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. 2018 Sep 12;10(9):1291.
doi: 10.3390/nu10091291.

Dietary Cows' Milk Protein A1 Beta-Casein Increases the Incidence of T1D in NOD Mice

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Free PMC article

Dietary Cows' Milk Protein A1 Beta-Casein Increases the Incidence of T1D in NOD Mice

Joanne S J Chia et al. Nutrients. .
Free PMC article

Abstract

The contribution of cows' milk containing beta-casein protein A1 variant to the development of type 1 diabetes (T1D) has been controversial for decades. Despite epidemiological data demonstrating a relationship between A1 beta-casein consumption and T1D incidence, direct evidence is limited. We demonstrate that early life exposure to A1 beta-casein through the diet can modify progression to diabetes in non-obese diabetic (NOD) mice, with the effect apparent in later generations. Adult NOD mice from the F0 generation and all subsequent generations (F1 to F4) were fed either A1 or A2 beta-casein supplemented diets. Diabetes incidence in F0⁻F2 generations was similar in both cohorts of mice. However, diabetes incidence doubled in the F3 generation NOD mice fed an A1 beta-casein supplemented diet. In F4 NOD mice, subclinical insulitis and altered glucose handling was evident as early as 10 weeks of age in A1 fed mice only. A significant decrease in the proportion of non-conventional regulatory T cell subset defined as CD4⁺CD25-FoxP3⁺ was evident in the F4 generation of A1 fed mice. This feeding intervention study demonstrates that dietary A1 beta-casein may affect glucose homeostasis and T1D progression, although this effect takes generations to manifest.

Keywords: NOD mice; beta-casein; cows’ milk; epigenetics; type 1 diabetes.

Conflict of interest statement

Sonja Kukuljan was a previous salaried employee of a2 Infant Nutrition Australia Private Limited. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Diabetes incidence in female mice. Diabetes incidence of mice in the (a) F1 generation; (b) F2 generation; (c) F3 generation.
Figure 2
Figure 2
Glucose handling capacity in F4 generation female NOD mice. (a) fasting  blood glucose levels and (b) body weights of 10- to 12-week old A1 (formula image) and A2 (formula image) beta-casein fed female mice. BGLs of female mice assessed in (c) glucose and (d) insulin tolerance tests. (e) distribution of insulitis in islets represented as a percentage of islet infiltration in 10-week old female mice fed either A1 or A2 beta-casein supplemented diets. Islets were scored blindly from individual mice. Islet inflammation was calculated on a scale from 0 to 4. 0—islets devoid of mononuclear cells; 1—minimal (<10%) focal islet infiltrate; 2—peri-islet infiltrate in <25% of islet circumference; 3—peri-islet infiltrate in >25% but <50% intra-islet and 4—>50% intra-islet infiltration.
Figure 3
Figure 3
Immune profile in F4 generation mice fed A1 and A2 beta-casein supplemented diets. Splenic leukocytes were obtained and stained with various antibodies. The percentages of the different immune subsets in the spleen were then assessed via flow cytometry. (a) conventional Tregs (CD4+CD25+FoxP3+); (b) non-conventional Tregs (CD4+CD25Foxp3+); (c) CD4+; (d) CD8+; (e) B cells; and (f) macrophages.
Figure 4
Figure 4
A1 beta-casein supplemented diet associated mechanisms in T1D development in NOD mice.

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References

    1. Jeker L.T., Bour-Jordan H., Bluestone J.A. Breakdown in peripheral tolerance in type 1 diabetes in mice and humans. Cold Spring Harb. Perspect. Med. 2012;2:a007807. doi: 10.1101/cshperspect.a007807. - DOI - PMC - PubMed
    1. Mathis D., Vence L., Benoist C. beta-Cell death during progression to diabetes. Nature. 2001;414:792–798. doi: 10.1038/414792a. - DOI - PubMed
    1. Atkinson M.A., Eisenbarth G.S., Michels A.W. Type 1 diabetes. Lancet. 2014;383:69–82. doi: 10.1016/S0140-6736(13)60591-7. - DOI - PMC - PubMed
    1. Polychronakos C., Li Q. Understanding type 1 diabetes through genetics: Advances and prospects. Nat. Rev. Genet. 2011;12:781–792. doi: 10.1038/nrg3069. - DOI - PubMed
    1. Burn P. Type 1 diabetes. Nat. Rev. Drug Discov. 2010;9:187–188. doi: 10.1038/nrd3097. - DOI - PubMed

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