Beta Caseins and Type 1 Diabetes
This section summarises the reported linkages between the consumption of milk protein variant beta casein A1 (A1) and development or incidence of type 1 diabetes; also known as Insulin dependent diabetes mellitus (IDDM), diabetes mellitus 1 (DM1), or childhood onset diabetes.
The linkages can be divided into three categories as follows:
- Epidemiology, which involves calculating the per capita intake of A1 (by way of milk consumption coupled with either milk analysis or herd gene frequency data) before comparing it with the incidence of disease;
- Studies which test A1- IDDM hypothesis by feeding trials utilising animal models of disease; and
- Other studies which include those that link beta caseins to immune response.
Although a number of animal feeding trials have produced results which support a causal relationship between A1 consumption and the development of diabetes, some investigations have been inconclusive. It could be reasoned that this is the case due to two possible causes:
- The inadequacy of the model to replicate the disease state in humans. Both the NOD mouse and BB rat models develop diabetes spontaneously through genetic deficiencies. One cannot assume these are the same as those in humans, which are yet to be completely discovered or understood.
- The diets which the animals were fed may not have been fully defined with regard to their exogenous opioid content. Such agents have been implicated in disease causation and it is know that similar agents are derived from cereals. Furthermore, in an internal report produced by a group associated with the 2002 study [1], it was noted that the hydrolysed protein (Pregestimal), which was used in this study as a control and supplement, contained high levels of the exogenous opioid beta casomorphin 7.
It could be observed that there are dual hypotheses with regard to the causative role of beta casein variants on the development of IDDM: one involving the opioid activity exhibited by BCM-7; the other concerning a possible antigenic determining role of beta casein in auto immune reactions.
Regardless, the firm relationship suggested by two independently performed epidemiological studies is not only consolidated by results from animal trials but also by a rapidly developing understanding of A1 derived BCM-7 and its biological characteristics (Studies on the Differential Digestion Products of beta casein types). The most well characterised function of this peptide is as an effector of opiate receptors, however it has also been shown to catalyse the oxidation of LDL and elicit effects not attributed to opioid function.
Epidemiology
An interest in the possibility that milk proteins may play a role in IDDM began in 1984 with the observed increase in its incidence among Western Samoan children coming to live in New Zealand. A review of contrasting environmental factors indicated that a significant difference in their diet was that the children consumed more cows' milk in New Zealand than in Western Samoa. [2]
Elliott et al. (1999) reported a regression coefficient of 0.72 in the plotted linear relationship between A1 consumption and incidence of IDDM. This relationship is stronger than that exhibited by other individual milk proteins, or the combined total milk proteins. [3]
Two years later, McLachlan (2001) published a paper pointing out that the calculated consumption of A1 across 16 countries correlated strongly (r2 = 0.75) with the incidence of IDDM in males under 15 years old [4]. In 2003, Laugesson and Elliott, examining the same relationship between A1 and IDDM, ratified this observation across 20 countries. [5] The latter of these two reports attracted an editorial in the NZ Medical Journal which encouraged that the presented hypotheses concerning A1 consumption and both IDDM and IHD be investigated further [6].
A paper published in 2002 concerning the measured levels of a number of milk protein variants across 5 Nordic countries compared with the incidence of IDDM concluded that beta casein A1, and not other milk proteins examined (bovine serum albumin, immunoglobulin G, lactoferrin), may contribute to observed variation in the diabetogenicity of cow's milk [7]. This paper stemmed from a doctoral thesis, which reported that the consumption of A1 by children (as opposed to adolescents) showed a regression coefficient of 0.9 (r2 = 0.81) in its relationship to type 1 diabetes [8].
A further study across the 5 Nordic countries has shown that this strong correlation between A1 consumption and type 1 diabetes was found in children under 2 implicating early childhood consumption of A1 in the incidence of type 1 diabetes. [9]
Animal Trials
An early animal study examining the possibility of a relationship between milk protein consumption and diabetes was conducted by Elliot and Martin (1984). This study involved feeding BB rats with milk protein or an amino acid diet. Elliott and Martin concluded that cows' milk may contain a diabetogenic agent [10]. A further study by Elliott conducted in 1992, showed that rather than all milk being causative of Type 1 diabetes, it was possible that there was a link between digested casein, and more specifically a hexapeptide peptide derived from digested beta-casein protein, and Type 1 diabetes [11]. The implication of a bioactive protein fragment generated by the digestion of beta casein A1 was then reported in 1995 [12], when, in an article title referring to beta casein variants as 'Jeckyl & Hyde', it was further noted that this peptide bound macrophages and had known immunological activity.
Supplementing previous research concerning the link between the A1 variant of the beta casein protein and Type 1 diabetes was a further study presented by Elliott in 1997, which reported that mice fed beta-casein A1 developed high levels of Type 1 diabetes, whereas those fed beta casein A2 did not [13], [14]. This study further implicates BCM-7 and its associated opioid activity as it reports that the diabetogenity is attenuated by naloxone, a specific opiate blocker.
BCM-7 was further implicated as the causative agent in a report published in the journal Diabetologia in 1999 [15]. A comprehensive summary of BCM-7 can be found in Section 2.
A publication encompassing a range of trials involving both the BB rat and NOD mouse, animal models of diabetes, was published in 2002 [16]. Its findings with regard to disease causation were inconclusive (discussed in Introduction to section). However, it did consider the possibility that, although it seems unlikely that a casein variant is an exclusive promoter of diabetes, it may enhance the outcome is some cases. It is of interest that wheat proteins were exemplified as promoters of diabetes in the conclusion of this paper, as wheat gluten, like A1, is a known source of a food derived exogenous opioid. [17]
Other Reports
Supporting the notion that some children may be more prone to A1 facilitated development of Type 1 diabetes, a genotype was identified that appears to predispose infants who have a high consumption of cows' milk to the development of IDDM [18].
A review by Pozzilli, published in 1999, considered beta casein as a major antigenic determinant for type 1 diabetes. Although he was not considering particular variants (i.e. A1 or A2), Pozzilli stated that beta casein is a good candidate milk component to explain the observed association between cow's milk consumption on IDDM. [19] This assertion was based on the hypothesis that the immune system produces antibodies to epitopes of beta casein, or fragments thereof, that are homologous to regions of GLUT2 (glucose transporter) on the beta cells of the pancreas.
Modifications to protein secondary structure imparted by single amino acid differences (such as between A1 and A2 variants) may warrant some consideration. More specifically, a small change in structure may expose an epitope in A1 which initiates the formation of auto antibodies.
A subsequent familial study measured and differentiated antibodies against A1 and A2 casein variants in four groups of people: IDDM patients, their siblings, individual parents, and healthy controls. It was found that antibodies against casein were present in all four groups, with the highest titres being found in diabetics. Increased amounts of anti-casein A1 antibodies were found among patients with IDDM and their siblings. On the other hand, the serum samples from parents and control persons contained antibodies against the A2 variant. This observation serves to underpin the linkage between A1, the exposure revealed by antibody response, and diabetes. [20]
The above studies were later supplemented by a publication addressing beta casein as an antigenic determinant for a range of auto immune disorders. It concluded that beta casein may be relevant in the development of autoimmune diabetes. [21]
References:
[1] National business Review, NZ. 28 November 2002
[8] Birgisdottir, 2003. Doctoral Thesis. Influence of Nutrition on prevention of diabetes mellitus. University of Iceland.
[11] Elliott, et al. 1992. In: Genetic and Environmental Risk Factors for Type 1 Diabetes (IDDM) including a discussion on the autoimmune basis. Ed. Laron and Karp. London. pp 57-61
[12] Elliott and Hill, 1995. Diabetes Prevention and Therapy. 9(1): 1-2
[13] Elliott, Wasmuth and Hill, 1997. 16th IDF Congress Helsinki
[14 ]Elliott, Wasmuth, Bibby and Hill. 1997, 58th Annual Meeting and Scientific Session, American Diabetes Association
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