Discussion
The worldwide trend of increased T1D prevalence likelihood has multiple etiologies, which may act through multiple mechanisms. By assessing the T1D prevalence rate data for 118 countries we have shown that globally and regionally population which had greater value of Ibs (less opportunity for natural selection) may have greater T1D prevalence and secondly, that newborn life expectancy was significantly associated with T1D prevalence rate at population level.
Overall, the operation of natural selection on contemporary populations is declining due to modern medicine,23 but the magnitude of the decline may differ between countries due to their specific level of sanitation, medical interventions and public health measures. Natural selection is still one of the major evolutionary forces that informs changes in gene frequencies in a population through the action of differential fertility and mortality over generations.38 For example, studies have shown that the increasing prevalence rates of a partially heritable disease, nasal septa and lacrimal bone defects may be attributed to the decreasing effect of natural selection.39 More than 40 genetic loci located in different chromosomes have been associated with T1D in multiple studies.1 ,2 Although T1D can be fatal, the majority of genetically predisposed people do not develop T1D.40 This allows for accumulation of genetic predisposition in human populations. This accumulation will increase when fewer persons who developed a disease would die. Differential fertility and mortality are the basic events of natural selection, which operate singly or jointly to determine the fitness (reproductive success) of a particular population in a given environment.38 The country-specific fertility-based and mortality-based Ibs at different levels may indicate their different successful reproduction opportunities of individuals in the succeeding countries.23 The reproduction success opportunity of each population may determine their magnitude of T1D genes accumulation, thus influenced prevalence rate of patients with T1D in their next generations. In the present study, the correlation of Ibs to the T1D prevalence rate has been observed, which was compatible with suggestion that lower opportunity for selection allows accumulation of unfavorable genes.23 ,41 Our analysis of correlations between T1D prevalence and Ibs by region or by WHO grouped countries seem to indicate that in regions where insulin was available earlier and that had better availability of healthcare the relationship is stronger. This provides the analog of a snapshot what could happen at different times in the same region as time from insulin introduction and improvement of healthcare increased. Thus, the distribution across different populations could be interpreted as a surrogate measure of the evolution in time of T1D prevalence after the introduction of insulin. Artificial insulin introduced for T1D treatment and increasing insulin availability may have played a key role in reducing natural selection as insulin enables countless people with onset of T1D to survive3 and maintain normal reproductive capacity.42 This may have been boosting T1D genes accumulation and prevalence of T1D. T1D can affect people of any age, but usually occurs in children or sexually mature young adults3 who have greater potential to reproduce than older adults. T1D has been historically, and continues to be, the most common type of diabetes in children and adolescents.43 Insulin is the priority for T1D treatment. Otherwise, patient with T1D may only live up to 1 year, some only a week. Several human generations have benefited from insulin since it was discovered and became available in early 1920s.44 Reduced natural selection boosted by insulin treatment of several generations may have enabled cumulative effect of T1D genes frequency in human population to occur quickly and to be noticeable for a couple of decades.9 Studies have shown that a partially heritable disease, phenylketonuria was only noticeable after being accumulated for several generations23 with about 2% increase in each.45
T1D prevalence/incidence is increasing worldwide46 with special regard to the developed countries.9 ,10 ,47 This may be partially attributable to earlier and greater affordability of insulin, in addition to relative more reduced natural selection (greater Ibs values) in those developed countries. Although exogenous insulin can be obtained from animals (bovine and porcine),44 production, transportation, storage and administration of such insulin was extremely expensive,48 which may be beyond the affordability of many patients with T1D, especially those from developing countries. Biosynthetic insulin based on DNA technology has been commercially available since 198244 and it has been thought that it can continue to accommodate global demand44 because of low cost from the production to administration. However, unfortunately life-saving insulin is still less accessible, affordable, or both to people diagnosed with diabetes in a developing country than their counterparts in the developed world.49 This lower survivorship of patients with T1D may contribute to lower prevalence figures directly, besides the fact that less predisposing genes have accumulated in the gene pools of those countries.
Our study showed that the relationship between life expectancy and T1D prevalence rate was exponential (figure 2, R2=0.5266). The Australian Institute of Health and Welfare (AIHW) also indicated the exponential relationship between T1D prevalence rate between age increase of Australian population through the Australian National Diabetes Register.50 Additionally, Neville et al51 reported that the increased longevity of diabetic patients contributed to the increasing prevalence of diabetes in Japanese population. The life expectancy gap between patients with T1D and non-diabetic people has reduced significantly52 due to developments in sanitation, medical interventions and public health measures. Therefore, the underlying reason for the exponential relationship in our study may be because the number of individual patients with T1D have increased in the human population.3 The American Diabetes Association has also stated that the majority of individuals with T1D are adults even though T1D has been more frequent and a relatively straightforward diagnosis in children.53
The correlations of T1D prevalence rates to both Ibs and life expectancy were not only observed worldwide, but also in different country groupings sharing specific characteristics such as geographic locations (table 2), culture backgrounds (table 3) and affiliations to international functional organizations (table 3). Results’ highlights indicated that the correlations of Ibs and life expectancy to T1D were significant or very strong in European country groupings (WHO-Europe in table 2 and EEA in table 3), but very weak in Asian country grouping (WHO-SEA in table 1 and ACD in table 3). This may be attributable to high-genetic predispositions13–15 ,46 in Europe, but low-genetic predisposition in Asia.46 ,53
Although we found that the correlations of Ibs and life expectancy to T1D prevalence rate existed globally and in different country groupings categorized with a variety of criteria, there are several limitations, including the intrinsic limitations (conceptualized as ecological fallacy) to this study.
First, the data analyzed were calculated for per capita in each country, so we could only demonstrate the relationships between T1D prevalence rate and Ibs and life expectancy at country/population level, which does not necessarily correspond to the same relationships holding true at the individual level. We also need to point out that it would be difficult to test the relationships at the individual level due to very rare T1D occurrence rate.
Second, the slow changes in the genetic code of the human populations may not fully explain the increasing T1D prevalence. Non-genetic (environmental) factors partially determine whether, and how risk-associated genotypes may lead to overt T1D disease. Unfortunately, our Ibs does not indicate if fitness change at population level is due to evolution of individuals or change/s. It may also be that altered lower natural immunity to infections following decades of using antibiotics may influence increased rates of autoimmune diseases including T1D.
Third, the data compiled and/or collected by the major international agencies (IDF, WHO, FAO and the World Bank) are fairly crude, and may contain some random errors.
Finally, current evidence of the increasing frequency of many heritable genetic disorders, including T1D does not appear to be available. To the best of our knowledge, the T1D prevalence rate for all age groups at country level published by IDF may be the only version to single out T1D prevalence worldwide after consulting the major diabetes research or data collecting institutions. This may be because clinically, adult T1D is difficult to discriminate from certain forms of type 2 diabetes and from latent autoimmune diabetes in adults (LADA).53 Therefore, we do not know how much this set of data was confounded by other forms of diabetes.
The current prevailing paradigm on the increasing prevalence of T1D is that environmental pressures are now able to trigger genotypes.8 ,9 ,12–17 Currently, medical gene intervention in modern medicine at this stage cannot remove T1D genes, and eugenics (improvement in the genetic stock) can offer no direction due to ethics issue. Therefore, study of T1D epidemiology based on prevalence/incidence T1D data of all age groups has become imperative as it may offer optimal solution to address or at least slow down T1D genetic load increases in different populations.