Early feeding and risk of type 1 diabetes: experiences from the Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR)

Abstract

Short-term breastfeeding and early exposure to complex dietary proteins, such as cow milk proteins and cereals, or to fruit, berries, and roots have been implicated as risk factors for β cell autoimmunity, clinical type 1 diabetes, or both. The Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR) is an international, randomized, double-blind, controlled intervention trial designed to answer the question of whether weaning to an extensively hydrolyzed formula in infancy will decrease the risk of type 1 diabetes later in childhood. In our pilot study, weaning to a highly hydrolyzed formula decreased by ≈ 50% the cumulative incidence of one or more diabetes-associated autoantibodies by a mean age of 4.7 y. This finding was confirmed in a recent follow-up analysis to 10 y of age. Currently, the full-scale TRIGR takes place in 77 centers in 15 countries. The TRIGR initially recruited 5606 newborn infants with a family member affected by type 1 diabetes and enrolled 2159 eligible subjects who carried a risk-conferring HLA genotype. All recruited mothers were encouraged to breastfeed. The intervention lasted for 6-8 mo with a minimum study formula exposure time of 2 mo, and hydrolyzed casein and standard cow milk-based weaning formulas were compared. Eighty percent of the participants were exposed to the study formula. The overall retention rate over the first 5 y was 87%, and protocol compliance was 94%. The randomization code will be opened when the last recruited child turns 10 y of age (ie, in 2017).

FIGURE 1.

Possible mechanisms by which an extensively hydrolyzed formula may protect against β cell autoimmunity and type 1 diabetes in children at increased genetic disease risk. The highly hydrolyzed formula (1) eliminates the exposure to intact bovine insulin (BI) present in conventional cow milk–based formulas (2); may decrease intestinal permeability, thereby decreasing the load of foreign peptides and proteins on the gut-associated lymphoid tissue in lamina propria (3); may induce the maturation of regulatory T cells (Treg) in the gut-associated lymphoid tissue, the function of which suppresses other T cells and their cytokine production, resulting in decreased intestinal inflammation; and/or (4) may support “healthy” microbial (•) diversity in the gut. DC, dendritic cell; HLA, human leukocyte antigen; IL, interleukin; INF-γ, interferon γ; T, T cell; Th, T helper; TNF, tumor necrosis factor.