About 10% of children and 2% of adults with Type 1 diabetes also have celiac disease, as compared to just 1% of the general population. Moreover, celiac disease and diabetes are known to have a common genetic susceptibility locus in the HLA system, specifically, HLA class II alleles on chromosome six.

The primary susceptibility genes for type-1 diabetes are HLA-DQB1 and HLA-DRB1, but they act in combination with non-immune system genes as well as environmental factors that are still undiscovered. Celiac disease also has a major susceptibility gene in the HLA system — HLA-DQB1 — as well as locations outside the HLA complex.

Recently, a research team led by John Todd, Ph.D., of the University of Cambridge, set out to better understand the connection between the two diseases, and to determine if they shared any non-HLA regions. They discovered another seven regions outside of the HLA system that are tied to both celiac disease and diabetes.

One of those regions is the 32-base pair insertion-deletion variant on chromosome three that leads to a non-functional CCR5 receptor on T cells. People who carry both pairs of these genes enjoy some protection against HIV infection, and its role in both celiac disease and diabetes indicates that lymphocytes are a key factor in both diseases. Carriers of these genes also face a greater risk of developing either celiac disease or diabetes, or both conditions in their lifetimes.

In genome-wide association studies, eight loci outside the HLA system have been associated with celiac disease. Similarly, 15 non-HLA loci have been linked with Type 1 diabetes.

Dr. Todd and colleagues genotyped single nucleotide polymorphisms (SNPs)—single letter variations in the genetic code—in the eight celiac loci and in the 15 diabetes loci.

They then screened DNA samples from 9,339 control subjects, 2,560 subjects with celiac disease, and 8,064 subjects with diabetes. They also tested the diabetic children, along with both biological parents in 2,828 families. The overall statistical significance was P<1.00×10−4.

At the same level of significance, three celiac disease locations—RGS1 on chromosome one, IL18RAP on chromosome two, and TAGAP on chromosome six—were also associated with Type 1 diabetes. The minor alleles of IL18RAP and TAGAP were associated with some protection from in Type 1 diabetes, but were associated with susceptibility in celiac disease.

The CCR5 variant on chromosome three was newly tied to Type 1 diabetes (at P=1.81×10−8) and was also tied with celiac disease, together with PTPN2 on chromosome 18 and CTLA4 on chromosome two. Counting SH2B3 on chromosome 12, which already known to be a shared locus—the number of non-HLA areas strongly tied to both celiac disease and diabetes stands at seven.

Dr. Todd and colleagues said it's possible that a common genetic background with respect to autoimmunity and inflammation—combined with disease-specific variation at HLA and non-HLA genes as well as non-genetic factors -- might lead to different clinical outcomes. It is possible that dietary exposure to gluten in the form of cereal grains might play a role in the pathogenesis of Type 1 diabetes.

These findings offer support a growing scientific view that many common diseases share genetic risk factors, and indicate that celiac and diabetes may in fact have common biological causes, and that the two disorders may be more closely linked than previously understood.

More research is needed to determine which shared risk factors might reveal previously unexpected biologic connections between diseases.

New England Journal of Medicine 2008; 359: 2767-77, 2837-2838

Celiac.com 11/06/2007 - This study investigated the effect of screening detected celiac disease in type I diabetic children in a multi-center case-control fashion.  The research team consisted of B Rami, Z Sumni, E Schober et al from Austria, Czech Republic, and Slovenia, among other European countries.

The team compared 98 diabetics with silent celiac disease to 196 control diabetics without celiac matched for age, sex, diabetes duration.  Mean age at diabetes diagnosis was 6.5 yrs, celiac diagnosis was 10.0 yrs.  Celiac screening included yearly antibody testing and positive patients underwent biopsy.  Hemoglobin A1c, hypoglycemia, ketoacidosis, insulin dosage, body-mass index, and height did not differ between cases and controls at celiac diagnosis or after a mean follow-up of 3.3 years.  After diagnosis of celiac disease, weight gain was diminished in boys with celiac disease compared to their controls.

Although a clear link between type I diabetes and increased risk of celiac disease is established, the benefit of a gluten-free diet is unclear in these children.  This study followed 98 patients with diabetes and silent celiac for a mean of 3.3 years and compared them to 196 controls.  This is the largest, best designed case-control study to date and it did not demonstrate any significant differences between the two groups, except for a decreased Body Mass Index (BMI - though still greater than non-diabetic, control children) in males after diagnosis. 

What is more intriguing is that at diagnosis, no significant differences in height, BMI, HbA1c, insulin need, or hypoglycemia events were seen, questioning the metabolic significance of silent celiac disease.  In this study, it is difficult to estimate the duration of silent celiac disease prior to diagnosis.  Although, given the fact that these patients were asymptomatic and their mean diabetes duration was 3.6 years, it likely implies that silent celiac disease was present for a few years.

The data regarding the benefit of a gluten-free diet in screening detected celiac disease in type I diabetic children is scant but is slowly increasing.  Numerous psychological (burden of gluten free diet in addition to diabetic diet), cost (of diet), and ethical issues (potential long-term benefits of gluten-free diet, compliance with diet) exist regarding these children and hopefully this question will be answered soon and with good, convincing data. 

Journal of Pediatric Gastroenterology and Nutrition, 41:317-321, 2005

It is well known that environmental nutrition and infections play a key role in the development of diabetes (type 1). A Czech research team made up of doctors David P. Funda, Anne Kaas, Helena Tlaskalová-Hogenová, Karsten Buschard recently set out to study the relationship between type 1 diabetes and both gluten-free and gluten enriched diets. The team tested the hypothesis that early introduction of gluten into the diet might increase diabetes incidence in mice.

For a period of 310 days, non-obese diabetic (NOD) mice were fed one of the following diets: standard diet, a gluten-free diet, a gluten + modified Altromin diet, or a hydrolyzed-casein based Pregestimil diet. The mice were observed for signs of diabetes, including evaluation for insulitis score, and numbers of gut mucosal lymphocytes.

Compared to mice fed the standard Altromin diet, mice fed on the gluten-free and the Pregestimil diets showd markedly lower incidence of diabetes. Incidence rates were as follows (p < 0.0001): NOD mice fed gluten-free diet (5.9%, n = 34) and Pregestimil diet (10%, n = 30) compared to mice on the standard Altromin diet (60.6%, n = 33).

Somewhat unexpectedly, the gluten+ diet also prevented diabetes to the same degree as the gluten-free diet (p<0.0001, 5.9% n=34). Of those mice who did develop diabetes, those on the gluten-free and Pregestimil diets did so at a later time than those on a standard diet.

Compared to control mice, non-diabetic NOD mice on the gluten-free diet and to a lesser extent also gluten+ and Pregestimil diets showed lower insulitis scores. No significant differences were found in the number of CD3+, TCR-+, and IgA+ cells in the small intestine. The researchers concluded that a gluten-enriched diet prevents diabetes in NOD mice at the same rate as a gluten-free diet.

Diabetes/Metabolism Research and Reviews, Volume 15, Issue 5 , Pages 323 - 327

This increase showed up without regard to the age at diagnosis [those diagnosed between 0 and 2 (2.2 [1.7–2.9], P 0.001) or 3 and 20 (3.4 [1.9 – 6.1], P 0.001) years of age.]

Given that 95% of individuals with celiac disease are HLA-DQ2 positive, these increased risk levels were comparatively low, though still significant.

Diabetes Care. 2006 Nov;29(11):2483-8.

The research team was made up of doctors P.M. Gillett, H.R. Gillett, D.M. Israel, D.L. Metzger, L. Stewart, J-P. Chanoine, H.J. Freeman.

The team looked at 233 children with Type1 diabetes. In a blind study, the children were screened for celiac disease using immunoglublin A endomysium antibody (EmA), and the Immunoglublin A tissue transglutaminase. Children with positive results were offered small bowel biopsies. For those confirmed with celiac disease, doctors recommended a gluten-free diet.

British Columbians with Type 1 Diabetes Get Celiac Disease at Rates Comparable to their European Counterparts

Nineteen children tested positive for EmA and showed elevated tTG levels. Of the 18 patients who agreed to biopsies, one was normal, three showed normal morphology with elevated Intraepithelial lymphocyte counts, and 14 biopsies showed morphological changes consistent with celiac disease.

9 of the 19 children who tested positive for EmA were asymptomatic. Seven patients showed only mildly elevated tTG levels. Of this second group, five refused biopsy and two showed normal biopsies.

In addition to the four known cases, the doctors uncovered at least 14 new cases of celiac disease. The total rate of biopsy confirmed celiac disease was 18 out of 233, or 7.7%. The doctors concluded that these results confirm that celiac disease is prevalent in pediatric type 1 diabetes.

The doctors say the study reinforces the importance of celiac screening for children with type 1 diabetes, and also the advisability of keeping an eye on tTg serology as part of determining the effects of and compliance to a gluten-free diet.

Participating Facilities
1. Division of Pediatric Gastroenterology at British Columbias Childrens Hospital Vancouver, British Columbia.
2. Division of Endocrinology, British Columbias Childrens Hospital, Vancouver, British Columbia.
3. Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia

Journal of Pediatric Gastroenterology & Nutrition: Volume 29(4)October 1999p 495.

About the Author: Jefferson Adams is a freelance health writer who lives in San Francisco and is a frequent author of articles for Celiac.com.

Celiac.com 12/28/2006 - The American Diabetes Associations (ADA) Clinical Practice Recommendations have been updated to include new information about treatment and prevention that reflects the latest research. Changes have been made in numerous areas, including the management of hyperglycemia in type 2 diabetes; nutrition recommendations; and screening and treatment for children who have both type 1 diabetes and celiac disease.

In 2006, the ADA published Medical Nutrition Therapy (MNT) guidelines for people with diabetes, specific to individual populations, such as those who are obese or pregnant. The Clinical Practice Recommendations have been updated to reflect these guidelines and to encourage people with diabetes or pre- diabetes to seek individualized MNT to help them achieve their treatment goals.

Information about how to treat children who are diagnosed with both type 1 diabetes and celiac disease was also added to the Clinical Practice Recommendations this year. Up to 16 percent of children with type 1 diabetes are also diagnosed with celiac disease, an immune disorder that affects the digestive system, damages the small intestine and interferes with the absorption of nutrients from food. The recommendations call for more aggressive screening for celiac disease in children with type 1 diabetes who present symptoms such as weight loss, growth failure, abdominal pain and chronic fatigue. A gluten-free diet is recommended for those who test positive for celiac.

Diabetes Care, published by the American Diabetes Association, is the leading peer-reviewed journal of clinical research into the nations fifth leading cause of death by disease. Diabetes also is a leading cause of heart disease and stroke, as well as the leading cause of adult blindness, kidney failure, and non-traumatic amputations.

For more information about diabetes call 1-800-DIABETES (1-800-342-2383).

Celiac.com 11/07/2006 – In the first multi-country population based study of its kind, Danish researchers have found that around 1 in 8 children with Type 1 diabetes also have celiac disease, and of these the prevalence of stunted growth is abnormally high. Dr. Dorte Hansen and colleages from Odense University Hospital screened 269 children with type 1 diabetes for celiac disease using immunoglobulin A anti-endomysium antibody, anti-tissue transglutaminase antibody, and intestinal biopsy. The researchers found 33 cases of celiac disease, and in 5 of these cases the children had no symptoms of the disease whatsoever. The children with celiac disease were diagnosed with diabetes at a significantly youger age than their non-celiac counterparts and each was also significantly shorter and lighter.

The 33 celiac disease patients were put on a strict gluten-free diet for 2 years, and amond the 24 who complied with the diet all symptoms resolved. Additionally most of the children gained weight and the children who were under 14 also regained their height.

A gluten-free diet relieved symptoms of celiac disease and restored normal growth patterns to most of the children. The doctors conclude that regular screening for celiac disease should be conducted in all children with type 1 diabetes.

Diabetes Care 2006;29:2452-2456.

Celiac.com 07/12/2005 – Australian researchers have determined that a gluten-free diet in children with Type 1 diabetes mellitus and celiac disease can improve both growth and diabetes control. In the study 21 children (mean age 7.5 years) with both conditions went on a gluten-free diet for 12 months, and their growth and insulin dosages were carefully measured and compared with that of two matched diabetic, non-celiac controls. The group on a gluten-free diet showed significant increases in weight and body mass index compared with the control group, although an increase in height found in the study was not found to be significant. At the time of diagnosis insulin dosages for the celiac disease group were less than that of the control group, but became similar to the controls once a gluten-free diet was started—although the increase in insulin dosage had no effect on HbA1c levels.

The researchers conclude: “Identification and dietary treatment of celiac disease in children with diabetes improved growth and influenced diabetic control. Evaluation of the outcome of treatment of celiac disease in diabetics should include assessments of gluten intake.” Obviously all children (and everyone) with celiac disease should be on a gluten-free diet, but what is noteworthy about this study is that a connection was found between insulin levels, diabetes control, and the gluten-free diet.

Diabetologia. 2005 Apr 14

Celiac.com 04/29/2005 – According to Italian researchers an improper immune response to wheat may play an important role in the pathogenesis of Type 1 diabetes. The researchers fed one group of female non-obese diabetic (NOD) mice a standard gluten-free diet, while another group of NOD mice was fed a standard gluten-free diet that also included wheat proteins. The researchers then evaluated the small intestinal architecture of the mice and found that the wheat-protein group "showed reduced villous height, increased intraepithelial infiltration by CD3(+) cells and enhanced expression of H2-IA and IFN-gamma mRNA when compared with mice on the gluten-free diet." After 43 weeks the cumulative incidence of diabetes was 65% in the gluten-free group, and 97% in the wheat-protein group. The researchers conclude that the mice that ate wheat proteins had a much higher incidence of diabetes and small intestinal enteropathy that included higher mucosal levels of pro-inflammatory cytokines.

Celiac.com 02/25/2005 - Today a team of scientists at Alba Therapeutics Corporation and the University of Maryland School of Medicine report a direct link between zonulin-mediated increased intestinal permeability and Type 1 Diabetes (T1D) in the BB/wor Rat Model of Diabetes. Even more remarkable, the investigators were able to successfully prevent the onset of the autoimmune destruction of pancreatic beta cells and the onset of T1D in these animals by using the specific zonulin blocker AT-1001. Daily, oral administration of the drug beginning before the onset of auto-immunity in the diabetic prone rats cut the incidence of the disease by 2/3, and completely blocked the development of autoimmune antibodies in the treatment responders.

Published in the latest issue of the Proceedings of the National Academy of Science (PNAS), these results constitute the first successful result in preventing the autoimmune process characteristic of T1D by blocking the zonulin-mediated abnormal intestinal permeability. These results go well beyond the development of a prevention strategy for T1D, says Dr. Alessio Fasano, lead author of the paper and Professor of Pediatrics, Medicine and Physiology and The University of Maryland School of Medicine. They open a new field of investigation in which the interplay between host and environment at the mucosal level may help us understanding the molecular basis of many diseases.

These results reinforce our conviction that the zonulin pathway provides a roadmap for the discovery and development of innovative products to treat many important diseases, including diabetes, in ways previously thought to be inconceivable stated Dr. Blake M. Paterson. These preclinical proof-of-concept results with AT-1001 support the salvaging of beta cell function in pre-diabetics or in new-onset diabetes, giving us the impetus to rapidly move through the development process, bringing this dream to a reality for treatment in the diabetes community.

T1D is an autoimmune disease that results in the destruction of the insulin producing cells of the pancreas, the islet beta cells. Current treatment of T1D is limited to the administration of insulin and other medications to treat the consequence of diabetes, elevated blood sugar and the complications thereof. The inability to treat the cause of T1D - a process known as autoimmunity, in which the bodys immune system attacks the beta cells of the pancreas - has been the key obstacle to the freeing patients from the yoke of this disease.

Autoimmune diseases are thought to occur in individuals with the genetic pre-disposition to attack and destroy various organ tissues by the bodys own immune system. This immune misrecognition is thought to be triggered by the presence of an environmental stimulus; in the case of T1D, the trigger is unknown. While the majority of research efforts have focused on identifying the trigger of T1D and modifying immune pathways, little is known about how such a trigger might enter the body and about how such an entry-way might serve as a target for the treatment of the disease. The discovery of zonulin - a gatekeeper of intestinal barrier function, and Open Original Shared Link, led to the hypothesis that its malfunction could be involved in a series of other autoimmune diseases characterized by a leaky gut, including T1D. Previous work by Dr. Alessio Fasano has shown a close association of celiac disease in children at risk of developing T1D and led to the novel discovery research in support of AT-1001.

About Alba:

Alba Therapeutics is a Baltimore based biopharmaceutical company dedicated to commercializing disease-modifying therapeutics and drug delivery adjuvants based on the zonulin pathway. Albas lead molecule, AT-1001, is targeted towards the treatment of Celiac Disease and Type 1 Diabetes and is in the final stages of pre-human testing.

Contact Alba Therapeutics Corporation, Baltimore Dr. Blake Paterson, 410-522-8708

Diabetes Care 2004;27:1294-1298.

Celiac.com 11/29/2004 - In an effort to determine the prevalence of biopsy-confirmed celiac disease in Italian children and adolescents with type 1 diabetes, and to determine whether age at onset of diabetes is independently associated with the diagnosis of celiac disease, Dr. Franco Cerutti and colleagues at the Universita di Torino, Italy looked at 4,322 children and adolescents (4-11 years old) who had type 1 diabetes. Yearly celiac disease screening was performed on them by using IgA/IgG anti-gliadin and IgA anti-endomysium antibodies, and those with positive antibody results were given a biopsy for confirmation. Out of 4,322 children screened 292 or 6.8% had celiac disease. In 89% of cases diabetes was diagnosed before celiac disease. Using logistic regression analyses the researchers determined that those diagnosed with diabetes at a younger age, those who are female, and those with a thyroid disorder are independently associated with the risk of having both diabetes and celiac disease.

The researchers conclude: "We have provided evidence that 1) the prevalence of biopsy-confirmed celiac disease in children and adolescents with type 1 diabetes is high (6.8%); 2) the risk of having both diseases is threefold higher in children diagnosed with type 1 diabetes at age 9 years; and 3) girls have a higher risk of having both diseases than boys."