In terms of providing a long-term beneficial impact on type 1 diabetes, perhaps no greater effort could be realised than to identify a means to prevent the disorder, especially in the general population. This statement finds a strong rationale on many levels. First amongst these is the observation that approximately 85% of new onset cases of type 1 diabetes occur in the general population (i.e. those without a family history of the disease). Hence, any meaningful effort to impact this disease must target the general population. Beyond this, effective models for disease prevention in population-based settings already exist (e.g. childhood vaccinations). This said, population-based efforts for type 1 diabetes prevention face a series of difficult challenges including the lack of any known 'disease inciting agent', a failure to understand the immunological means by which type 1 diabetes develops, the financial costs associated with population based measures, as well as the difficult situation of having many (too many?) potential candidates for testing with no clear favourites. While difficult to envision how this goal might be achieved with the present state of affairs, the old adage 'an ounce of prevention is worth a pound of cure' is a driving principle, for many.
The increasing incidence and prevalence of type 1 diabetes around the world alongside its challenging public health burden, combined with recent scientific advances, have fostered a growing interest in the notion of general population studies. This, largely but not exclusively, is for the purpose of disease prevention.
The incidence of type 1 diabetes has been increasing for the last four decades in Europe, the United States and Australia. Even within this observation, what is most striking is that the disease is occurring much earlier in life. In European children aged 1 to 5 years, the incidence is increasing at a rate of 5.4% annually – a rate much higher than other age groups. This increase in incidence will lead to a doubling of the number of cases in that age group in Europe in this decade. In fact, projections suggest that children between the ages of 1 and 5 years will soon represent the peak age of onset of type 1 diabetes in several European countries. In addition to this earlier age of onset of type 1 diabetes, the disease is occurring increasingly in individuals who had been previously considered to be at low-moderate genetic risk, suggesting that there is now a lower threshold for developing the disease. It is this type of information, combined with the need to 'do something early' that drives interest in general population studies.
What general population studies will be performed in the future?
We know that the cause or 'etiology' of type 1 diabetes arises from contributions of both genetics and environmental factors, yet the aforementioned increases would appear likely to have arisen from environmental factors. We do not know, however, what specifically in the environment has changed; either more harmful factors are now present or something protective has been removed. This forms an ideal, but extremely difficult notion for investigation. One topic under intensive interest of recent involves the role of microorganisms, the so-called microbiota that reside in the gastrointestinal tract and live in a symbiotic relationship with the human body. Investigators are addressing whether the increasing incidence, earlier age of onset, and lower threshold of risk of development of type 1 diabetes is the result of a change in the microorganism composition within the intestinal tract that leads to an altered immune response (especially in early childhood). Possible explanations for a change in the makeup of the intestinal microbiota in early childhood include administration of antibiotics to mothers or infants, antibiotics in the food supply, changes in breast milk immune factors, or undefined environmental factors. Indeed, one major research initiative designed to test this, and other hypotheses is the international consortium – The Environmental Determinants of Diabetes in the Young (TEDDY). TEDDY, a prospective clinical study, is following approximately 8000 children who have increased genetic risk to sample their environmental exposures and assess their development of the beta cell autoimmunity associated with type 1 diabetes and the onset of the disease.
Primary versus secondary prevention of type 1 diabetes
Not all notions of prevention are created equal; indeed, two exist in the context of what will likely occur in settings of type 1 diabetes in the general population: primary and secondary prevention. 'Primary prevention' refers to the prevention of beta cell-specific autoimmune attack on the insulin-producing beta cells in the pancreas that is associated with type 1 diabetes. 'Secondary prevention' refers to the prevention of insulin dependence in at-risk individuals after the onset of beta cell-specific autoimmunity.
The potential future for primary prevention
Primary prevention of type 1 diabetes will likely focus in the near future on developing vaccines for universal infant and childhood immunization, which are likely the most cost-effective approach to the prevention of type 1 diabetes. This said, the question arises as to what form of vaccine would one develop? First amongst the potential efforts would be to develop diabetes-related viral vaccines to prevent infection with viruses associated with the disease in multiple countries over time. A second choice would be to develop beta cell antigen-specific immunoregulatory vaccines that prevent the onset or progression of the autoimmune response associated with type 1 diabetes. Third would be a vaccine capable of augmenting or accelerating the aforementioned microbiome-induced immunoregulation in infancy. For any diabetes vaccine that is developed, both the safety and efficacy in preventing type 1 diabetes will need to be demonstrated in clinical trials.
The potential future for secondary prevention
We have come to appreciate that the onset of the autoimmunity associated with type 1 diabetes in childhood commonly begins in the first few years of life although overt diabetes with insulin dependence may not occur until years or even more than a decade later. This prolonged incubation period, which reflects gradual autoimmune destruction of beta cells, provides a window of opportunity for secondary prevention interventions to delay and ultimately prevent insulin dependence. Again, general population screening must become universal for the aforementioned reason that some 85% of new cases arise from this group. At present, such screening programmes are not deemed cost-effective, so future efforts must focus on this shortcoming.
In contrast to primary prevention with universal childhood intervention, secondary prevention will target specifically a subset of children who have evidence of onset of the beta cell-specific autoimmunity associated with type 1 diabetes. Childhood population-based screening will be required. Children who are identified as being at-risk will subsequently need to be followed to monitor their progression and to intervene to prevent the onset of overt type 1 diabetes with insulin dependence. In terms of what forms of therapy form candidates for population based interventions, these can be classified by those interventions focused on preserving the survival of beta cells by targeting alone or in combination: inflammation in and around the pancreatic islets; beta cell-specific autoimmunity; strengthening the health and survival of the beta cell directly; and/or addressing glucose intolerance and insulin resistance.
^ Skyler JS, Ricordi C. Stopping type 1 attempts to prevent or cure type 1 diabetes in man. Diabetes 2011;00:1–8
^ Gillespie KM et al. The rising incidence of childhood type 1 diabetes and reducted contribution of high-risk HLA haplotypes. Lancet 2004;00:1699–1700