Cow's milk formula feeding induces primary immunization to insulin in infants at genetic risk for type 1 diabetes.

Abstract

Insulin autoantibodies (IAAs) often appear as the first sign of islet cell autoimmunity in prediabetic children. Because cow's milk contains bovine insulin, we followed the development of insulin-binding antibodies in children fed with cow's milk formula. Bovine insulin- and human insulin-binding antibodies by enzyme immunoassay and IAA by radioimmunoassay were analyzed in 200 infants carrying HLA-DQB1*0302 but no protective alleles who participated in a Finnish population-based birth-cohort study. Based on the prospectively registered information, the first 100 infants enrolled in the study who were exposed to cow's milk formula before age 12 weeks and the first 100 infants enrolled in the study who were exclusively breast-fed for longer than their first 12 weeks of life were selected for the present study. Also, 11 children from the birth cohort who developed at least two diabetes-associated autoantibodies, 98 children with newly diagnosed type 1 diabetes, and 92 healthy children were studied. We found that the amount of IgG-antibodies binding to bovine insulin was higher at age 3 months in infants who were exposed to cow's milk formula than in infants who were exclusively breast-fed at that age (median 0.521 vs. 0.190; P < 0.0001). The antibodies binding to bovine insulin cross-reacted with human insulin. None of these infants tested positive for IAA. The levels of bovine insulin-binding antibodies declined in both groups at ages 12 and 18 months, whereas in the 11 children with at least two diabetes-associated autoantibodies the levels increased during the follow-up period (P < 0.0001). IgG antibodies correlated with IgG2 antibodies binding to bovine insulin (r = 0.43, P = 0.004) and IAA (r = 0.27, P = 0.02) in diabetic children, but not in healthy children. Cow's milk feeding is an environmental trigger of immunity to insulin in infancy that may explain the epidemiological link between the risk of type 1 diabetes and early exposure to cow's milk formulas. This immune response to insulin may later be diverted into autoaggressive immunity against beta-cells in some individuals, as indicated by our findings in children with diabetes-associated autoantibodies.

Effect of coincident enterovirus infection and cows' milk exposure on immunisation to insulin in early infancy

“…We confirmed the observation that early feeding of cows' milk formula induces IgG-antibodies binding to bovine insulin [3,4]. In the infants exposed to cows' milk formulas before the age of 3 months, increased concentration of antibodies to bovine insulin at 6 and 9 months of age were associated with a positive T-cell response to enterovirus antigen at 3 months age.…”

“…EIA for bovine insulin-binding antibodies was carried out as described [3,4]. A p value below 0.05 was considered significant.…”

Short-term exclusive breastfeeding predisposes young children with increased genetic risk of Type I diabetes to progressive beta-cell autoimmunity

“…This supports an association between exposure to cows' milk and Type I diabetes [12,13], whereas the data on T-cell responses to proteins of cows' milk remains controversial [14]. Cows' milk was recently reported to be an environmental trigger of an immune response to insulin during infancy [15].…”

Serum fatty acids and risk of advanced β-cell autoimmunity: a nested case–control study among children with HLA-conferred susceptibility to type I diabetes

“…In addition, the amount of cow's milk used later in childhood could be related to the risk of type I diabetes (Verge et al, 1994;Virtanen et al, 2000;Wahlberg et al, 2006). It has been suggested that either milk proteins or insulin in milk might trigger the immunization leading to type I diabetes (Vaarala et al, 1999;Schrezenmeir and Jagla, 2000) However, until now there is no unequivocal evidence for a mechanism or for the fraction of milk that possibly facilitates progression to type I diabetes.…”