The effects of gluten on type 1 diabetes

ABSTRACT

The onset of Type 1 Diabetes is partially affected by genetics and partially affected by environmental factors.  Genetic components cannot be changed, but if the environmental components can be identified and modified then the potential to decrease the number of Type 1 Diabetes cases is possible.  Gluten has been identified as a possible environmental factor that plays a role in the onset of the disease as well as the course of the disease.  Therefore, scholarly articles were investigated containing both literature reviews and original studies to research this topic.  Both animal and human studies have been conducted to determine how gluten affects patients with Type 1 Diabetes both pre-diagnosis and post-diagnosis.  Animal studies have concluded that the lack of gluten exposure in utero can prevent Type 1 Diabetes in mice.  These studies have not been conducted in humans.  However, there are human studies that have shown that once a patient receives a diagnosis, the removal of gluten can delay the actual onset as well as the course of the disease.  Additional studies addressing the role of gluten in Type 1 Diabetes are addressed as well.

INTRODUCTION

            Type 1 Diabetes (T1D) is a lifelong autoimmune disease that results in being dependent on insulin since the body can no longer produce it.  It can be life threatening and have a great impact on the lifestyle and quality of life of the individual diagnosed.  It is important to study and understand why this disease presents and if there is anything that can be done to prevent it.

There are several factors that contribute to the onset of T1D.  It is suggested that what determines if someone gets T1D is both genetic and environmental (Gloria, Camhi, Sturgeon, Yan, & Fasano, 2015).  What has been unknown is what the environmental factors are.  Gloria et al. state that some environmental factors that are of interest are viruses.  Others that may have an effect, but are not as widely accepted, are climate and nutrition.  Also, Hogg-Kollars, Dulaimi, Trait, & Rostami (2014) propose that additional environmental factors are toxins, exposure to milk very early, and gluten. 

While the genetic component may not be manipulatable, the environmental factors are something we can change to help prevent or delay the onset of further cases of T1D.  It is important to attempt to identify and focus on the factors that we can control concerning the environmental factors given that T1D is a disease with no cure.  It is also important to identify those environmental factors that could prolong remission before the full onset of the disease. 

Gluten is a promising topic of study as it has been shown through current research that a diet containing gluten can increase the likelihood of T1D onset.  It has also been shown that the removal of gluten might also prevent or decrease the chance of T1D onset and prolong the remission period after initial diagnosis.  It is therefore a potential key environmental factor that deserves investigation.

Addressing the effects of gluten on T1D both pre-diagnosis and post-diagnosis can benefit the health status of the individual.  A simple dietary change could mean the difference between a slight inconvenience and lifetime diagnosis of an incurable disease. 

METHODS

Overview

            To obtain and assess only the highest quality information, several procedures were put in place during the search process.  First, only scholarly articles were considered for this review. Second, only sites known to host scholarly and peer reviewed articles were searched.

            The sites searched were PubMed, Google Scholar, and Research Gate.  The search string used was “Gluten AND Free AND Type AND 1 AND Diabetes” for the basic search.  Depending on the quantity of results, the search was modified.  A common modification included using “NOT Celiac”.  Many articles focused on Celiac Disease and contained only a few sentences on T1D so it was beneficial to exclude those articles. 

Research Gate did not produce any articles of interest and therefore the focus was PubMed and Google Scholar.  They both produced numerous articles but many were older than five years.  All articles older than five years, except for two, were excluded even if the studies would have provided value.  The two studies over five years that were kept were because they were human studies.  Human studies are hard to come by, in which case it was acceptable to keep these particular studies for review.

RESULTS

Pre-diagnosis and prevention

Secondulfo et al. (2004) studied the intestinal permeability in T1D patients who did not have Celiac disease.  The study lasted 5.7 years and included 46 patients with T1D.  The method was to investigate the small bowel mucosa and intestinal permeability through lactulose/mannitol tests.  With P < 0.0001, the lactulose/mannitol ratio .038 in T1D patients and .014 in the control group. The conclusion was the loss of function in the intestinal barrier could be a factor in the development of T1D.   This is important because gluten is a leading cause of intestinal permeability (Myers, 2013).

Antvorskov et al. (2016) conducted a study to determine the effect of ingesting gluten during pregnancy and the onset of diabetes in the offspring of mice.  They claimed that other studies have shown that T1D is influenced by consuming gluten.   Their particular aim was to show that T1D could be prevented if a gluten-free diet during pregnancy was adopted. The methods involved purchasing 4-week old breeding mice and then dividing them into seven different groups.  Each group was given gluten at a different time during pregnancy.  Once the offspring weaned, they were monitored to record the incidents of T1D.  The Kaplan-Meier estimation was used to assess diabetes incidence and in order to calculate the difference between groups, they used the log-rank test.  The most notable conclusion of the study was that the lowest incidence of T1D was seen in the mice that had no gluten exposure at all in utero.  With P < 0.0001, the incidence of T1D in the control group was 62.5% but in the group of mice not exposed to gluten it was 8.2%.  This was concluded as remarkable. They further concluded that this could be translated to humans and pregnant women should remove gluten from their diet.

A different perspective

Hummel, Pfluger, Hummel, Bonifacio & Ziegler (2011) conducted a study to determine the safety and possible reduced risk of removing gluten from the diets of at-risk children for T1D. They gathered 150 infants with relatives who had T1D and randomly assigned them to groups.  Groups received gluten at various ages during infancy.   Of the original children, 70% adhered to the diet.  There were no significant differences in the health and diagnosis of T1D in the study groups and control groups.  Thirteen children in the late-exposure groups and eleven children in the control group developed islet autoantibodies (where P=0.6).  They concluded that it is safe to remove gluten but does not appear to reduce the risk of developing T1D.

A study was done on first degree relatives of people with T1D that were identified to be at risk for developing T1D after extensive blood testing (Pastore et al., 2013).  The study was done on 17 participants.  It consisted of six months on a gluten-free diet and six months on a gluten-containing diet.   Measurements after the first six months did not indicate that the immune response was any lower. Insulin response increased (P=0.04) in 12 of the 14 participants after six months without gluten and decreased in 10 of the participants following the six months including gluten (P=0.07).   This is not quite in alignment with some other studies regarding gluten.   However, it did indicate that there was a positive effect on the insulin secretion and insulin sensitivity as noted above.  It was not clear as to why this occurred, but one thought was that the different types of carbohydrates might play a role.  This revelation, however, supports the potential negative effects of gluten.

Quite a unique study was done on humans that involved the nasal ingestion of gluten (Haut-Jorgensen, Nielsen, Engkilde, Lerche, Larsen, & Buschard, 2017).  The study was conducted because it was found that bakers appeared to have a lower incidence of T1D and they wanted to see if it was due to daily inhaling of gluten.  Using the Statistics Denmark (DST), they obtained gender and birth information.  Then they used Danish National Patient Registry (DNPR) to obtains hospital admissions and diagnosis information.   After analyzing over a million patients, it was determined that bakers and grain agriculture workers had the lowest incidence of T1D (P<0.001).  They randomly sampled the nasal passages of several of these people and they were all found to contain gluten.  They recommend further studies to determine if T1D can be prevented by gluten administered intranasally.

Post-diagnosis

            Svensson et al. (2016) aimed to show that adhering to a gluten-free diet post diagnosis may alter the actual onset and natural course of the disease.  The methods involved studying 15 newly diagnosed children over the course of 12 months and were compared against two prior cohorts.  They were instructed to follow a gluten-free diet for 12 months.  Partial remission was defined as having an IDAA1c (insulin does-adjusted A1c) less than or equal to 9.  One year after the study completed and based on their IDAA1c, three times as many participants were still in partial remission (P < 0.05) as compared to the cohorts.  Additionally, HbA1c was 21% lower on average among the children (P < 0.0001).  The conclusion was that a gluten-free diet has better outcomes for T1D regarding HbA1c and IDAA1c.

A remarkable case study was done with a 5-year-old boy (Sildorf, Fredheim, Svensson, & Buschard, 2012).  While it only involved one participant and cannot be generalized, it is worth inclusion.  He was diagnosed with T1D and did not have Celiac Disease.  His parents opted for a plan that would preserve the beta (insulin producing) cells.  The boy was then put on a gluten-free diet.  This was put into place about two weeks post diagnosis.  He was still in the Honeymoon Period at this point. After someone is diagnosed with T1D, they go through what is commonly referred to as a Honeymoon Period.  This is the period where the body is still producing insulin and before all the insulin producing cells are killed off.  Generally during this time, artificial insulin requirements are less (Sokolowska, Chobot & Jarosz-Chobot, 2016).  The attempt was to delay or prevent the complete destruction of his beta cells.

            The boy entered complete remission 7-8 weeks post diagnosis and remained that way all the way through to the last documented test which was 20 months after diagnosis.  It is noted that this remission could be due to the gluten-free diet or the low glycemic index of the diet.  Perhaps a combination of the two is most plausible.  Given prior animal studies, however, Sildorf et al., proposed that the most likely candidate is the gluten-free diet and suggested a gluten-free diet for all newly diagnosed patients with T1D.

DISCUSSION

Pre-diagnosis and prevention

It is much easier to conduct studies on animals than on humans.  When dealing with a lifetime of disease it may not always be ethical to conduct studies on humans.  Therefore, studies on mice have been numerous compared to those in humans regarding a gluten free diet in utero as well as post birth.  It is conclusive that a gluten-free diet during pregnancy can prevent T1D in the mice offspring.  Further studies in this regard would be beneficial.

Given that gluten has been shown to have an intestinal permeability effect and that T1D has an environmental effect triggering an immune response, it is logical to highly consider gluten as a culprit.  First degree relatives are especially at risk for developing the disease in which case minimizing the environmental factors is key.  The studies addressed so far seem to agree that removing gluten from the diet of an infant cannot guarantee the prevention of T1D.  The studies indicate that the focus should be in-utero and post diagnosis. 

Post-diagnosis

            Prevention of T1D hasn’t been definitively proven, but delayed onset post-diagnosis has promising results to date.  The results from Sildorf, Fredheim, Svensson, & Buschard (2012) cannot be generalized to population at-large, but the case study is encouraging.    In addition to that, positive outcomes in terms of HbA1c and IDAA1c show promise in studies.  The treatment option of a gluten-free diet immediately after diagnosis is a logical next step given the safety was shown and the positive outcome shown.  If patients and the parents of patients are educated in the most recent research regarding delayed onset treatment options, then there is the potential to save lives, prevent diabetes related complications, and improve the quality of life.  With the latest research, a T1D diagnosis does not need to be an immediate life sentence.

Additional research

            While much research has been done on this topic, there is much more that is needed.  Human studies would be greatly beneficial to definitively show the affect gluten has on the onset and outcome of a T1D diagnosis.  Maternal diets and early childhood diets would be a beneficial area to do human testing in. It is non-invasive and can support an already existing eating plan (assuming other variables are equal).    More research on gluten itself to get conclusive results regarding its health effects would also be beneficial. 

CONCLUSION

Adopting a gluten-free diet has been shown to be safe and without adverse health risks (Hummel, Pfluger, Hummel, Bonifacio & Ziegler, 2011).   Sildorf et al., Svensson et al., and Pastore et al. have shown promising human studies concluding that the removal of gluten can delay or prevent the onset of T1D post-diagnosis. While it does not make sense to remove gluten from general consumption for the average population, it was shown that there are ways to help decrease the onset of T1D in those predisposed to the disease.  Further studies should be conducted to increase general knowledge and pinpoint the exact formula for potential T1D prevention through the removal of gluten.

Recommendations

Several general recommendations would seem appropriate.  First, for those people who are genetically predisposed for T1D, it would be beneficial to seek nutrition counseling and adopt a gluten-free diet.  If done properly, there does not need to be any nutritional deficiencies.  Second, if someone is diagnosed with T1D, then studies suggest that adopting a gluten-free diet can prolong the onset and outcome of the disease.  This is important because once the disease fully sets in, there is no reversal.  A controversial suggestion would be for mothers-to-be who are genetically predisposed for T1D, and hence may have kids who are genetically predisposed, could adopt a gluten-free diet.  

Lastly, it is important to recognize the emotional impact of a person, especially children, newly diagnosed with T1D.  When discussing treatment options, sensitivity and understanding should be paramount because not only are they dealing with the disease but may now be facing removal of food that they enjoy.  It is important to reinforce healthy habits and that satisfying food can easily be obtained even if a gluten-free lifestyle is adopted.

REFERENCES

Antvorskov, J. C., Josefsen, K., Haupt-Jorgensen, M., Fundova, P., Funda, D.P. & Buschard, K. (2016). Gluten-Free Diet Only during Pregnancy Efficiently Prevents Diabetes in NOD Mouse Offspring. Journal of Diabetes Research, 3047574. DOI: 10.1155/2016/3047574

Haut-Jorgensen, M., Nielsen, E., Engkilde, K., Lerche, M., Larsen, J. & Buschard, K. (2017). Occupation with grain crops is associated with lower type 1 diabetes incidence: Registry-based case-control study. PLoS One, 12(7).  e0181143. DOI:  10.1371/journal.pone.0181143

Hogg-Kollars, S., Dulaimi, D. A., Trait, K. & Rostami, K. (2014). Type 1 Diabetes mellitus and gluten induced disorders. Gastroenterol Hepatol Bed Bench, 7(4), 189–197

Hummel, S., Pfluger, M., Hummel, M., Bonifacio, E. & Ziegler, AG. (2011). Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study.  Diabetes Care, 34(6). 1301-5. doi: 10.2337/dc10-2456

Myers, A. (2013). 9 signs you have a leaky gut. Retrieved from https://www.mindbodygreen.com/0-10908/9-signs-you-have-a-leaky-gut.html

Pastore, M., Bazzigaluppi, E., Belloni, C., Arcovio, C., Bonifiacio, E. & Bosi, E. (2003). Six Months of Gluten-Free Diet Do Not Influence Autoantibody Titers, but Improve Insulin Secretion in Subjects at High Risk for Type 1 Diabetes. The Journal of Clinical Endocrinology & Metabolism, 88 (1). 162-165. DOI: https://doi.org/10.1210/jc.2002-021177

Secondulfo M, Iafusco D, Carratu R, deMagistris L, Sapone A, Generoso M. (2014).  Ultrastructural mucosal alterations and increased intestinal permeability in non-celiac, type I diabetic patients. Dig Liver Dis. 36. 35–45. doi: 10.1016/j.dld.2003.09.016

Sildorf, S, M., Fredheim, S., Svensson, J. & Buschard, K. (2012). Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus. BMJ Case Reports, v.2012. DOI:  10.1136/bcr.02.2012.5878

Sokolowska, M., Chobot, A. & Jarosz-Chobot P. (2016).  The honeymoon phase – what we know today about the factors that can modulate the remission period in type 1 diabetes.  Pediatric Endocrinology, Diabetes, and Metabolism, 22 (2). 66-70. DOI: 10.18544/PEDM-22.02.0053

Svensson, J., Sildorf, S.M., Pipper, C. B., Kyvsgaard, J. N., Bojstrup, J., Pociot, F.M., … Burschard, K. (2016). Potential beneficial effects of a gluten-free diet in newly diagnosed children with type 1 diabetes: a pilot study.  Springerplus, 5(1). 994. doi:  10.1186/s40064-016-2641-3