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In animal models it is possible to manipulate the environment to assess the relevance of various factors in the development of a disease. In genetically susceptible rats and mice, exposure to certain viruses and toxins can alter the proportion developing Type 1 diabetes (Mordes et al. 1987). In the BB rat, diet influences the later expression of diabetes (Scott et a i 1988). Minor differences in temperature have also been shown to influence the rate of diabetes in the NOD mouse model, with higher incidence in those kept in a cooler environment (Williams

et al. 1990).

4.6.2 Toxins and dietary factors In humans such experiments are obviously impossible, though 'natural experiments’ do occasionally occur. Ingestion of the rat poison PNU (N-3 pyridylmethyl N-p-nitrophenyl) -’Vacor’- results in an insulin- dependent form of diabetes (Prosser et al. 1978); maternal consumption of nitrosamine-rich foods such as smoked mutton around the time of conception is

associated with an increased incidence of Type 1 diabetes in the offspring (Helgasson et al. 1981). Indirect evidence of the role of dietary factors has come from the finding of significant correlations of the consumption of unfermented milk products and of coffee against the incidence of Type 1 diabetes in different countries (Scott, 1990; Tuomilehto et al. 1990). A recent, nationwide case-control study in Sweden has identified differences in protein and nitrosamine consumption in early life in children who develop Type 1 diabetes (Dahlquist et al. 1990).

Cow’s milk has been under suspicion for a number of years. Alteration of the protein components of laboratory chow can alter the incidence of diabetes in the NOD mouse and BB rat models. Animals reared on a diet free of cow’s milk for the first 3 months of life do not develop diabetes (Elliott et al. 1984). There is epidemiological evidence to support a role for these proteins in the aetiology of Type 1 diabetes. Several ecological studies have shown a correlation between national average cow’s milk consumption and the incidence of diabetes (Dahl-Jorgansen etal. 1991), a nationwide case-control study in Sweden found an increased level of protein consumption in children with diabetes (Dahlquist et al.

1990) and, in Finland, the risk of Type 1 diabetes was significantly lower in children who were exclusively breast fed for 3 months or in whom supplementary milk feeding was not introduced until they were more than 4 months of age (Virtanen

et al. 1991). Antibodies to bovine serum albumin were detected in all children in

a recent study, but the levels of IgG antibodies were significantly higher in children with newly diagnosed diabetes than in 79 normal children (Karjalainen etal. 1992). It has been suggested that a 17 amino acid peptide sequence in bovine serum albumin (ABBOS) may be the reactive epitope. This differs markedly from the equivalent sequence in man and other species, including the rat. Antibodies to this peptide cross-react with a beta cell specific surface antigen (p69) and an elegant hypothesis has been put forward whereby early exposure to bovine serum albumin, at a stage when it able to cross the immature gut wall, triggers an immune response against the ABBOS peptide in genetically susceptible individuals. The p69 antigen is only expressed on the cell surface when it is induced by gamma-

interferon during unrelated infectious events, but when these occur, the immune system is primed to attack the epitope that this antigen shares with the ABBOS protein. Repeated childhood infections would result in frequent exposure of this self antigen, setting the scene for a smouldering immune attack directed against the beta cell, with both relapses and remissions (Karjalainen et al. 1992). Delaying exposure to cow’s milk until the gut is mature and therefore impermeable to large peptides such as might this mean that anti-ABBOS immunity (and therefore anti- p69 immunity) could be prevented. Proponents of the hypothesis would add that the rapid rise in incidence may be due to changes in the processing of milk products, for example in the formulation of infant feeds. The milk hypothesis remains speculative but it seems promising, and can be tested.

4.6.3 Infective agents Infective agents, particularly viruses, remain the most popular and plausible environmental "trigger" setting off the autoimmune process that leads to Type 1 diabetes in genetically susceptible individuals. They are compatible with many of the epidemiological features of the disease. Despite much searching there remains no definitely identified infective agent causing Type 1 diabetes. The long ’incubation period’ of the disease makes it necessary to look for infection many years before the development of overt diabetes, perhaps in utero. The congenital rubella syndrome provides the strongest link between a virus and the development of Type 1 diabetes. Ginsberg-Fellner et al found that 30 of a cohort of 242 (12%) had developed apparently typical insulin-dependent diabetes, while a further 17 had impaired glucose tolerance (Ginsberg-Fellner et ai. 1985). It is not yet clear as to whether these children have true Type 1 diabetes. Cytomegalovirus (CMV) a relatively common, subclinical intra-uterine infection, has recently been associated with autoimmune type 1 diabetes. A child with congenital CMV infection developed diabetes at the age of 13 months (Ward etal. 1979) and CMV inclusion bodies have been found in the beta cells of children dying of disseminated CMV infection (Jenson et al. 1980). Pak and colleagues have reported that, using nucleic acid hybridisation techniques, CMV specific viral genome was found in the lymphocyte DNA of 22% of newly diagnosed diabetic

patients compared with 2.6% of controls (Pak et al. 1988). This could be the result of transmission of infection in the gametes if viral DNA has been incorporated into the parents genome. It could also be the result of infection transmitted through the placenta or acquired postnatally. Infection in infancy, when the immune system is immature, is particularly likely to result in persistent viral infection (Haywood, 1986). There have also been links with coxsackie B4 and B5, with reports of high titres of antibodies against these viruses in up to 60% of new cases of Type 1 diabetes (Barrett-Connor, 1985). Since these are taken to represent recent infection, and the disease is known to have a long latency, their role is probably to precipitate clinical diabetes in those with established beta cell damage.

4.6.4 Conclusion:

In conclusion, environmental factors probably play an important role in the development of childhood diabetes in genetically susceptible individuals although (and despite much speculation) the nature of the environmental agent or agents responsible is unknown. Since almost 50% of all cases occur by the age of fifteen, and the disease is known to have a long incubation period, exposure to an environmental agent would need to occur early in life or perhaps even in utero. Contact with the agent might trigger a series of autoimmune processes which eventually result in beta cell destruction. An alternative hypothesis would be that most or all genetically susceptible individuals undergo some form of subclinical damage to their beta cells, and that the role of environmental agents is to sustain or enhance this to the point of clinical diabetes. Current research into the pathogenesis of Type I diabetes is directed towards reliable detection before the onset of glucose intolerance, in the hope that the disease can be aborted at this early stage. True prevention of diabetes is a much longer term objective, and despite present uncertainty, is most likely to be achieved by the epidemiological approach.

CHAPTER 5 - METHODS OF INVESTIGATION: FAMILY STUDIES