Уважаемый коллега,
пожалуй самое недавнее по теме о роли инсулина в женском молоке описано в этой статье:
Pediatr Allergy Immunol. 2006 Nov;17(7):538-43.
Dietary insulin as an immunogen and tolerogen.
Имея под рукой полный текст, здесь приведу Вам ее фрагменты: введение и дискуссию, если нужна будет целиком сообщите мейл через ЛС
Dietary exposure to bovine insulin (BI) in cow's milk (CM) induces both a humoral and cellular immune response in infants (1, 2). Immunization to insulin, reflected by antibodies to BI, is associated with, but not predictive of, progression to clinical type 1 diabetes (T1D). BI differs from human insulin (HI) by three amino acids and has been reported to be a stronger immunogen in humans than HI (3–5). We have previously shown that the development of insulin antibodies in children is modified by various factors, such as maternal T1D (2), maternal diet during breast-feeding (6) and infections during the first months of life (7). Maternal T1D was associated with a decreased immune response to dietary insulin in infants (2). We hypothesized that insulin transferred from the maternal circulation to the fetus complexed to insulin antibodies of immunoglobulin G (IgG) class may promote tolerance induction to dietary insulin. Alternatively, exogenous insulin treatment could induce tolerance in the child if insulin is present in breast milk, either free or antibody-bound. In another study (6), maternal avoidance of CM products during the first 3 months of breast- feeding was associated with higher levels of insulin antibodies at 18 months of age in children, suggesting that ingestion of BI-containing foods during lactation may support the development of insulin-specific tolerance in the offspring. CM-derived antigens have been demonstrated to be immunogenic in infants diagnosed with CM allergy during exclusive breast-feeding (8, 9). Similarly, immunogenic levels of dietary CM insulin could be present in breast milk.
HI in breast milk may support the maturation of the intestinal epithelium, analogous to observations in a rat model (10, 11). Accordingly, breast milk insulin could modify oral immune responses by its direct effect on the mucosa. HI in breast milk may also have a role as a tolerogen. Despite HI as a self-antigen expressed in thymus, insulin-specific immune responses might be present in humans indicating that the mechanisms of peripheral tolerance are involved in the control of this response. HI in breast milk could modify immunity to dietary insulin by inducing oral tolerance to insulin, similarly as reported for other oral antigens (12).
------------
The presence of insulin and other serum proteins and hormones in breast milk has been demonstrated previously in different species (15, 16). Insulin is an important growth factor that has been shown to support the development of epithelial cell lining in the intestine (10, 11). Little is known about the role of milk insulin as a mucosal antigen. However, oral antigen administration has been studied in the treatment and prevention of immune-mediated diseases (17). Our results here suggest that the concentration of breast milk insulin modifies the levels of insulin-binding IgG antibodies induced by dietary CM insulin in infants. Thus, higher concentrations of breast milk insulin were associated with lower levels of BI antibodies in the subjects studied. This kind of inverse association between breast milk insulin and antibody response to insulin in children was only seen at 6 months of age in children who received CM-based formula and not in children who received casein hydrolysate, which does not induce such high levels of insulin-binding antibodies in the infants (1, 2). Only later at 12 months of age, when all children were exposed to CM proteins, an inverse correlation was seen in the entire study group. This suggests that HI in breast milk is tolerogenic, whereas dietary BI, which differs from HI by three amino acids, is immunogenic in humans. The difference of three amino acids between HI and BI has been shown to make a difference in relation to several aspects of the insulin-specific immune response. In patients with T1D, treatment with BI induced high levels of insulin antibodies, which decreased after switching to pork insulin (3, 18). In mice expressing transgenic HI in the islets, BI but not HI was immunogenic (19). Following DNA vaccination, a difference of only one amino acid between the two insulin molecules in position 30 of the insulin B-chain determined protection from T1D (20). Furthermore, various species of insulin differ with regard to the induction of antibody production and functional T-helper cell subtype (21). Also, the epitope specificity and avidity of CD8-cells induced by various insulin molecules differ (22).
In humans, BI in CM-based formula induces higher levels of insulin IgG antibodies than HI does in breast-fed infants (1, 2). Instead, HI in breast milk seems to be tolerogenic and may downregulate the IgG response to dietary BI as suggested by our data. In our previous study (7), the levels of insulin-binding antibodies in children showed an association with the extent of CM exposure and breast-feeding. We found that the highest levels of IgG class insulin antibodies at 3 months of age were observed in infants who had not been breast-fed and received only CM-based formula, whereas moderate levels were seen in children who received both breast milk and CM-based formula, and exclusively breast-fed infants had the lowest levels of insulin antibodies. It is possible that breast-feeding modifies the response to CM insulin, as it has been shown to modify the response to wheat gluten and the development of celiac disease (23). Our results indirectly support the view presented by others that HI added to CM-based formula could enhance oral tolerance to insulin (24), but the potential impact of this phenomenon in the prevention of T1D still remains open.
In contrast to the tolerogenic effect of breast milk insulin, our observations in children who developed beta-cell autoimmunity suggest that in this subgroup of children breast milk insulin does not promote tolerance. The highest levels of breast milk insulin were detected in children who developed beta-cell autoimmunity, even though the children were matched for maternal T1D. We have shown that aberrant gut immunity, e.g., enhanced immune activation, is associated with T1D (25, 26). Recently children with T1D were reported to show an aberrant intestinal immune response to gliadin when their intestinal biopsies were studied after gliadin challenge (27). Thus, children prone to develop beta-cell autoimmunity may represent a subgroup of children who are not able to develop oral tolerance to insulin, and their responses to insulin may be enhanced by breast milk insulin.
We used a sandwich-EIA method to detect insulin in breast milk samples. There are no available assays to specifically measure BI or HI because the antibodies against BI and HI show substantial cross-reactivity between the two insulin molecules. Most likely breast milk samples contain both HI and BI, with the latter derived from maternal diet. CM contains, however, BI maximally 0.33 mg/l (15). If a mother is challenged to CM, which contains β-lactoglobulin at a concentration of approximately 3.6 g/l, β-lactoglobulin will be present at a median concentration of 0.12 μg/l (range 0.01–7.84 μg/l) in her breast milk (9). Accordingly, the BI concentrations in human breast milk must maximally be in the range of nanograms/liter. Based on this, we conclude that a majority of the insulin detected in human breast milk must be of human origin. The T1D mothers on daily insulin injections had higher levels of insulin in breast milk than the non-diabetic mothers as reported earlier by Jovanovic-Peterson et al. (28). Patients with T1D often have higher plasma insulin levels than unaffected individuals and this is likely reflected in breast milk insulin concentrations. Because breast milk insulin concentrations show an inverse association with circulating insulin antibody titers in infants, our previous findings of decreased insulin-specific immunity in infants of diabetic mothers (2) may be explained by increased postnatal exposure to oral insulin when breast-fed. The risk of T1D is lower in children of diabetic mothers than fathers (29), and postnatal oral tolerization to insulin via breast milk during infancy may be a contributing factor.
We conclude that breast milk-derived insulin seems to modify the humoral responses to dietary BI towards tolerance. However, high levels of breast milk insulin were associated with beta-cell autoimmunity in some infants suggesting that breast milk insulin may not promote tolerance to insulin in children prone to beta-cell autoimmunity.