The Great Milk Peptide Debate

During digestion, dietary proteins are typically hydrolyzed to di- and tri-peptides for absorption and utilization. Interestingly, some bioactive peptides cross the mucosal barrier to mediate a physiological response at various molecular targets within several systems. Cardiovascular, nervous, digestive, and immune systems are among those targeted by some of these unique peptides (Korhonen, H. and Pihlanto, A., 2007).

Among the thousands of physiological proteins, one protein associated with diabetes is of particular interest. That protein is the hormone insulin, which is secreted by specialized cells in the pancreas. Insulin promotes the absorption of amino acids and glucose by tissues, the cells of which subsequently utilize the nutrients for an array of metabolic functions. Some investigators suggest that the etiology of type 1 diabetes (T1D) is linked to pancreatic inflammation, immunological perturbations initiated by dietary antigens, and/or the body’s inability to differentiate between self and foreign proteins and the gut-associated immune system (Leech, S., 1998; Vaarala, O., 2008).

Elliott (1992, 1999) suggested that food-derived peptides, specifically those derived from milk, may have an adverse effect on health by increasing the risk of insulin-dependent diabetes among Polynesian children. This position was based on the relationship of T1D and the consumption of variants A1 and B β-casein from cow’s milk. The authors noted that β-casomorphin (BCM-7) from β-casein may function as an immunosuppressant and impair tolerance to dietary antigens in the gut immune system, which may contribute to the onset of T1D. However, numerous international clinical studies over the past decade do not support that association.

Other epidemiological assessments of dietary peptides from meat, poultry, fish, cereals vegetables, and bacteria sources, suggest some of these are bioactive and can mediate effects on blood pressure, immune system, mineral transport, and possibly function as antagonists or agonists of opioid receptors (Teschemacher, H., 2003). Food opioid peptides, also known as exogenous opioids or exorphins, have been identified based on their amino acid sequences and bioinformatic screening. Classic pharmacological bioassays have confirmed their opioid activity, yet, in most cases, the binding affinities were several orders of magnitude less than controls, such as morphine and its derivatives. However, the pharmacology of these compounds has not been extensively studied.

There are 13 genetic variants of β-casein in dairy cattle. Among those variants are A1, A2, and B, which are also found in human milk. The amino acid sequences of β-casomorphins among these bovine variants and those found in human milk are similar, often differing only by a single amino acid. In in vitro studies, BCM-7 can be produced from A1 and B during typical digestive processes; however, BCM-7 is not a product of A2 digestion. Yet these in vitro observations were inconsistent following digestion in the gut of humans, and quantification of these hydrolytic products has not been reported. However, depending on the proteolytic systems applied in milk fermentation and cheese production, BCM-7 can be produced.

Several systematic reviews examined the potential health effects of dairy products and the impact of β-casomorphins and related peptides on health (Ovensen, L., 2004; Swinburn, B. et al., 2004; Truswell, A.S., 2005; de Noni, I. et al., 2009). These reviews acknowledged that case studies suggested early milk consumption by children may predispose them to T1D; these results were not confirmed through prospective studies.

Another four prospective studies indicated that consumption of low-fat dairy products was associated with a decreased risk of type 2 diabetes, an adult-onset disease. These conclusions were supported by the most recent review by the European Food Safety Authority (EFSA, 2009). Upon examination of an array of environmental and genetic factors that contribute to diabetes and immunological responses to cow’s milk proteins, particularly β-casomorphin 7, EFSA stated that the suggested milk protein and T1D link remains unclear, and the implications of the variants difficult to interpret.

Additional evidence against the role of milk proteins, even breast feeding, and the development of T1D was provided through epidemiological studies and animal models (Schrezenmeir, J. and Jagla, A., 2000; Pozzilli, P., 1999). Other reports argue the A1 variant of β-casein is diabetogenic (Merriman, T.R., 2007; Allison, A.J. and Clarke, A.J., 2006). These reports advance biological data indicating A1 β-casein antibody titers were greater among T1D patients vs A2 β-casein titers, the differences of which were significant when compared to controls and parents. However, it appears that the antibody titers were not specific to T1D. On the other hand, ecological data, primarily based on A1/A2 variations among livestock breeds, do not demonstrate causation, even among countries where there is considerable dairy consumption.

T1D is an autoimmune disease that is on the rise in Europe and the United States (Bruno, G. et al., 2009; American Diabetes Association, 2009). Globally, T1D is the second-most-common chronic childhood disease after allergies. For those in the United States who are younger than age 20, about one in every 400 to 600 has TID, and 2 million adolescents (or one in six overweight adolescents) ages 12–19 have pre-diabetes.

Many hypotheses have been advanced to the etiology and apparent increase in T1D, particularly in developed countries. Our diets contain a broad range of biologically active peptides. Dairy products provide an array of nutrients necessary for normal growth and development of children and adolescents. Yet, the dairy debate continues with respect to an apparent T1D and BCM-7 association. As some milk producers change their bovine livestock to reduce those with the A1 and B alleles, the potential impact on milk composition and implications of these changes on public health remain to be determined.

References for the studies cited in this article are available from the authors.

by Roger Clemens, Dr.P.H.,
Contributing Editor
Scientific Advisor, ETHorn, La Mirada, Calif.
[email protected]

by Wayne Bidlack , Ph.D.,
Contributing Editor
Professor, California State Polytechnic University, Pomona 
[email protected]