Dietary intervention in infancy and later signs of beta-cell autoimmunity

Mikael Knip, Suvi M Virtanen, Karri Seppä, Jorma Ilonen, Erkki Savilahti, Outi Vaarala, Antti Reunanen, Kari Teramo, Anu-Maaria Hämäläinen, Johanna Paronen, Hans-Michael Dosch, Timo Hakulinen, Hans K Akerblom, Finnish TRIGR Study Group, H K Åkerblom, V Eskola, H Haavisto, A-M Hämäläinen, C Holm, A-L Järvenpää, R Jokisalo, M-L Käär, U Kaski, J Komulainen, P Korpela, P Lautala, K Niemi, A Nuuja, P Rantanen, R Renko, M Renlund, M Salo, T Talvitie, T Uotila, G Wetterstrand, H Hyöty, J Ilonen, P Klemetti, M Knip, P K Kulmala, J Paronen, A Reunanen, T Saukkonen, E Savilahti, K Savola, K Teramo, O Vaarala, S M Virtanen, Mikael Knip, Suvi M Virtanen, Karri Seppä, Jorma Ilonen, Erkki Savilahti, Outi Vaarala, Antti Reunanen, Kari Teramo, Anu-Maaria Hämäläinen, Johanna Paronen, Hans-Michael Dosch, Timo Hakulinen, Hans K Akerblom, Finnish TRIGR Study Group, H K Åkerblom, V Eskola, H Haavisto, A-M Hämäläinen, C Holm, A-L Järvenpää, R Jokisalo, M-L Käär, U Kaski, J Komulainen, P Korpela, P Lautala, K Niemi, A Nuuja, P Rantanen, R Renko, M Renlund, M Salo, T Talvitie, T Uotila, G Wetterstrand, H Hyöty, J Ilonen, P Klemetti, M Knip, P K Kulmala, J Paronen, A Reunanen, T Saukkonen, E Savilahti, K Savola, K Teramo, O Vaarala, S M Virtanen

Abstract

Background: Early exposure to complex dietary proteins may increase the risk of beta-cell autoimmunity and type 1 diabetes in children with genetic susceptibility. We tested the hypothesis that supplementing breast milk with highly hydrolyzed milk formula would decrease the cumulative incidence of diabetes-associated autoantibodies in such children.

Methods: In this double-blind, randomized trial, we assigned 230 infants with HLA-conferred susceptibility to type 1 diabetes and at least one family member with type 1 diabetes to receive either a casein hydrolysate formula or a conventional, cow's-milk-based formula (control) whenever breast milk was not available during the first 6 to 8 months of life. Autoantibodies to insulin, glutamic acid decarboxylase (GAD), the insulinoma-associated 2 molecule (IA-2), and zinc transporter 8 were analyzed with the use of radiobinding assays, and islet-cell antibodies were analyzed with the use of immunofluorescence, during a median observation period of 10 years (mean, 7.5). The children were monitored for incident type 1 diabetes until they were 10 years of age.

Results: The unadjusted hazard ratio for positivity for one or more autoantibodies in the casein hydrolysate group, as compared with the control group, was 0.54 (95% confidence interval [CI], 0.29 to 0.95), and the hazard ratio adjusted for an observed difference in the duration of exposure to the study formula was 0.51 (95% CI, 0.28 to 0.91). The unadjusted hazard ratio for positivity for two or more autoantibodies was 0.52 (95% CI, 0.21 to 1.17), and the adjusted hazard ratio was 0.47 (95% CI, 0.19 to 1.07). The rate of reported adverse events was similar in the two groups.

Conclusions: Dietary intervention during infancy appears to have a long-lasting effect on markers of beta-cell autoimmunity--markers that may reflect an autoimmune process leading to type 1 diabetes. (ClinicalTrials.gov number, NCT00570102.).

Figures

Figure 1. Screening, Randomization, and Follow-up
Figure 1. Screening, Randomization, and Follow-up
Figure 2. Cumulative Incidence of Islet-Cell Antibodies,…
Figure 2. Cumulative Incidence of Islet-Cell Antibodies, Insulin Autoantibodies, and Autoantibodies to the Insulinoma-Associated 2 Molecule (IA-2) in the Two Study Groups
The cumulative incidence of islet-cell antibodies (Panel A), insulin autoantibodies (Panel B), and IA-2 autoantibodies (Panel C) in the casein hydrolysate group and in the control group, according to the age of the children at the time the autoantibodies were detected, is shown, with the use of nonparametric maximum-likelihood estimates (black) and fitted curves (blue) of the regression models. For the nonparametric maximum-likelihood estimates, gray rectangles show the intervals within which any curve would maximize the likelihood. The P values are derived from analyses adjusted for the duration of exposure to the study formula.
Figure 3. Cumulative Incidences of at Least…
Figure 3. Cumulative Incidences of at Least One Autoantibody and of at Least Two Autoantibodies
The cumulative incidences of at least one autoantibody (Panel A) and at least two autoantibodies (Panel B) in the casein hydrolysate group and in the control group, according to the age of the children at the time the autoantibodies were detected, are shown, with the use of nonparametric maximum-likelihood estimates (black) and fitted curves (blue) of the regression models. For the nonparametric maximum-likelihood estimates, gray rectangles show the intervals within which any curve would maximize the likelihood. The P values are derived from analyses adjusted for the duration of exposure to the study formula.

Source: PubMed

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