NOD mice: Gluten-free diets and diabetes

Type 1 diabetes mellitus is an autoimmune disease where both genetic and environmental factors, such as diet, combine to trigger the disease. Type 1 diabetes has been found to occur more frequently in individuals who also suffer from coeliac disease. This may be because both diseases share the same genetic risk factors and exposure to gluten could potentially be a dietary risk factor for both diseases.

This is where we turn to the non-obese diabetic or NOD mouse. First developed in 1980 in Japan, this mouse spontaneously develops Type 1 diabetes as its immune system attacks the cells of its own pancreas,  with 60-80% of females and 20-30% in male mice becoming diabetic. This mouse has been used as one model in research to try and understand Type 1 diabetes in human.

Back in 1999, evidence was suggesting that plant proteins in the diet of NOD mice was the environmental factor that was triggering their diabetes, particularly wheat and soy proteins. David Funda and his colleagues from Copenhagen and Prague decided to test this by feeding NOD mice either regular mouse food made from cereals and legumes, or a gluten-free equivalent of the the same diet with the wheat removed.

They found that by feeding the diet without wheat, the NOD mice develop far less diabetes and occurred later in life, compared to those fed the regular food.

NOD 1

Source: Funda, 1999.

This dramatic result suggested that gluten was a key factor in triggering diabetes in these mice. It should be noted that they fed the sames diets to the mothers of these mice so that the mice used in the study also had/didn’t have exposure to gluten before they were born. The same authors have recently shown that it is exposure during pregnancy that is most important in triggering diabetes in these mice (Antvorskov 2016).

The details of these diets and the ingredients used are shown in the table below. If you take the wheat out you have to replace it with sometime to keep the levels of proteins the same. In this case, they replaced it with meat protein while trying to keep other nutrients at similar levels.

NOD 2

Source: Funda, 1999.

However, it is good science to try to find evidence that the effect you saw was actually caused by the thing you think caused it. Was it actually gluten triggering the diabetes in these mice?

To test this, the same authors carried out another study using the same diets and the same type of mice as before. Only, this time, they included a third group of mice that were fed the wheat-free/gluten-free diet with pure gluten added back in (Funda, 2008).

NOD 3

Source: (Funda, 2008).

Perhaps surprisingly, as you can see from the chart above, the mice fed the gluten-free diet with added gluten were protected from diabetes just as much as those fed the gluten-free diet. This suggested that the story wasn’t so simple as first thought.

In fact, the diet with added gluten contained rather more gluten than the normal diet, as the scientists were expecting it to have a bad effect, but they wanted to make sure it was bad.

NOD 4

Source: (Funda, 2008).

This suggested it wasn’t gluten itself that was triggering diabetes in NOD mice.

However, taking the wheat out of the diet did prevent the diabetes, which leaves us with the question as to what was having the effect. Wheat is more than just gluten and taking the wheat out of the diet removes more than just gluten.

A recent study from Israel added an interesting twist to this question by testing different types of wheat (Gorelick, 2017). The modern bread wheat that we eat today has changed a lot in recent decades through selective breeding and hybridisation. This study compared the normal mouse diet that caused diabetes in NOD mice with versions of the same diet in which the type of the wheat was changed.

This included modern wheat and four old varieties of wheat called landraces.

  • Diet 1: A non-wheat diet replacing wheat with maize.
  • Diet 2: Standard modern bread wheat (Triticum aestivum).
  • Diet 3: An old bread wheat (Triticum aestivum), a landrace wheat from Israel.
  • Diet 4: Wild emmer wheat (Triticum turgidum ssp. dicoccoides).
  • Diet 5: Emmer wheat (Triticum turgidum spp. dicoccum), also known as farro.

As you can see in the charts below, only the modern wheat caused high levels of diabetes in NOD mice. Mice fed the diets made with old wheat varieties showed almost no diabetes during the time of the study, similar to the previous gluten-free diets.*

NOD 5NOD 6

Source: (Gorelick, 2017).

This suggests that modern wheat has a key effect but it is unlikely to be due to gluten, both because isolated gluten from modern wheat did not cause diabetes, and old varieties of wheat did not, even though they also contain gluten.

This suggests something else in modern wheat is having the effect on these mice. Wheat flour contains a complex mixture of several types of storage proteins such as gliadins, glutenins, globulins, and triticins. The α-gliadins possess the ones with the most links to celiac. However, other wheat proteins may be involved in triggering Type 1 diabetes in these NOD mice. For example, a wheat globulin protein, Glb1, has been identified as a trigger of diabetes in another animal model, the BioBreeding rat (MacFarlane, 2003). The proteins from the older varieties of wheat have yet to be analysed to unravel why they are less likely to trigger diabetes in NOD mice.

As usual, it is worth bearing in mind that these NOD mice are a model used to study diabetes, but they are not small furry humans. Caution should be used when trying to transfer results from the mice directly to human diabetes. However, it is interesting to see such contrasting effects of different types of wheat. While the grains may look similar on the outside, the proteins they contain can be quite different.

As always, more research will be needed to understand exactly what is going on.

 

*Curiously, in this study, the maize diet also triggered diabetes in the NOD mice. Plant proteins other than wheat are known to be a diabetic tigger in these mice.

References:

Funda DPKaas ABock TTlaskalová-Hogenová HBuschard K.  (1999) Gluten-free diet prevents diabetes in NOD mice. Diabetes Metab Res Rev. 15(5):323-7.
“BACKGROUND: Epidemiological as well as animal studies have shown that environmental factors such as nutrition contribute to the development of diabetes. In this study we investigated whether the early introduction of a gluten-free diet can influence the onset and/or incidence of diabetes, as well as insulitis and the number of gut mucosal lymphocytes, in non-obese diabetic (NOD) mice. METHODS: Gluten-free and standard Altromin diets (with the same milk protein and vitamin content) were given to breeding pairs of NOD mice as well as to the first generation of NOD female mice, which were then observed for 320 days. RESULTS: A substantially lower diabetes incidence (chi(2)=15.8, p=0.00007) was observed in NOD mice on the gluten-free diet (15%, n=27) compared to mice on the standard diet (64%, n=28). In addition, mice on the gluten-free diet developed diabetes significantly later (244+/-24 days SEM) compared to those on the standard diet (197+/-8 days, p=0.03). No differences in the number of CD3(+), TCR-gammadelta(+), IgA(+), and IgM(+) cells in the small intestine were observed. CONCLUSION: We showed that gluten-free diet both delayed and to a large extent prevented diabetes in NOD mice that have never been exposed to gluten.”
Funda DPKaas ATlaskalová-Hogenová HBuschard K. (2008) Gluten-free but also gluten-enriched (gluten+) diet prevent diabetes in NOD mice; the gluten enigma in type 1 diabetesDiabetes Metab Res Rev. 24(1):59-63.
BACKGROUND: Environmental factors such as nutrition or exposure to infections play a substantial role in the pathogenesis of type 1 diabetes (T1D). We have previously shown that gluten-free, non-purified diet largely prevented diabetes in non-obese diabetic (NOD) mice. In this study we tested hypothesis that early introduction of gluten-enriched (gluten+) diet may increase diabetes incidence in NOD mice.METHODS: Standard, gluten-free, gluten+ modified Altromin diets and hydrolysed-casein-based Pregestimil diet were fed to NOD females and diabetes incidence was followed for 310 days. Insulitis score and numbers of gut mucosal lymphocytes were determined in non-diabetic animals.RESULTS: A significantly lower diabetes incidence (p < 0.0001) was observed in 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). Surprisingly, gluten+ diet also prevented diabetes incidence, even at the level found with the gluten-free diet (p < 0.0001, 5.9%, n = 34). The minority of mice, which developed diabetes on all the three diabetes-protective (gluten+, gluten-free, Pregestimil) diets, did that slightly later compared to those on the standard diet. Lower insulitis score compared to control mice was found in non-diabetic NOD mice on the gluten-free, and to a lesser extent also gluten+ and Pregestimil diets. No substantial differences in the number of CD3(+), TCR-gammadelta(+), and IgA(+) cells in the small intestine were documented.CONCLUSIONS: Gluten+ diet prevents diabetes in NOD mice at the level found with the non-purified gluten-free diet. Possible mechanisms of the enigmatic, dual effect of dietary gluten on the development of T1D are discussed.
Gorelick J, Yarmolinsky L, Budovsky A, Khalfin B, Klein JD, Pinchasov Y, Bushuev MA, Rudchenko T, Ben-Shabat S. (2017 ) The Impact of Diet Wheat Source on the Onset of Type 1 Diabetes Mellitus-Lessons Learned from the Non-Obese Diabetic (NOD) Mouse ModelNutrients. 10;9(5).
Nutrition, especially wheat consumption, is a major factor involved in the onset of type 1 diabetes (T1D) and other autoimmune diseases such as celiac. While modern wheat cultivars possess similar gliadin proteins associated with the onset of celiac disease and T1D, alternative dietary wheat sources from Israeli landraces and native ancestral species may be lacking the epitopes linked with T1D, potentially reducing the incidence of T1D. The Non-Obese Diabetic (NOD) mouse model was used to monitor the effects of dietary wheat sources on the onset and development of T1D. The effects of modern wheat flour were compared with those from either T. aestivumT. turgidum spp. dicoccoides, or T. turgidum spp. dicoccum landraces or a non-wheat diet. Animals which received wheat from local landraces or ancestral species such as emmer displayed a lower incidence of T1D and related complications compared to animals fed a modern wheat variety. This study is the first report of the diabetogenic properties of various dietary wheat sources and suggests that alternative dietary wheat sources may lack T1D linked epitopes, thus reducing the incidence of T1D.
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One Response to NOD mice: Gluten-free diets and diabetes

  1. italianirish92 says:

    Interesting stuff. I always wonder how studies like this control for pesticides in the food they feed to the animals. Unless they choose organic for the studies, who’s to say something like glyphosate isn’t the culprit for earlier onset T1DM? The processed gluten along with specialty grown wheat varieties may have lower levels than conventional wheat. Maybe this can account for the inconsistencies. What do you think?

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