Hydrolyzed infant formula and early ß-cell autoimmunity: a randomized clinical trial.

IMPORTANCE: The disease process leading to clinical type 1 diabetes often starts during the first years of life. Early exposure to complex dietary proteins may increase the risk of ß-cell autoimmunity in children at genetic risk for type 1 diabetes. Extensively hydrolyzed formulas do not contain intact proteins. OBJECTIVE: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of diabetes-associated autoantibodies in young children. DESIGN, SETTING, AND PARTICIPANTS: A double-blind randomized clinical trial of 2159 infants with HLA-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1078 were randomized to be weaned to the extensively hydrolyzed casein formula and 1081 were randomized to be weaned to a conventional cows' milk-based formula. The participants were observed to April 16, 2013. INTERVENTIONS: The participants received either a casein hydrolysate or a conventional cows' milk formula supplemented with 20% of the casein hydrolysate. MAIN OUTCOMES: AND MEASURES: Primary outcome was positivity for at least 2 diabetes-associated autoantibodies out of 4 analyzed. Autoantibodies to insulin, glutamic acid decarboxylase, and the insulinoma-associated-2 (IA-2) molecule were analyzed using radiobinding assays and islet cell antibodies with immunofluorescence during a median observation period of 7.0 years (mean, 6.3 years). RESULTS: The absolute risk of positivity for 2 or more islet autoantibodies was 13.4% among those randomized to the casein hydrolysate formula (n = 139) vs 11.4% among those randomized to the conventional formula (n = 117). The unadjusted hazard ratio for positivity for 2 or more autoantibodies among those randomized to be weaned to the casein hydrolysate was 1.21 (95% CI, 0.94-1.54), compared with those randomized to the conventional formula, while the hazard ratio adjusted for HLA risk, duration of breastfeeding, vitamin D use, study formula duration and consumption, and region was 1.23 (95% CI, 0.96-1.58). There were no clinically significant differences in the rate of reported adverse events between the 2 groups. CONCLUSIONS AND RELEVANCE: Among infants at risk for type 1 diabetes, the use of a hydrolyzed formula, when compared with a conventional formula, did not reduce the incidence of diabetes-associated autoantibodies after 7 years. These findings do not support a benefit from hydrolyzed formula. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00179777.

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

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.).

Infant feeding and the risk of type 1 diabetes.

Type 1 diabetes is generally considered to be a chronic, immune-mediated disease with a subclinical prodrome during which beta cell autoimmunity becomes overt disease at a variable rate in genetically susceptible individuals. Accumulated evidence supports a critical role of environmental factors in its development. Prospective birth cohort studies show that the first signs of beta cell autoimmunity may be initiated during the first year of life. This implies that risk factors for beta cell autoimmunity and type 1 diabetes must be operative in infancy. Early nutrition provides essential exogenous exposures in that period. This article discusses the role of factors related to infant nutrition in the development of beta cell autoimmunity and type 1 diabetes and the potential mechanistic pathways involved. So far, no specific dietary factor has been shown to be an unequivocal risk factor for beta cell autoimmunity or type 1 diabetes, and there are a number of contradictory observations with regard to the effect of various foods. This may reflect geographic and cultural differences in infant-feeding practices. Most studies suggest that the early introduction of complex foreign proteins may be a risk factor for beta cell autoimmunity, and a pilot intervention trial has implied that weaning to a highly hydrolyzed formula may decrease the risk of beta cell autoimmunity. Lack of vitamin D supplementation and accelerated growth might increase the risk of type 1 diabetes. Additional work, which includes the application of modern approaches such as metabolomics and epigenomics, is needed to discern the contribution of dietary factors in infancy to the diabetic disease process.

Relative validity of a dietary interview for assessing infant diet and compliance in a dietary intervention trial.

The objective of this study was to assess the relative validity of a dietary interview method for use in an infant population. A dietary interview covering a 1-month period was completed during a study visit at 3 or 6 months of age. It included structured questions and a short food frequency questionnaire (FFQ). The information was compared with data from two 48-h recall interviews conducted during the month previous to the study visit. The agreement between the FFQ and 48-h recalls was analysed as proportion of subjects classified into the same categories of consumption frequency and by the kappa analysis. A total of 100 subjects, at the age of 2-3 months (n = 50) and 5-6 months (n = 50), were included. The kappa values for breastmilk and study formula ranged from 0.82 to 0.95, indicating very good agreement. The agreement for other foods and vitamin D supplementation ranged from fair to very good. We also found a strong correlation for the reported amount of study formula consumed per feeding at 3 months (r(s) = 0.87, n = 24) and 6 months of age (r(s) = 0.73, n = 35) between the questionnaire and 48-h recall data. However, the average amount of study formula per feeding was significantly higher when estimated for a 1-month period, compared with a mean calculated from the two 48-h recalls. As a conclusion, the interview was found to be a useful tool for assessing diet and compliance in a dietary intervention for infants.

Early nutrition and later diabetes risk.

Early feeding may modify the risk of both type 1 (T1D) and type 2 diabetes (T2D) later in life. The information generated so far is, however, controversial. When evaluating studies on the impact of early feeding on risk of later diabetes, the data have to be assessed critically and possible confounding factors have to be considered. The study design may induce biases and there are considerable differences in early feeding practices across various countries and cultures. Accordingly it may not be possible to generalise observations based on one population. Long breastfeeding, exclusive breastfeeding in particular, and supplementation with vitamin D in infancy have been reported to confer partial protection against beta-cell autoimmunity and TID. In contrast, early exposure to cow's milk proteins and cereals and heavy weight in infancy have been implicated as risk factors for T1D. Long breastfeeding has also been observed to protect against T2D in aboriginal populations. Poor fetal nutrition resulting in low birth weight has been identified as a factor contributing to later insulin resistance and T2D. Recent data indicate that current overweight and obesity are stronger determinants of insulin resistance than birth weight among preschool children. High-nutrient diet and rapid growth in early infancy have been reported to adversely programme the principal components of the metabolic syndrome including insulin resistance and T2D. It is an important scientific and public-health objective to define protective and predisposing effects of early nutrition on the development of diabetes, since early feeding can potentially be modified to minimise the risk of later chronic diseases.