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

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


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.

MeSH terms

  • Animal Feed
  • Animal Nutritional Physiological Phenomena
  • Animals
  • Biomarkers / blood
  • Blood Glucose / metabolism
  • Caseins / administration & dosage
  • Caseins / toxicity*
  • Cells, Cultured
  • Coculture Techniques
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / etiology*
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology
  • Dietary Supplements / toxicity*
  • Female
  • Gastrointestinal Microbiome
  • Gene-Environment Interaction
  • Genetic Predisposition to Disease
  • Male
  • Mice, Inbred NOD
  • Risk Factors
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism


  • Biomarkers
  • Blood Glucose
  • Caseins