We have investigated the effects of early dietary food supplements on the rate of diabetes development in the NOD mouse using controlled conditions. The findings show little effects on overall diabetes incidence and mild to moderate increases in diabetes rate when cereal food supplements are added to a basal calorie-controlled diet. The increased rates were not associated with any single food supplement and for wheat appeared to be dose dependent.
The relative strength of this study is that experimental diets and conditions were controlled with respect to diet protein, fat and carbohydrate content as well as energy intake. To achieve this, we relied on noncommercial sources of mouse feed since commercial sources were found to have numerous components and were inconsistent from batch to batch. All diets were prepared in one institute. In order to obtain a low-diabetogenic diet, both casein and wheat sources of protein were eliminated. Elimination of only wheat was only partially effective in reducing diabetes rate. The findings with respect to wheat and casein as potentially diabetogenic in the NOD mouse have been previously reported [4
]. The relatively slow diabetes rate (around 37% by age 25 weeks) observed when the source of protein was limited to soy and poultry was reproducible in 2 trials in our experiments, suggesting that the finding is bona fide. Thus, we recommend such a diet for future studies in which conditions that increase diabetogenicity in the NOD mouse are investigated.
Using the low-diabetogenicity diet, we were able to investigate the effects of single food source supplements on diabetes development. The results were not entirely confirmatory of previous findings. We and others had previously shown a marked decrease in diabetes incidence when wheat and barley were removed from the diet of NOD mice [8
]. We could not entirely reproduce this effect in the current series of experiments under controlled dietary conditions. Certainly the absence of wheat contributed to low diabetogenicity, but adding wheat proteins as a supplement to a low-diabetogenic, wheat-free diet increased diabetes rate only when low concentrations (5% weight/weight) were used and not at all when 30% of the diet ingredients were wheat derived. Since previous effects were observed by removal of wheat from complex diets such as Altromin 1324 which contains 30% wheat source (and was shown to be a high-diabetogenic diet again in the current series of experiments), it is likely that diabetogenic effects of wheat are complex and vary depending upon other components of the diet. It should also be noted that the addition of any single wheat component at a concentration corresponding to 30% whole wheat did not increase diabetes rate. Finally, a dose-dependent effect whereby only low concentrations are diabetogenic could be explained by tolerogenic effects of high antigen concentration and the possibility that wheat also has components [22
] that have antidiabetic properties. These include unsaturated fatty acids and vitamin E, which have been suggested to delay diabetes onset [23
], as well as large amounts of phytic acid (up to 1,100 mg/ 100 g in wheat). Studies in rodent models as well as in humans indicate that phytic acid leads to a clear reduction of postprandial blood glucose levels [24
]. Therefore, a decreased requirement for postprandial insulin secretion might preserve the pancreatic β cells which could delay the diabetes onset in prediabetic NOD mice.
The addition of foods other than wheat was variable in its effects on diabetes development, but generally increased the rate without affecting overall incidence. The strongest effect was observed when 5% corn was added. Together with the finding that 5% wheat was also diabetogenic, it is tempting to conclude that cereals are generally diabetogenic at certain concentrations. The dose dependency of corn and other cereals requires further investigation. The mechanism of the effects of cereals is not clear. Sequence homologies have been described for the wheat storage protein Glb1 and tight junction proteins which are involved into the permeability control of intestinal epithelium [27
]. Of interest, similar sequence homologies are present for Glb1 protein from corn. Little or no effect on diabetes development was observed when potato, apple and carrot were added to the low-diabetogenicity diet. The absence of an effect on diabetes when dried whole unpeeled potato was added to the diet is inconsistent with a former study describing diabetogenicity of bacterial toxins on the potato peel [28
]. Finally, none of the diets affected the development of insulin autoantibodies. In previous NOD studies, we have seen a relationship of insulin autoantibodies with diabetes incidence also in relation to wheat exposure [8
]. For the current study, the differences in diabetes development at 25 weeks of age may not be sufficiently marked to see an effect at the level of insulin autoantibodies with the number of mice used.
In conclusion, diabetes development in the NOD mouse is influenced by dietary modifications. Using single foods as supplements to a low-diabetogenic casein and wheat-free diet, diabetogenic effects were observed for cereals, but were relatively mild compared to previous findings. In addition, there was a suggestion that the dose of the cereal supplement could be important for diabetogenicity, with greatest effects seen at low cereal dose.