Celiac Disease and Type 1 Diabetes Mellitus: History
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Contributor:
Ingo Eland
,
Lars Klieverik
,
Abbas Ali Mansour
,
Abdulbaqi Al-Toma

Celiac disease (CeD) is associated with type 1 diabetes mellitus (T1DM), and both have the same genetic background. Type 1 diabetes mellitus (T1DM), an autoimmune disease, is caused by insulin deficiency due to destruction of the insulin-producing pancreatic beta cells.

  • celiac disease
  • gluten-free diet
  • type 1 diabetes mellitus
  • HbA1c
  • quality of life

1. Celiac Disease and Type 1 Diabetes Mellitus: The Association

Several studies have shown the importance of adequate glycemic control in avoiding long-term diabetic complications and that partial endogenous insulin production facilitates good glycemic control [1][2].
Patients with type 1 diabetes mellitus (T1DM) have an increased risk of developing other autoimmune disorders such as Hashimoto’s thyroiditis, Addison disease, atrophic gastritis, pernicious anemia, vitiligo, and celiac disease (CeD) [3]. These auto-immune diseases share a similar genetic background and are associated with autoantibodies that can be detected before the development of clinical manifestations. A coexisting autoimmune disorder can complicate diabetes management. Screening protocols have been advocated to detect these disorders [4].
CeD is an autoimmune disorder in genetically predisposed individuals precipitated by exposure to gluten, a protein found in wheat, rye, barley and others, resulting in a multisystem inflammation with enteropathy as a central feature. CeD is almost always restricted to human leukocyte antigen (HLA) HLA-DQ2 or DQ8 positive individuals. The association between T1DM and CeD dates back to 1969 [5].
The genetic risk factors associated with both diseases include HLA genes and non-HLA genes. Genetic factors contribute to about 50% of the risk of T1DM [6]. The genes most strongly associated with T1DM are HLA-DQ2 and DQ8. These HLA-alleles have been linked to an increased risk of CeD. As a result, T1DM patients are more likely to develop CeD [6][7].
Studies in animals support a link between gluten and T1DM. It is suggested that gluten affects the β-cells, with a possible link to the development of T1DM. Other components may exert an additional effect, such as the innate and adaptive immune systems, pro-inflammation, and gut microbiota and permeability [7][8][9][10][11][12].
Furthermore, gliadin has been shown to affect the pancreas [13], possibly by inducing inflammation [9] and β-cell stress [10]. The incidence of T1DM in mice was reduced from 64% to 15% by applying a lifelong gluten-free diet GFD [12][14].
In addition to the genetic connection between T1DM and CeD, studies suggest that higher gluten consumption may escalate the incidence of T1DM. For example, a study found a proportional increase in the risk of T1DM in the offspring of pregnant women who consumed more gluten [15]. In another study, a GFD improved insulin secretion in subjects at high risk for T1DM [16]. A small study from Denmark showed significant improvement in glycemic control following a one-year GFD in 15 children with newly diagnosed T1DM [17].
There is some evidence suggesting that a GFD might positively influence T1DM pathology, onset, and clinical course [18]. However, studies in humans are rare. There is no clear evidence that a GFD can prevent the development of CeD in patients with T1DM [19]. Such an approach is not recommended as it makes future CeD diagnosis difficult [20].
Several environmental factors were studied as precipitating factors for the development of CeD or T1DM. Enterovirus infections, specifically Coxsackie, have been linked to the development of T1DM [21][22]. Rotavirus has been linked to an increased risk of T1DM and CeD [23]. Furthermore, altered gut permeability and microbiota seem to be factors that contribute to the development of both of these two diseases [24].

2. Micro- or Macroangiopathic Complications in Coexistent T1DM and Celiac Disease

Few studies have been published dealing with the vascular complications of T1DM in the presence of CeD. Interestingly, Bakker et al. [25] showed that retinopathy is less prevalent in T1DM patients with CeD compared to controls (T1DM patients without CeD). This could imply that a GFD has a beneficial effect on vascular complications in T1DM patients.
Similar findings were observed by Picarelli et al. [26]. They studied whether CeD in patients with T1DM is associated with different expressions of hemostatic factors and if that is associated with an effect on the development of complications. They found that CeD may have a protective role in the prothrombotic state of T1DM. Patients with CeD had significantly lower cholesterol, triglycerides, HbA1c, factor VII antigen, coagulant activity, and prothrombin degradation fragments.
Contrary to these studies, Pitocco et al. [27] found that the carotid intima-media layer was thicker in T1DM patients with a long duration of CeD, compared to those diabetics without CeD. Data from the Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) showed that the risk of cardiovascular disease in children with T1DM and untreated CeD may be increased by an unfavorable lipid profile (low HDL-C levels and high LDL-C values) [28]. These data underscore the fact that a strict GFD is mandatory for these young patients.
A multicenter longitudinal analysis from the German-Austrian DPV (Diabetes Patienten Verlaufsdokumentation) Database investigated whether CeD associated with T1DM increases the risk of microvascular complications [29]. Nephropathy and retinopathy occurred earlier in the presence of CeD. The incidence of retinopathy and nephropathy was higher in patients with T1DM and CeD than in those without CeD. This research did not investigate the possible protective effect of a GFD on the microvascular complications in T1DM and CeD.
In a case–control study [30] performed in Sheffield, U.K., T1DM patients aged > 16 years (n = 1000) were assessed for CeD. CeD was found in 3.3% of the study population. HbA1c, lipid profile, nephropathy stage, retinopathy stage, and degree of neuropathy before and after 1 year on a GFD were assessed. At the time of diagnosis of CeD, adult patients with T1DM had worse glycemic control, lower total cholesterol, lower HDL cholesterol, and a higher prevalence of retinopathy, nephropathy, and peripheral neuropathy. After following a GFD for one year, there was an improvement in the lipid profile, HbA1c, and markers for nephropathy. Of particular importance, if GFD has a protective role against the development of micro- and macroangiopathic complications, then a misdiagnosis of CeD in adult patients with T1DM would be associated with a higher prevalence of nephropathy, peripheral neuropathy, and retinopathy.
Creanzo et al. [31] found that the coexistence of T1DM and CeD is associated with lower eGFR values than those with T1DM alone.
These findings underscore the importance of regular screening for CeD in T1DM patients to timely detect those at risk of developing CeD.
On the other hand, GFD has been shown to have a protective rather than a detrimental effect on micro- and macrovascular complications [25][26], even in children [32][33].
To summarize, there seems to be greater agreement between studies on the benefits of GFD regarding long-term vascular complications. However, there are substantial differences between these studies, and consequently, the inconsistent and inconclusive results regarding the influence of a GFD on glycemic control, insulin dose, HbA1c, glucose excretion, and hypoglycemic episodes in patients with T1DM and CeD, they could be due to the type of diet that they actually follow. A GFD could mean the use of foods rich in fats with a high glycemic index and a more unfavorable impact, or it could mean a diet based mainly on vegetables with a more favorable impact on glycemic values, HbA1c, insulin requirement, lipid profiles, and even the incidence of long-term diabetic complications. Thus, investigating the ingredients of GFD would be more interesting.
Further investigations are needed to explore the mechanism by which therapy with a GFD might prevent micro- and macrovascular complications of T1DM. Theoretically, greater dietary adherence and regular assessment and coaching by an experienced dietitian might result in better and healthier eating habits.

This entry is adapted from the peer-reviewed paper 10.3390/nu15010199

References

  1. McGill, D.E.; Levitsky, L.L. Management of Hypoglycemia in Children and Adolescents with Type 1 Diabetes Mellitus. Curr. Diabetes Rep. 2016, 16, 88.
  2. Böber, E.; Dündar, B.; Büyükgebiz, A. Partial Remission Phase and Metabolic Control in Type 1 Diabetes Mellitus in Children and Adolescents. J. Pediatr. Endocrinol. Metab. 2001, 14, 435–442.
  3. Barker, J.M. Clinical review: Type 1 Diabetes-Associated Autoimmunity: Natural History, Genetic Associations, and Screening. J. Clin. Endocrinol. Metab. 2006, 91, 1210–1217.
  4. Nederstigt, C.; Uitbeijerse, B.S.; Janssen, L.G.M.; Corssmit, E.P.M.; de Koning, E.J.P.; Dekkers, O.M. Associated auto-immune disease in type 1 diabetes patients: A systematic review and meta-analysis. Eur. J. Endocrinol. 2019, 180, 135–144.
  5. Walker-Smith, J.A.; Grigor, W. Coeliac Disease in a Diabetic Child. Lancet 1969, 293, 1021.
  6. Pociot, F.; Lernmark, Å. Genetic risk factors for type 1 diabetes. Lancet 2016, 387, 2331–2339.
  7. 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.
  8. Drago, S.; El Asmar, R.; Di Pierro, M.; Grazia Clemente, M.; Tripathi, A.; Sapone, A.; Thakar, M.; Iacono, G.; Carroccio, A.; D’Agate, C.; et al. Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand. J. Gastroenterol. 2006, 41, 408–419.
  9. 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.
  10. 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.
  11. Ejsing-Duun, M.; Josephsen, J.; Aasted, B.; Buschard, K.; Hansen, A.K. Dietary Gluten Reduces the Number of Intestinal Regulatory T Cells in Mice. Scand. J. Immunol. 2008, 67, 553–559.
  12. 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.
  13. Bruun, S.W.; Josefsen, K.; Tanassi, J.T.; Marek, A.; Pedersen, M.H.F.; 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.
  14. Funda, D.P.; 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.
  15. Antvorskov, J.C.; Halldorsson, T.I.; Josefsen, K.; Svensson, J.; Granström, C.; Roep, B.O.; Olesen, T.H.; Hrolfsdottir, L.; Buschard, K.; Olsen, S. Association between maternal gluten intake and type 1 diabetes in offspring: National prospective cohort study in Denmark. BMJ 2018, 362, k3547.
  16. 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.
  17. Svensson, J.; Sildorf, S.M.; Pipper, C.B.; Kyvsgaard, J.N.; Bøjstrup, 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.
  18. 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, bcr0220125878.
  19. 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.
  20. Al-Toma, A.; Volta, U.; Auricchio, R.; Castillejo, G.; Sanders, D.S.; Cellier, C.; Mulder, C.J.; Lundin, K.E.A. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United Eur. Gastroenterol. J. 2019, 7, 583–613.
  21. Filippi, C.M.; von Herrath, M.G. Viral Trigger for Type 1 Diabetes: Pros and cons. Diabetes 2008, 57, 2863–2871.
  22. Kahrs, C.R.; Chuda, K.; Tapia, G.; Stene, L.C.; Mårild, K.; Rasmussen, T.; Rønningen, K.S.; Lundin, K.E.A.; Kramna, L.; Cinek, O.; et al. Enterovirus as trigger of coeliac disease: Nested case-control study within prospective birth cohort. BMJ 2019, 364, l231.
  23. Stene, L.C.; Honeyman, M.C.; Hoffenberg, E.; Haas, J.E.; Sokol, R.J.; Emery, L.; Taki, I.; Norris, J.M.; Erlich, H.A.; Eisenbarth, G.S.; et al. Rotavirus Infection Frequency and Risk of Celiac Disease Autoimmunity in Early Childhood: A Longitudinal Study. Am. J. Gastroenterol. 2006, 101, 2333–2340.
  24. Ilonen, J.; Lempainen, J.; Veijola, R. The heterogeneous pathogenesis of type 1 diabetes mellitus. Nat. Rev. Endocrinol. 2019, 15, 635–650.
  25. Bakker, S.F.; Tushuizen, M.E.; Von Blomberg, M.E.; Mulder, C.J.; Simsek, S. Type 1 diabetes and celiac disease in adults: Glycemic control and diabetic complications. Acta Diabetol. 2012, 50, 319–324.
  26. Picarelli, A.; Di Tola, M.; Sabbatella, L.; Mercuri, V.; Pietrobono, D.; Bassotti, G.; D’Amico, T.; Donato, G.; Picarelli, G.; Marino, M.; et al. Type 1 diabetes mellitus and celiac disease: Endothelial dysfunction. Acta Diabetol. 2011, 50, 497–503.
  27. Pitocco, D.; Giubilato, S.; Martini, F.; Zaccardi, F.; Pazzano, V.; Manto, A.; Cammarota, G.; Di Stasio, E.; Pedicino, D.; Liuzzo, G.; et al. Combined atherogenic effects of celiac disease and type 1 diabetes mellitus. Atherosclerosis 2011, 217, 531–535.
  28. Salardi, S.; Maltoni, G.; Zucchini, S.; Iafusco, D.; Zanfardino, A.; Confetto, S.; Toni, S.; Zioutas, M.; Marigliano, M.; Cauvin, V.; et al. Whole lipid profile and not only HDL cholesterol is impaired in children with coexisting type 1 diabetes and untreated celiac disease. Acta Diabetol. 2017, 54, 889–894.
  29. Rohrer, T.R.; Wolf, J.; Liptay, S.; Zimmer, K.-P.; Fröhlich-Reiterer, E.; Scheuing, N.; Marg, W.; Stern, M.; Kapellen, T.M.; Hauffa, B.P.; et al. Microvascular Complications in Childhood-Onset Type 1 Diabetes and Celiac Disease: A Multicenter Longitudinal Analysis of 56,514 Patients from the German-Austrian DPV Database. Diabetes Care 2015, 38, 801–807.
  30. Leeds, J.S.; Hopper, A.D.; Hadjivassiliou, M.; Tesfaye, S.; Sanders, D.S. High Prevalence of Microvascular Complications in Adults with Type 1 Diabetes and Newly Diagnosed Celiac Disease. Diabetes Care 2011, 34, 2158–2163.
  31. Creanza, A.; Lupoli, R.; Lembo, E.; Tecce, N.; Della Pepa, G.; Lombardi, G.; Riccardi, G.; Di Bonito, P.; Capaldo, B. Glycemic control and microvascular complications in adults with type 1 diabetes and long-lasting treated celiac disease: A case-control study. Diabetes Res. Clin. Pract. 2018, 143, 282–287.
  32. Malalasekera, V.; Cameron, F.; Grixti, E.; Thomas, M.C. Potential reno-protective effects of a gluten-free diet in type 1 diabetes. Diabetologia 2009, 52, 798–800.
  33. Pham-Short, A.; Donaghue, K.C.; Ambler, G.; Chan, A.K.; Hing, S.; Cusumano, J.; Craig, M.E. Early elevation of albumin excretion rate is associated with poor gluten-free diet adherence in young people with coeliac disease and diabetes. Diabet. Med. 2013, 31, 208–212.
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