A global survey published at the end of the century suggested that no population is exempt from childhood type 1 diabetes, but also documented a >350-fold difference in incidence rates. This overview has focused on Europe and North America, since information for the first half of the century could not be obtained from other parts of the world. The best evidence available suggests that childhood diabetes showed a stable and relatively low incidence over the first half of the 20th century, followed by a clear increase that began at some time around or soon after the middle of the century. This increase occurred around the same time in Scandinavia, the U.K., the U.S., and Sardinia but may have occurred later in other parts of the world. The majority of populations studied in the second half of the century have shown a rising incidence until the 1980s. Within Europe, a continued linear increase beyond this point has been reported from Finland, but other high incidence zones appear to have reached a plateau over the past two decades. The overall trend in Europe is however upwards, with the most rapid rate of increase contributed by former communist bloc countries in Central and Eastern Europe. Meanwhile, high incidence rates are now reported from a number of non-Europid populations -- Kuwait has the seventh highest rate in the world -- suggesting that genetic susceptibility may not vary as widely among ethnic groups as was previously believed.
The aim of this review has been to identify long-term changes in the behavior of this evolving disease rather than try to explain why they occurred. Some implications of this analysis do however deserve brief consideration. To begin with, a rising incidence in a stable population implies an etiological role for environmental factors. Since immune responses heralding later development of type 1 diabetes frequently appear within the first few years of life, the relevant environmental exposures are likely to be encountered very early in development. Since there is also good evidence for a long silent gap between initial exposure and onset of disease, factors modulating the rate at which the disease process unfolds may also be relevant. Genetic susceptibility will determine the probability of an unwanted outcome to the initial exposure, but additional environmental factors, possibly interacting with other genetic influences, may well modulate the rate of progression. For example, rapid growth in early childhood increases the risk of diabetes, possibly by increasing the work-load on ß-cells, and children grow considerably faster than they did a century ago. In 1970, Swedish boys were (depending on social class) 14.5-16.8 cm taller by age 15 years than in 1883. Early growth velocity and obesity may however be more important than final attained height in predisposing to diabetes. For whatever reason, an extremely rapid increase in the age-group under 5 years has been documented in some populations over the past 10-20 years[50,51,53,58].
Many attempts have been made to explain the rise of childhood type 1 diabetes over the past 30 years. A common starting point has been the assumption that something new has entered the childhood environment, and early nutrition or infection have seemed the most promising areas of enquiry. The leading hypotheses have related to early exposure to cow's milk or to enterovirus infection. Despite a wealth of indirect evidence, we still lack proof that either plays a major role in causation of the disease, and it has been plausibly argued that both exert their influence via modulation of the developing mucosal immune system. Breast-feeding patterns do not reflect changes in the incidence of childhood diabetes. Two of three American women breast-fed in 1911-1955, falling to 22% in 1972, and rising back to 60% in the 1980s and 1990s. There is little to suggest that this is in any way related to changes in the incidence of childhood diabetes. Equally, hypotheses based around enteroviral infection must take account of the fact that the proportion of women not exposed during pregnancy is increasing, and that infection in early childhood has become less common in the course of the century. These considerations do not exclude arguments based on changing antigenicity of feeds or viruses, or timing of exposure to them, but there is at present little evidence that antigens novel to the 20th century could explain the long-term trends described here.
The alternative possibility is that protective factors have been lost from the childhood environment. The hygiene hypothesis, initially developed to explain the parallel rise of asthma and allergy, argues that exposure to a range of infective agents in early childhood is necessary for successful maturation of the neonatal immune repertoire. In the absence of such exposure, a robust Th1 repertoire does not develop and potentially harmful Th2 patterns of response will persist in genetically susceptible individuals. Although this concept may prove unduly simplistic, lack of early stimulation could give rise to a failure of early immune regulation that might, according to genetic susceptibility, permit patterns of response predisposing to autoimmunity or allergy to develop at opposite ends of the Th1/Th2 spectrum. A number of recent reviews have attempted to link the rise of asthma and atopy to that of autoimmune disorders such as type 1 diabetes[65,66], and it is therefore of interest that an exhaustive survey of the early asthma literature also concluded that Scandinavia, Britain, the U.S., and Australasia showed an increase beginning in the early 1950s. Epidemiological evidence for the hygiene hypothesis is inconsistent for childhood type 1 diabetes, but it is notorious that the NOD mouse is less likely to develop diabetes in the presence of pinworms and other infections. Pinworm infestation was common in the childhood populations of Europe and North America around the mid-century, and this potentially protective exposure has largely been lost since that time.
Where is the increase coming from? An example may help to illustrate this point. Type 2 diabetes has appeared earlier in successive generations and now presents in teenagers. Although this trend mimics genetic anticipation, it is environmentally mediated, since increasing obesity within the population as a whole means that genetically susceptible individuals develop the disease earlier than they would in a less permissive environment. Has a comparable process, possibly with quite unrelated causes, occurred in type 1 diabetes? This view was first proposed by Kurtz et al. in 1988, based upon the data presented in Figure 3. An updated version of their proposal, which I refer to as the "spring harvest hypothesis," would go as follows: we may assume that the number of children with genetic predisposition to immune-mediated ß-cell injury has not changed to any great extent over time. A rise in childhood type 1 diabetes might then reflect increased exposure to isolated initiating factors in early childhood. Alternatively, the initial exposure might be widespread or even ubiquitous, resulting in a relatively common but indolent immune-mediated process. A more permissive environment would facilitate this disease process, thus producing a left shift in age at onset. Assuming a finite pool of susceptible individuals within the population, an increase in the younger age-group should be balanced by a reduction in the older age-group, and there is some evidence that this has occurred. Sequential Norwegian data, presented in Figure 4, show that the increase in the 0-14 year age-group has overtaken that in the 15-29 year age-group. Recent comparison of incidence trends in the 0-14 and 15-39 year age-groups in Belgium (1989-2000) and in the 0-14 and 15-34 year age-groups in Sweden (1983-1998) has shown that in both cases, the increase in the younger age-group has been balanced by a fall in the older age-group, with no overall increase in incidence[70,71]. The incidence of type 1 diabetes in later life remains conjectural, but a Danish study has estimated the lifetime risk as 1.5%. Given a susceptible subpopulation of this size, a small shift in the median age at onset could easily manifest as a major change in incidence in the younger age-groups. A further expectation of the spring harvest hypothesis can be tested. There is a strong inverse association between age at diagnosis and prevalence of HLA alleles conferring susceptibility to type 1 diabetes. A more permissive environment would be expected to increase the penetrance of susceptibility alleles, and this should be reflected in slow progressive dilution of the highest risk alleles characteristic of childhood-onset disease. Evidence of this effect could be sought in long-term population-based studies.
Incidence of diabetes in the 0-14 and 15-29 year age-groups in Norway at different time points in the 20th century. Data from refs. 18,33,35,76.
In conclusion, the quest to understand type 1 diabetes has largely been driven by the mechanistic approach, which has striven to characterize the disease in terms of defining molecular abnormalities. This goal has proved elusive. Given the complexity and diversity of biological systems, it seems increasingly likely that the mechanistic approach will need to be supplemented by a more ecological concept of balanced competition between complex biological processes, a dynamic interaction with more than one possible outcome. The traditional antithesis between genes and environment assumed that genes were hardwired into the phenotype, whereas growth and early adaptation to the environment are now viewed as an interactive process in which early experience of the outside world is fed back to determine lasting patterns of gene expression. The biological signature of each individual thus derives from a dynamic process of adaptation, a process with a history. René Dubos expressed this many years ago when he stated that "socially and individually the response of human beings to the conditions of the present is always conditioned by the biological remembrance of things past." We are indeed part of all that we have met.
The implications of the changing demography of type 1 diabetes for our understanding of the disease are considerable. From the point of view of the geneticist, it means that patterns of inheritance that confer susceptibility to immune-mediated loss of pancreatic ß-cells became progressively maladaptive in a late 20th century environment. For the immunologist, it implies that the ontogeny of the immune response in early childhood is changing in such a way that potentially harmful responses are now more prevalent, or more aggressive, in the subpopulation of genetically susceptible children. The task for the epidemiologist is to explain this. For the clinician, it means that childhood diabetes was in the past a partly preventable condition, and could become so again.
Many people helped me in preparing this review. Robert Tattersall allowed me access to material from his forthcoming history of diabetes, and Kirsten Kyvik and Jan Östman guided me to early sources in Norway and Sweden. Kristian Hanssen helped me with information about the work of his father, Per, and Knut Westlund sent additional material, adding "you must be joking" when asked for a photograph! Finally, the author gratefully acknowledges the early investigators, now almost wholly forgotten, whose work made this analysis possible. Representative of these is Per Hanssen, whose 1946 thesis proved invaluable. I worked from a signed copy presented by the author to the Danish Nobel Laureate August Krogh. The great man had not bothered to cut the pages. He should have done so; a good study shines like a beacon in the archives.
Diabetes. 2002;51(12) © 2002 American Diabetes Association, Inc.
Cite this: The Rise of Childhood Type 1 Diabetes in the 20th Century - Medscape - Dec 01, 2002.