Beta-casein Variants and Type 1 Diabetes: Type 1 diabetes and environmental modifiers

Type 1 diabetes mellitus (DM-1) is widely understood to be caused by an autoimmune process that destroys the insulin-secreting beta-cells in the pancreatic islets (1). While it is accepted that genetic factors play a key role in its development, environmental and nutritional factors are believed to be modifiers (2-4), as only ~5% or fewer subjects with genetic susceptibility to DM-1 develop the clinical disease (5). In Australian children, DM-1 incidence increased significantly between 2000-2004, from 19 to 24 new cases per 100,000 of the population (6), a trend that is reflected globally (7). There are major regional and between-country differences in the incidence of DM-1 (8), and even between high income OECD countries the incidence varies by a factor of more than 20 (9). These differences have been shown to correlate with milk consumption in general but particularly with intake of A1 beta-casein (10-14). Various case-control and prospective cohort studies support the hypothesis that exposure to cow’s milk during infancy and childhood is a potential environmental modifier in DM-1 development (15-21), but other studies have been inconclusive (22-24). Some of the variation between study results may be explained by differences in milk protein composition within different countries (14, 25) or by weaning practice variations in some countries (e.g. to hydrolysed formula) (22, 23, 26). A recent double-blind, randomised trial of the first nutritional primary prevention study for DM-1 (TRIGR) has found that autoantibody development can be delayed by giving hydrolysed formula (rather than regular cow’s-milk formula) during the first 6–8 months in 'at-risk’ infants (1). Several studies report that breast feeding is protective (15, 27-29).

Milk protein A1 beta-casein implicated as a risk factor

A range of studies in developed countries have found that most of the between-country differences in the incidence of DM-1 can be explained by intake levels of the specific milk protein variant A1 beta-casein (11-14), and that this is a much stronger explanatory factor than total milk protein consumption per se (11, 13). In this document, we review the evidence that A1 beta-casein is a risk factor for DM-1.

A1 beta-casein and its digestion product beta-casomorphin-7 (BCM-7)

Beta-casein makes up approximately 30% of the total protein in cow’s milk (30), or around 2.5 grams per 250ml glass. There are two major genetic variants of beta-casein: A1 and A2. The difference between the A1 and A2 beta-casein variants is a single amino acid substitution at the 67th position of the 209 amino acid chain. This difference in structure results in A1 beta-casein preferentially releasing an opioid peptide called beta-casomorphin-7 (BCM-7) upon digestion (Figure: 1). BCM-7 has demonstrated potential to elicit opioid activity on a range of tissues and organs via its affinity to mu- and delta-opiate receptors (31, 32).

t1d-release
Figure 1: Release of beta-casomorphin-7 [adapted from reference (33)].

A1 beta-casein consumption correlates significantly with DM-1 incidence

Ecological evidence across 20 developed nations, and within regions of Germany and Scandinavia, show strong correlations between the consumption of A1 beta-casein and the incidence of DM-1: correlation coefficients range between 0.87 to 0.98 (Figure: 2) (11-13, 34). In addition, a recent study reported that A1 beta-casein consumption during early childhood may be more important than during adolescence for DM-1 development (14). Birgisdottir et al. (2006) compared A1 beta-casein consumption among 2-year olds and among 11 to 14-year olds in Iceland and Scandinavia (i.e. Norway, Denmark, Sweden and Finland) and evaluated this against the incidence of DM-1 (14). For the 2-year olds, but not the 11 to 14-year olds, A1 beta-casein consumption correlated strongly with DM-1 incidence (r=0.9; p=0.037).

t1d-correlation
Figure 2: Correlation of A1 beta-casein per capita (excluding cheese) in grams/day and new cases of DM-1 in 0 to 14-year olds between 1990-94 (r=0.92, 95% CI: 0.72-0.97) (p<0.0001). Dotted lines are the 95% confidence limits of the regression line [adapted from reference (13)].

A1 beta-casein reported as diabetogenic following animal trials

Results consistent with data from ecological studies have also been reported in animal feeding trials. These studies suggest a link between A1 beta-casein consumption and the development of DM-1 (35, 36). BCM-7, an exogenous opioid peptide derived from A1 beta-casein, has been implicated as one of the possible mediators, as the diabetogenity of A1 beta-casein is attenuated by naloxone (36), the specific opiate blocker.

Human Data: Milk and A1 beta-casein in DM-1 cases

Various case-control studies (15-18, 21, 28) suggest that exposure to cow’s milk is linked to the development of DM-1. In addition, the magnitude of exposure to cows’ milk, rather than early exposure per se, may be a factor (20, 21). This was demonstrated in the results of a Finnish case-control study, which showed that children with DM-1 (n=33) had a greater likelihood of high milk consumption (>540 mL/milk/day) [odds ratio 5.37, 95% CI: 1.6 to 18.4] compared to controls (n=254) (21). A limited number of human trials also suggest that beta-casein may stimulate a T-cell immune response (37-39) or an antibody immune response in the development of DM-1 (40, 41). For instance, Monetini et al. (2001) showed significantly higher levels of antibodies to beta-casein in bottle-fed infants (n=12) under 4 months of age compared with exclusively breast-fed infants (n=16) (p<000.1), and significantly higher levels of antibodies in prepubertal children with DM-1 (n=37) compared to age-matched controls (n=31) (p=0.03) (41). How this should be interpreted is open to debate. It is possible that this is a manifestation of those with DM-1 being particularly sensitive to antibody reactions. However, in one of the only human studies to investigate differences in antibody response to A1 and A2 beta-casein, Padberg et al. (1999) showed that the ratio of A1 to A2 beta-casein antibodies was higher in those with DM-1 compared with case controls (p<0.001) (42). These results suggest that A1 beta-casein may be a modifier in the development of DM-1 in ‘at risk’ individuals.

Commentary

There are two possible mechanisms by which A1 beta-casein may contribute to the development of DM-1. The first relates to the opioid activity of the A1 beta-casein derived BCM-7, while the second relates to the potential molecular mimicry (or cross-reactivity) between beta-casein, and an epitope of the pancreatic beta-cell glucose transporter GLUT-2 (39, 43), as autoantibodies to GLUT-2 have been described in patients with recent-onset DM-1 (44). In terms of the first possibility, it is hypothesised that BCM-7’s opioid characteristics might contribute to the impairment of the development of gut-associated immune tolerance in ‘at risk’ individuals and as such “it might act as an adjuvant in the autoimmune reaction involved in the destruction of beta-cells in prediabetic subjects” (2, 32, 36, 45). This is supported by the attenuation of A1 beta-casein’s apparent diabetogenicity following the administration of the opioid antagonist naloxone (36). The second mechanism involves the potential antigenic determination characteristic of beta-casein, which may lead to the autoimmune destruction of pancreatic beta-cells (43, 44). More specifically, Cavallo et al. (1996) have suggested that there may be molecular mimicry between a sequence of the beta-casein protein and an epitope of the GLUT 2 transporter (39), which may give rise to autoantibodies capable of targeting pancreatic beta-cells.

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