Is Disease Prevention Possible

Although p-cell function can be preserved and extended beyond the time of diagnosis, there is little realistic hope of restoring normal metabolic function at this stage of the disease. it is therefore logical to attempt p-cell rescue at an earlier stage when the p-cell mass is largely intact. Work done over the past 25 years has transformed our understanding of the sequence of events culminating in immune-mediated p-cell failure, but the average diabetes specialist is still in the position of a nephrologist unable to identify renal dysfunction until his patients present for dialysis. Some 90-95% of children with type 1 diabetes have (HLA) human leukocyte antigen genotypes conferring susceptibility to the disease, but only around 5% of those with the highest risk combination will develop diabetes in childhood. Prospective studies have shown that islet autoantibodies typically appear within the first three years of life3, although this should not be taken as dogma, and the influence of maternal age upon risk of diabetes in the offspring strongly suggests that prenatal influences may also have a part to play4. Single islet autoantibodies have little prognostic significance, but a mature humoral immune response involving multiple epitopes of more than one islet antigen is now taken to presage almost inevitable progression to diabetes, even after decades have elapsed5. Siblings of a child with diabetes are some 15 times more likely to develop diabetes that those with no family history, and there is a corresponding boost in the prognostic significance of gene and antibody markers in this high-risk population. Family members therefore provide a convenient, accessible and highly motivated group for trials of new therapies.

Against the background of this information, intervention can be considered at three levels: before detectable abnormalities are present (primary intervention); after development of immune markers of progression but before the onset of hyperglycaemia (secondary prevention); and after presentation with overt hyperglycaemia (tertiary prevention). Primary prevention should be offered as early in life as possible; in practice from soon after birth. For the reasons given above, children born to a family affected by diabetes, especially those who carry high-risk HLA genotypes, are most appropriate for trial interventions. Safety is the major criterion for any form of primary prevention, since this will inevitably have to be offered to many who would not in any case have developed the disease.

The safest and most rational form of primary prevention would be modification of environmental determinants of disease. Leading candidates in type 1 diabetes are viruses and infant nutrition. The congenital rubella syndrome is sometimes cited as evidence that a virus can cause type 1 diabetes, and that type 1 diabetes can be prevented by routine rubella vaccination. It is, however, far from certain that children with this syndrome have typical type 1 diabetes, and some clearly have an insulin-resistant form of the disease. Associations between enteroviral exposure in utero and subsequent development of diabetes in the child6,7 raise the possibility that women might at some future date be vaccinated against a range of viruses, but the evidence base for such an intervention is far from established. The alternative environmental explanation, that exposure to cows' milk at an early stage of development might be diabetogenic, remains controversial8. The hypothesis is, however, susceptible to experimental testing, and a major multinational trial known as TRIGR (Trial to Reduce IDDM in the Genetically at Risk) is currently underway9. More direct forms of immune intervention in the newborn would appear unjustified at our present level of understanding of the disease process, although various forms of vaccination are under consideration.

Secondary prevention is based on prediction by means of circulating islet autoantibodies. The major trials described by Dr Skyler, DPT-1 (parenteral and oral insulin) and END IT (nicotinamide), were both based on the traditional islet cell antibodies (ICA) assay, and have confirmed its value as a predictive tool. Two developments, recognition of the predictive power of autoantibody combinations, and introduction of low volume radiobinding assays capable of automation, have advanced the field since then10. ENDIT, for example, screened >40 000 first-degree relatives in order to recruit 552 to a five-year placebo-controlled trial of high-dose nicotinamide. Reliance on ICA as the primary screening method meant inclusion of a proportion of lower-risk individuals who subsequently proved to carry no additional antibodies. In contrast, the vast majority of individuals with multiple autoantibodies will eventually develop diabetes5, and the increased efficiency of screening is such that two trials the size of ENDIT could have been mounted from the same screening population11.

ENDIT and DPT-1 have demonstrated the feasibility of large-scale controlled trials in antibody-positive first-degree relatives, but the logistics of these trials are on a continental scale, meaning that choice of one intervention might well delay the opportunity to test another by several years. Development of surrogate markers would help to overcome the scale and duration of trials based on progression to diabetes, but the development of cellular markers for this purpose is still in its infancy. For these reasons the current preferred strategy is to pilot interventions after diagnosis as a means of screening out those most suitable for use in major trials of secondary intervention2.

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