as well as in β-cells in islet of Langerhans [5].

A certain kind of news is the information that type 1 diabetes and celiac disease have similar genetic background related to HLA-DQ2 / DQ8. This statement has become a base for the research on gluten-free diet application in patients with this type of genetic system but without celiac disease symptoms in early period after type 1 diabetes diagnosis.

There is more and more information available about the influence of such a diet on regression of type 1 diabetes. It was revealed that gluten-free diet may have a positive influence on maintaining β-cells functions in patients with a high factor of genetic risk in type 1 diabetes progression. The mechanism of gluten-free diet for the protection of β-cells function has yet to be explained. The question whether a gluten-free diet practice in patients who are genetically predisposed to type 1 diabetes and celiac disease may prevent diabetes progression or whether it can be applied in patients with new diagnosed diabetes to slow down the progress of disease, needs further research.

Investigation and prevention of type 1 diabetes have a long-standing history. It is believed that the progression of this disease depends on not only genetic but also environmental factors that, in people genetically predisposed, can induct autoimmune processes [14,15].

The role of the induction of autoimmune processes that lead to diabetes progression is put down to bacterial flora, i.a [7].

Much attention is also paid to dietary factors [16,17].

Cow’s milk is considered to be one of the dietary factors [18].

For many years, this factor has been the subject of research as a part of big international programme TRIGR (Trial to Reduce IDDM in Genetically at Risk) run in 77 science centres on 3 continents (Australia, Europe, North America) [19–21]. 

Another environmental factor that was a subject of research is gluten [17]

The experimental research on gluten-free diet application in diabetes prevention in mice has been conducted by Fund et al. since 90’s of the last century [22,23]. These authors showed a significantly lower rate of diabetes occurrence in mice put on a gluten-free diet.

Recently, Sweden authors have issued a report in which they revealed that gluten-free diet application in mice decreases the level of NKG2D receptor and its ligand expression. These changes influence immune processes, hence they may contribute to lower occurrence of type 1 diabetes [24].

Interesting experimental cell research on gluten-free diet role in inhibition of type 1 diabetes progress in mice has been presented recently by Danish investigators [25].

American authors have drawn attention to the fact that the application of gluten-free diet in experimental research is associated with the change oinf bacterial flora of bowels, and these changes limit hyperglycemia occurrence in investigated mice [26]

Similar research was conducted by Danish investigators who stated that gluten-free diet application in pregnant mice and in new-born mice decreases incidence of diabetes what may be related to the changes in bacterial flora of bowels and therefore may limit the occurrence of immune reaction in bowels and pancreas [27]. Similar observations were performed by Canadian authors [28].

The attempts to determine factors that influence the progress of autoimmune processes, hence in effect contributing to the progress of diabetes, lead to the formulation of diabetes prevention programmes [29,30].

Nowadays, the most expanded actions are put in secondary prevention category that is applied after the start of an autoimmunization process. Its scope is to protect undestroyed β-cells of pancreas. As a part of this actions, experimental therapies are applied [31,32].

This kind of therapies is also used in Poland [33,34].

However, the special attention is paid to research on possibilities of primary prevention application.

The goal of this kind of prevention is the elimination or “neutralization” of pathogenetic factors that lead to disease progress. In the case of type 1 diabetes, the modification of environmental factors in the potential possibility. The exchange of genetic pool is currently not possible.

Due to the fact that among environmental factors, significant role is assigned to diet, hence the programmes aimed at determining nutritional factors that may influence on activating autoimmune processes in patients genetically predisposed to diabetes.

Researches mentioned above, mainly experimental ones, reveal that gluten may be one of such factors. Generally in the past it was stated that gluten intolerance occurs in patients who had type 1 diabetes diagnosed earlier. At present, it is believed that gluten may be the initial factor activating autoimmune processes in relation to β-cells [26,35].

For the time being, there are many ambiguities hence the researches require further continuation.

The comprehensive based-on-literature review of researches on trials of primary and secondary prevention application was presented by Skyler JS [36].

The research progress is very clear but the final effects will be known later [37].


1. Hogg-Kollars S, A Dulaimi D, Tait K, Rostami K. Type 1 diabetes mellitus and gluten induced disorders. Gastroenterol Hepatol Bed Bench. 2014;7:189-197.

2. Kakleas K, Soldatou A, Karachaliou F, Karavanaki K. Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus (T1DM). Autoimmun Rev, 2015 May 20. pii: S1568-9972(15)00110-X. [Epub ahead of print].

3. Otto-Buczkowska E, Jarosz-Chobot P, Minkina-Pedras M. et al. Concomitance of autoimmune diseases and type 1 diabetes in children based on literature and own observations. Przegl Lek 2008; 65:140-144. 

4. Frisk G, Hansson T, Dahlbom I, Tuvemo T. A unifying hypothesis on the development of type 1 diabetes and celiac disease: gluten consumption may be shared causative factor. Med Hypotheses. 2008;70:1207-1209.

5. Kagohashi Y, Otani H. Role of nutritional factors at the early life stages in the pathogenesis and clinical course of type 1 diabetes. Biomed Res Int. 2015;2015:382165.

6. Brown CT, Davis-Richardson AG, Giongo A, Gano KA, Crabb DB et al. Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS One. 2011;6:e25792.

7. Endesfelder D, Castell W, Ardissone A et al. Compromised gut microbiota networks in children with anti-islet cell autoimmunity. Diabetes. 2014;63:2006-2014.

8. Dezsöfi A, Szebeni B, Hermann C et al. Frequencies of Genetic Polymorphisms of TLR4 and CD14 and of HLA-DQ Genotypes in Children with Celiac Disease, Type 1 Diabetes Mellitus, or Both. J Pediatr Gastroenterol Nutr. 2008;47:283-287.

9. Nenna R, Mora B, Megiorni F et al. HLA-DQB1*02 Dose Effect on RIA Anti-tissue Transglutaminase Autoantibody Levels and Clinicopathological Expressivity of Celiac Disease. J Pediatr Gastroenterol Nutr. 2008;47:288-292.

10. Pabijasz, D, Grzybowska-Chlebowczyk U, Woś H. Evaluation of intestinal permeability on the basis of zonulin levels, in children with inflammatory bowel disease. Post N Med 2013; 5: 346-350.

11. Hansson T, Dahlbom I, Tuvemo T, Frisk G. Silent coeliac disease is over-represented in children with type 1 diabetes and their siblings. Acta Paediatr. 2015;104:185-191.

12. Szaflarska-Popławska A. Coeliac disease in type 1 diabetes mellitus. [in] Alterations in glucose homeostasis in children, adolescents and young adults. Otto-Buczkowska E. (red.) Nova New York 2015:203-214.

13. Woś H., Grzybowska-Chlebowczyk U. Współwystępowanie celiakii i cukrzycy. In: Cukrzyca w populacji wieku rozwojowego. Otto-Buczkowska E. (red.) Cornetis Wrocław 2009:319-326.

14. Skyler JS. Toward primary prevention of type 1 diabetes. JAMA. 2015;313:1520-1521.

15. Hummel S, Vehik K, Uusitalo U et al. TEDDY Study Group. Infant feeding patterns in families with a diabetes history – observations from The Environmental Determinants of Diabetes in the Young (TEDDY) birth cohort study. Public Health Nutr. 2014;17:2853-2862

16. Kagohashi Y, Otani H. Role of nutritional factors at the early life stages in the pathogenesis and clinical course of type 1 diabetes. Biomed Res Int. 2015;2015:382165. 

17. Antvorskov JC, Josefsen K, Engkilde K et al. Dietary gluten and the development of type 1 diabetes. Diabetologia. 2014;57:1770-1780.

18. Akerblom HK, Virtanen SM, Ilonen J et al. National TRIGR Study Groups. Dietary manipulation of beta cell autoimmunity in infants at increased risk of type 1 diabetes: a pilot study. Diabetologia. 2005;48:829-837.

19. Franciscus M, Nucci A, Bradley B et al. TRIGR Investigators. Recruitment and retention of participants for an international type 1 diabetes prevention trial: a coordinators’ perspective. Clin Trials. 2014;11:150-158. 

20. Knip M, Virtanen SM, Becker D, Dupré J et al. TRIGR Study Group.Early feeding and risk of type 1 diabetes: experiences from the Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR). Am J Clin Nutr. 2011;94(6 Suppl):1814S-1820S.

21. Knip M, Åkerblom HK, Becker D et al. TRIGR Study Group. Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial. JAMA. 2014;311:2279-2287.

22. Funda DP, Kaas A, Bock T, Tlaskalová-Hogenová H, Buschard K. Gluten-free diet prevents diabetes in NOD mice. Diabetes Metab Res Rev. 1999;15:323-327.

23. Funda DP, Kaas A, Tlaskalová-Hogenová 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.

24. Adlercreutz EH, Weile C, Larsen J, Engkilde K et al. A gluten-free diet lowers NKG2D and ligand expression in BALB/c and non-obese diabetic (NOD) mice. Clin Exp Immunol. 2014;177:391-403.

25. Larsen J, Weile C, Antvorskov JC, Engkilde K et al. Effect of dietary gluten on dendritic cells and innate immune subsets in BALB/c and NOD mice. PLoS One. 2015;10:e0118618.

26. Marietta EV, Gomez AM, Yeoman C. et al. 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.

27. Hansen CH, Krych L, Buschard K et al.  A maternal gluten-free diet reduces inflammation and diabetes incidence in the offspring of NOD mice. Diabetes. 2014;63:2821-2832.

28. Patrick C, Wang GS, Lefebvre DE et al. Promotion of autoimmune diabetes by cereal diet in the presence or absence of microbes associated with gut immune activation, regulatory imbalance, and altered cathelicidin antimicrobial Peptide. Diabetes. 2013;62:2036-2047.

29. Michels A, Zhang L, Khadra A, Kushner JA et al. Prediction and prevention of type 1 diabetes: update on success of prediction and struggles at prevention. Pediatr Diabetes. 2015 Jul 23. doi: 10.1111/pedi.12299. [Epub ahead of print].

30. Tandon N. Understanding type 1 diabetes through genetics: advances and prospects. Indian J Endocrinol Metab. 2015;19(Suppl 1):S39-43.

31. Morran MP, Vonberg A, Khadra A, Pietropaolo M. Immunogenetics of type 1 diabetes mellitus. Mol Aspects Med. 2015;42:42-60

32. Skyler JS. Immune intervention for type 1 diabetes, 2013-2014. http://www.ncbi.nlm.nih.gov/pubmed/25679434 Diabetes Technol Ther. 2015;17 Suppl 1:S80-87. 

33. Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A. et al. Administration of CD4+CD25highCD127- regulatory T cells preserves β-cell function in type 1 diabetes in children. Diabetes Care. 2012; 35: 1817-1820.

34. Marek-Trzonkowska N, Myśliwiec M, Dobyszuk A et al. Therapy of type 1 diabetes with CD4(+)CD25(high)CD127-regulatory T cells prolongs survival of pancreatic islets – results of one year follow-up. Clin Immunol. 2014; 153: 23-30.

35. Verbeke S, Cruchet S, Gotteland M et al. Risk markers for insulin-dependent diabetes mellitus and duration of exposure to gluten in celiac patients. Rev Med Chil. 2004;132:979-984.

36. Skyler JS. Primary and secondary prevention of Type 1 diabetes. Diabet Med. 2013; 30: 161-169.

37. Skyler JS. Prevention and reversal of type 1 diabetes -past challenges and future opportunities. Diabetes Care. 2015;38:997-1007.

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DOI: 10.18544/PEDM-21.04.0042
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