Gluten and Glucose Management in Type 1 Diabetes

Abstract

The prevalence of coeliac disease in patients with type 1 diabetes is significantly increased when compared to the general population. An explanation of the association between the development of both diseases may be explained by the inheritance of common major histocompatibility complex immunogenotypes that influence the presentation of auto antigens to CD4+ T-Cells. The subsequent loss of self tolerance results in destruction of the small bowel villi and pancreatic β-cells in coeliac and type 1 diabetes respectively. The diagnosis of coeliac disease in type 1 diabetic patients occurs commonly as a result of screening of individuals with subclinical coeliac disease. Recent studies have demonstrated the clinical benefit of treating subclinical coeliac disease in children with improvement in growth parameters, resolution of anaemia and fewer hypoglycaemic episodes. There is no current clinical evidence supporting routine screening of adult type 1 diabetic patients for coeliac disease. After the diagnosis of coeliac disease, type 1 diabetic patients should be commenced on a gluten-free diet with care co-ordinated between a dietician, gastroenterologist and diabetologist.

Introduction

Coeliac disease is a complex multifactorial autoimmune disease that is influenced by both genetic and environmental factors. Environmental exposure to gluten present in wheat, barley protein and rye results in immune mediated injury of the mucosa of the small intestine. Coeliac disease may be classified as symptomatic (diarrhoea with or without malabsorption) or subclinical (without gastrointestinal symptoms but may have extra-intestinal symptoms). Symptomatic coeliac disease is relatively rare occurring with a clinical frequency of one in 3,345 people worldwide, while asymptomatic coeliac disease detected on serological screening affects one of every 120–300 persons worldwide.^[1,2]

Type 1 diabetes is a relatively common disease accounting for 5–10% of all diabetes and is increasing in prevalence. It is a complex multifactorial autoimmune mediated disease characterised by the destruction of pancreatic β-cells leading to absolute insulin deficiency and subsequent ketoacidosis. The environmental antigen(s) has not been conclusively identified in type 1 diabetes though recent reports suggest that insulin may be the causative agent.^[3,4]

The association between coeliac disease and type 1 diabetes is estimated at 2–10% in European populations.^[5,6] In addition, both diseases are known to cluster with other organ specific autoimmune disorders such as autoimmune thyroid disorder and Addison's disease giving rise to Autoimmune Polyendocrine Syndrome type II.^[7.8] In this review we explore the common immune pathology between coeliac disease and type 1 diabetes, the role of screening for coeliac disease in individuals with type 1 diabetes and finally the clinical management of patients affected by both diseases.

Immunogenetics

A partial explanation for the association between type 1 diabetes and coeliac disease is their similarities in immunogenotype, with both diseases being associated with inheritance of the MHC genes located on the short arm of Chromosome 6 (6p21.31). The MHC class II genes encode for a cell surface HLA class II molecule (MHC class II molecule) that is expressed on APC. The HLA class II molecule is a heterodimer composed of an alpha and a beta subunit and the latter may be encoded by the alleles of the DP, DQ or DR genes.^[9,10]

Type 1 Diabetes

Type 1 diabetes has a concordance rate of 30–50% in monozygotic twins indicating a significant environmental contribution to the development of the disease phenotype. The average risk to siblings of an affected individual is estimated at 6%. Inheritance of one of the MHC class II haplotypes DR4 DQA1*0301/DQB1*0302 or DR3 DQA1*0502/DQB1*0201 increases the risk of type 1 diabetes. One of these haplotypes is found in 90% of children affected. The DR4 DQA1*0301/DQB1*0302 and DR3 DQA1*0502/DQB1*0201 haplotypes encode genes to form HLA-DQ8 and HLA-DQ2 class II molecules respectively. The combination heterozygous genotype DR4 DQA1*0301-DQB1*0302/DR3 DQA1*0502- DQB1*0201 confers the greatest susceptibility to the development of type 1 diabetes which commonly presents as diabetic ketosis in infancy. The MHC class II locus is estimated to confer 50% of the genetic susceptibility to type 1 diabetes with the remainder from genes outside the MHC.^[11,12]

Coeliac Disease

The total genetic contribution to development of coeliac disease has been estimated from monogenetic twin concordance data as 70% compared with 30% in HLA-identical siblings, indicating a contribution from loci outside the MHC genes such as 5q31-33. The most common MHC class II haplotypes inherited in coeliac disease are the HLA DR3 DQA1* 0502/DQB1*0201 encoding the HLA DQ2 class II molecule. The HLA DQ2 cell surface receptor is expressed in 90% of coeliac patients. The DR4 DQA1*0301/DQB1*0302 haplotype encoding the HLA-DQ8 class II molecule is also found in individuals with coeliac disease but more rarely. It is important to note that inheritance of these haplotypes confers susceptibility to coeliac disease but additional environmental triggers are necessary for disease development.^[13,14]

The HLA DR4 and DR3 loci occur frequently in type 1 diabetes and coeliac disease ( Table 1 ). The similar genetic background is the likely explanation for the common clinical concurrence of both conditions.^[15,16]

Pathogenesis

Coeliac Disease

The key event in the development of coeliac disease in genetically susceptible individuals is the ingestion of gluten – the storage protein of wheat. Gliadin is the alcohol soluble fraction of gluten and this has been investigated extensively. The current disease model for coeliac disease involves the deamidation of gliadin by tissue transglutaminase to glutamic acid peptides (Figure 1). Specifically a 33-amino-acid (33-mer) peptide that resists digestion by gastric and intestinal proteolytic enzymes, in vitro and in vivo, is immunogenic in coeliac patients. The 33-mer peptide is deaminated by transglutaminase on the subepithelial layer of the intestine. The deaminated peptide residues are then processed by APC to three epitopes that bind to the HLA DQ2 or DQ8. The T-cell receptor on intestinal CD4+ T-cells in the lamina propria recognise the epitopes displayed on the HLA DQ2/DQ8 as foreign and initiates the production of proinflammatory cytokines. This inflammatory environment results in immune deregulation and loss of tolerance with activation of CD8+ T-cells and B-cells in the intestinal epithelium. The pathophysiological result is intraepithelial lymphocytosis, villous atrophy and the production of transglutaminase antibodies.^[13,17]

Figure 1. Activation of the immune system by gluten in coeliac disease. Gluten is degraded by gastrointestinal enzymes to a 33 amino acid (33-mer) peptide. The 33-mer peptide is absorbed across the small bowel epithelium to the subepithelial layer in the lamina propria. Tissue transglutaminase deaminates the 33-mer peptide. The deaminated peptides are processed by APC to three epitopes that bind to the HLA-DQ2 or DQ8 molecules. The T-cell receptor on T-cells then cross-react with the HLA molecule leading to the initiation of an autoreactive immune response with subsequent activation of B-cells, CD4+ Th1 cells and NK cells. The resultant proinflammatory environment results in further immune activation and migration of lymphocytes resulting in the characteristic pathological finding of increased intraepithelial lymphocytes and villous atrophy. APC = antigen presenting cells; HLA = human leukocyte antigen; NK = natural killer cells.

Figure 1.

Activation of the immune system by gluten in coeliac disease. Gluten is degraded by gastrointestinal enzymes to a 33 amino acid (33-mer) peptide. The 33-mer peptide is absorbed across the small bowel epithelium to the subepithelial layer in the lamina propria. Tissue transglutaminase deaminates the 33-mer peptide. The deaminated peptides are processed by APC to three epitopes that bind to the HLA-DQ2 or DQ8 molecules. The T-cell receptor on T-cells then cross-react with the HLA molecule leading to the initiation of an autoreactive immune response with subsequent activation of B-cells, CD4+ Th1 cells and NK cells. The resultant proinflammatory environment results in further immune activation and migration of lymphocytes resulting in the characteristic pathological finding of increased intraepithelial lymphocytes and villous atrophy. APC = antigen presenting cells; HLA = human leukocyte antigen; NK = natural killer cells.

Type 1 Diabetes

Overt symptoms of diabetes do not occur until approximately 80% of the β-cells have been destroyed, making it difficult to identify the precipitating environmental event.^[18] It has recently been suggested that insulin may be the primary auto antigen.^[19,20] In vivo, this auto antigen may be displayed on APC activating CD4+ T cells to initiate an immune response (Figure 2). Evidence to support this disease model of type 1 diabetes mainly originates from clinical trials involving administration of cyclosporin to achieve T-cell suppression. This treatment induced remission with enhanced insulin secretion. However the significant side effects of cyclosporin prevented the widespread use of this therapeutic strategy. Of late more targeted therapy with an anti T-cell monoclonal antibody (hOKT3gamma)Ab improved C-peptide responses with a single treatment lasting up to one year.^[21] The anti T-cell monoclonal antibody (ChAglyCD3) has been shown to maintain β-cell function for at least 18 months.^[22] These clinical trials demonstrate the pivotal role of T-cells in the development of symptomatic disease.

Figure 2. Proposed autoimmune mechanism of the development of type 1 diabetes. An auto-antigen, proposed to be insulin, is presented to an APC. The antigen is processed to epitopes which are bound and displayed on HLA DQ2/DQ8. Cross-reaction occurs between CD4+ T-cell and APC to initiate autoimmune reaction directed at the β-cells of the pancreatic islets. A component of the T-cell mediated immune response involves the activation of B-cells to produce autoreactive antibodies. The ultimate result is immune mediated destruction of pancreatic β-cells with concomitant insulin deficiency and subsequent ketoacidosis. APC = antigen presenting cells; HLA = human leukocyte antigen

Figure 2.

Proposed autoimmune mechanism of the development of type 1 diabetes. An auto-antigen, proposed to be insulin, is presented to an APC. The antigen is processed to epitopes which are bound and displayed on HLA DQ2/DQ8. Cross-reaction occurs between CD4+ T-cell and APC to initiate autoimmune reaction directed at the β-cells of the pancreatic islets. A component of the T-cell mediated immune response involves the activation of B-cells to produce autoreactive antibodies. The ultimate result is immune mediated destruction of pancreatic β-cells with concomitant insulin deficiency and subsequent ketoacidosis. APC = antigen presenting cells; HLA = human leukocyte antigen

In summary the development of both coeliac disease and type 1 diabetes share a similar immunopathogenesis requiring the activation of auto reactive T-cells in genetically susceptible individuals. Coeliac disease however differs from type 1 diabetes in that the environmental antigenic trigger gliadin (a component of gluten) has been identified and avoidance leads to remission of the disease.

Screening

The diagnosis of coeliac disease in individuals with type 1 diabetes is most commonly due to screening since most affected patients have subclinical disease. A minority will present with overt classical coeliac disease characterised by growth failure, muscle wasting, pallor, oedema and rickets. Screening for coeliac disease involves testing for circulating endomysial or transglutaminase antibodies, with diagnosis being confirmed by small bowel biopsy demonstrating infiltration of the intestinal mucosa by lymphocytes and the development of crypt hyperplasia and villous atrophy.^[2]

Many clinicians have suggested that all children with type 1 diabetes should be screened for coeliac disease and treated. However, others have questioned the potential benefits of treatment and the risks of screening. Support for the effectiveness of screening is provided by the facts that coeliac disease is known to be more common in type 1 diabetic patients (mean 4.1%, range 0–10.4%) than the general population (0.3–0.5%) and is usually subclinical. A highly effective treatment is available, withdrawal of gluten from the diet. Studies of non-diabetic coeliac children suggest that treatment may avoid the complications of growth failure, low bone density and potential neurological abnormalities. Glycaemic control may also be improved by a reduction in hypoglycaemic episodes caused by erratic absorption of glucose. Finally it is speculated that treatment of coeliac disease in type 1 diabetes could reduce the likelihood of the development of other autoimmune diseases such as Grave's or Addison's disease or non-Hodgkin's lymphoma of the small bowel.^[23]

Screening for coeliac disease was deemed inappropriate in children with type 1 diabetes by some clinicians since classical coeliac disease is easy to recognise. Screening therefore would only identify subclinical disease. The long-term outcome of subclinical coeliac disease in type 1 diabetes was unknown, as were the benefits of treatment. The definitive diagnosis of subclinical coeliac disease also requires invasive investigation with associated risk and treatment of coeliac disease in type 1 diabetes possibly leading to further complexity and psychological burden in patients. Screening of children with increased hypoglycaemic episodes for coeliac disease would be justified however.^[23,24]

Recent investigations have clarified many of the issues regarding the screening of children with type 1 diabetes for coeliac disease. An Italian multicentre study found the prevalence of biopsy proven coeliac disease in children with diabetes to be high (6.8%). Diabetes is usually diagnosed prior to the development of coeliac disease. The risk of the development of coeliac disease is correlated with earlier onset of type 1 diabetes, with three times the risk of onset at age less than four, than in children older than nine. The study also detected a trend of decreased prevalence of coeliac disease detection after 10 years duration of diabetes.^[25]

One group has shown that at diagnosis of type 1 diabetes raised EMA were predictive for the development of coeliac disease. In children who were negative for EMA antibodies at diagnosis seroconversion took place in the next 2.8–10.8 years in those who subsequently developed coeliac disease. All patients were asymptomatic at diagnosis. A recommendation of screening at two-year intervals for asymptomatic patients was suggested as a safe and cost-effective strategy.^[26]

A Danish study found the highest prevalence (10%) of coeliac disease in children (<16>1C remained unchanged in patients on a GFD though two patients experienced fewer hypoglycaemic episodes. Compliance with diet was good with 24 of the 31 patients having disappearance of the coeliac antibodies.^[27]

Clinical Management

The cornerstone of the treatment of coeliac disease is the initiation and maintenance of a GFD.^[28] However, commencement of a GFD in patients initially diagnosed with coeliac disease does not offer protection from the development of type 1 diabetes.^[27] Similarly, removal of gluten from the diet of individuals at high risk of the development of type 1 diabetes does reduce the incidence of coelic disease.^[29,30]

Care of type 1 diabetic patients with coeliac disease should be co-ordinated between a dietician, gastroenterologist and diabetologist. Patient compliance with treatment is highest in coeliac patients when the GFD is commenced as young children rather than as adolescents.^[31] Patient compliance with GFD may be monitored by self-reported diet, growth charts and/or transglutaminase antibody titres.^[32] Studies of GFD in type 1 diabetic patients with coeliac disease have demonstrated good compliance rates.^[33-36] However, it remains to be determined if these compliance rates can be achieved in a normal clinical setting.

The effect of GFD on glycaemic control in type 1 diabetic patients has been examined by a number of studies. Prior to treatment with GFD type 1 diabetic patients with coeliac disease have lower insulin requirements and BMI than type 1 diabetic (non coeliac) control patients. With treatment their insulin requirements increase as BMI increases. The overall effect on metabolic control remains unclear, one study has reported improvement in HbA_1C ^[35] while two others have reported that HbA_1C remains unchanged,^[27,33] and a reduction in microvascular complications or diabetic nephropathy has not been observed in type 1 diabetic patients affected with coeliac disease treated with GFD as when compared to diabetic patient controls.^[26,37] Standard glycaemic targets referenced to the patient's age should be pursued.^[38] As previously discussed there may be a reduction in hypoglycaemic episodes thereby allowing for tighter glycaemic control to be achieved.^[39]

Conclusions

Coeliac disease and type 1 diabetes may occur in patients as a result of their common immunogenotypes. Though both diseases differ in organ specificity they appear to share a similar pathogenic mechanism involving the deregulation of T-cell responses and the loss of self tolerance with resultant tissue damage to the small bowel (coeliac) and β-cells of the pancreatic islets (type 1 diabetes). Treatment of children, diagnosed first with coeliac disease with GFD does not provide subsequent protection from the development of type 1 diabetes.

Recent evidence has provided support for the screening of type 1 diabetic patients under the age of sixteen for subclinical coeliac disease given the resolution of gastrointestinal symptoms and improvement in growth parameters. Serological screening (EMA and tTGA with concurrent serum IgA) should be carried out every two years for a ten-year duration post diagnosis of type 1 diabetes. Positive serology should lead to formal small bowel biopsy to examine for partial or total villous atrophy ( Table 2 ). Treatment with a GFD may also reduce the number of hypoglycaemic episodes in patients, though overall glycaemic control remains unchanged.

Widespread screening for coeliac disease in adults with type 1 diabetes is not recommended since the clinical benefit is unknown. However, adult patients with type 1 diabetes with symptoms of coeliac disease or recurrent hypoglycaemic episodes or multiple endocrine diseases should be investigated for coeliac disease. Future screening studies of adult type 1 diabetic patients with subclinical coeliac disease should aim to demonstrate clinical benefit of initiation of GFD by improvement in metabolic control or possibly reduction in prevalence of non-Hodgkin's lymphoma of the small bowel.

References

1. Farrell RJ, Kelly CP. Coeliac Sprue. N Engl J Med 2002;346:180-8.
2. Green PHR, Jabri B. Coeliac disease. Lancet 2003;362:383-91.
3. Daneman D. Type 1 Diabetes. Lancet 2006;367:847-58.
4. American Diabetes Association. Standards of Medical Care in Diabetes 2007. Diabetes Care 2007;30:S4-S41.
5. Collin P, Kaukinen K, Valimaki M et al. Endocrinological disorders and coeliac disease. Endocr Rev 2002;23:464-83.
6. Hansen D, Brennedbaek FN, Hansen LK et al. High prevalence of coeliac disease in Danish children with type 1 diabetes mellitus. Acta Paediatr 2001;90:1238-43.
7. Eisenbarth GS, Gottlieb PA. Autoimmune Polyendocrine Syndromes. N Engl J Med 2004;350:2068-79.
8. Cronin CC, Shanahan F. Insulin-dependant diabetes mellitus and coeliac disease. Lancet 1997;349:1096-7.
9. McDevitt HO. Discovering the role of the Major histocompatibility complex in the immune response. Ann Rev Immunol 2000;18:1-17.
10. Kumanovics A, Takada T, Lindahl KF. Genomic organisation of the mammalian MHC. Ann Rev Immunol 2003;21:629-57.
11. Jahromi MN, Eisenbarth GS. Genetic determinants of type 1 diabetes across populations. Ann N Y Acad Sci 2006;1079:289-99.
12. Lambert AP, Gillespie KM, Thomson G et al. Absolute risk of childhoodonset type 1 diabetes defined by human leukocyte antigen class II genotype: A Population-Based Study in the United Kingdom. J Clin Endocrinol Metab 2004;89:4037-43.
13. McManus R, Kelleher D. Celiac disease the villian unmasked? N Engl J Med 2003;348:2573-4.
14. Sollid LM. Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol 2002;2:647-55.
15. Bao F, Yu L, Wang T et al. One third of HLA DQ2 homozygous patients with type 1 diabetes express coeliac disease-associated transglutminase autoantibiodies. J Autoimmun 1999;13:143-8.
16. Saukkonen T, Ilonen J, Akerblom HK, Savilahti E. Prevalence of coeliac disease in siblings of patients with Type 1 diabetes is related to the prevalence of DQB1*02 allele. Diabetologia 2001;44:1051-3.
17. Kagnoff MF. Overview and pathogenesis of celiac disease. Gastroenterology 2005;128:S10-S18.
18. Gillespie KM. Type 1 diabetes: pathogenesis and prevention. CMAJ 2006;175:165-70.
19. Kent SC, Chen Y, Bregoli L et al. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognise an insulin epitope. Nature 2005;435:224-8.
20. Nakayama M, Abiru N, Moriyama H et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 2005;535:220-3.
21. Herold KC. Treatment of type 1 diabetes mellitus to preserve insulin secretion. Endocrinol Metab Clin North Am 2004;33:93-111.
22. Keymeulen B, Vandemeulebroucke E, Zieger AG et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005;353:2598-608.
23. Freemark M and Levitsk LL. Screening for coeliac disease in children with type 1 diabetes. Diabetes Care 2003;26:1932-39.
24. Murray JA. Celiac disease in patients with an affected member, type 1 diabetes, iron deficiency, or osteoporosis. Gastroenterology 2005;128:S52-S56.
25. Ceritti F, Beuno G, Chiarelli F et al. Younger age at onset and sex predict celiac disease in children and adolescents with type 1 diabetes. Diabetes Care 2004;27:1294-8.
26. Glastras SJ, Craig ME, Verge CF et al. The Role of autoimmunity at diagnosis of type 1 diabetes in the development of thyroid and celiac disease and microvascular complications. Diabetes Care 2005; 28:2170-5.
27. Ludvigsson JF, J Ludvisson J, Ekbom A et al. Coeliac Disease and Risk of Subsequent Type 1 Diabetes. Diabetes Care 2006;29:2483-8.
28. Rewer M, Liu Edwin, Simmons J et al. Coeliac disease associated with type 1 diabetes mellitus. Endocrinol Metab Clin N Am 2004;33:197-214.
29. Hummel M, Bonifacio E, Naserke HE, Ziegler AG. Elimination of dietary gluten does not reduce titres of Type 1 diabetes-associated autoantibiodies in high risk subjects. Diabetes Care 2002; 25:1111-16.
30. Pastrone MR, Bazzigaluppi E, Belloni C et al. Six months of gluten-free diet do not influence autoantobody titres but improve insulin secretion in subjects at high risk for type 1 diabetes. J Clinical Endocrinology Metab 2003;88:162-5.
31. Cranney A, Rostom A, Sy R et al. Consequences of testing for celiac disease. Gastroenterology 2005;128:S109-S20.
32. Pieta MM. Follow-up of patients with coeliac disease: achieving compliance with treatment. Gastroenterology 2005;128:S135-S141.
33. Amin R, Murphy N, Edge J et al. Longitudinal study of the effects of a gluten-free diet on glycemic control and weight gain in subjects with type 1 diabetes and coeliac disease. Diabetes Care 2006; 25:1117-22.
34. Hansen D, Brock-Jacobben B, Lund E et al. Clinical benefit of glutenfree diet in type 1 diabetic children with screening-detected coeliac disease. Diabetes Care 2006;29:2452-6.
35. Sanhchez-Albisua I, Wolf J, Neu A et al. Coeliac disease in children with Type 1 diabetes mellitus; the effect of the gluten-free diet. Diabetic Medicine 2005;22:1079-82.
36. Saadah OI, Zacharin M, O'Callaghan A et al. Effect of gluten-free diet and adherence on growth and diabetic control in diabetics and coeliac disease. Arch Dis Child 2004;89:871-6.
37. Skovbjery H, Tarnow L, Locht H, Parving HH. The prevalence of coeliac disease in adult Danish patients with type 1 diabetes with and without nephropathy. Diabetologia 2005;48:1416-17.
38. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2003;27(suppl 2):S84-S89.
39. Mohn A, Cerruto M, Lafusco D et al. Celiac disease in children and adolescents with type 1 diabetes: importance of hypoglycaemia. J Pediatr Gastroenterol Nutr 2001;32:37-40.

Source : http://www.medscape.com/viewarticle/574648