Chapter 1 The Epidemiology of Type 1 Diabetes Mellitus

Type 1 diabetes mellitus (type 1 diabetes, insulin-dependent diabetes mellitus), one of the most common chronic diseases in childhood, is caused by insulin deficiency following autoimmune destruction of the pancreatic beta cells. Until the one and only therapeutic option – the life-long supplementation of insulin or its analogues – was established, affected children died within a short time. Although extensive investigations on the pathogenesis of type 1 diabetes have been performed, the underlying causes and mechanisms are still far from be‐ ing completely understood. The consequence is a lack of prevention strategies or causal therapies.


Introduction
Type 1 diabetes mellitus (type 1 diabetes, insulin-dependent diabetes mellitus), one of the most common chronic diseases in childhood, is caused by insulin deficiency following autoimmune destruction of the pancreatic beta cells. Until the one and only therapeutic optionthe life-long supplementation of insulin or its analogues -was established, affected children died within a short time. Although extensive investigations on the pathogenesis of type 1 diabetes have been performed, the underlying causes and mechanisms are still far from being completely understood. The consequence is a lack of prevention strategies or causal therapies.
Great affords have been made to assess the incidence and prevalence of type 1 diabetes. The epidemiology of type 1 diabetes is estimated with different methods ranging from small cross-sectional studies to nationwide registries. Understanding the epidemiology of type 1 diabetes may identify risk factors, e.g. genetic predisposition or environmental factors, and may thereby elucidate the pathogenesis of type 1 diabetes. This could be one way to establish possible preventive or causal therapeutic strategies. However, the findings on the possible trigger factors of type 1 diabetes and its epidemiology are sometimes controversial or even contradictory.
In the present chapter, the incidence and prevalence of type 1 diabetes during the last decades will be described. Some fundamental facts about the estimation of type 1 diabetes epidemiology may facilitate understanding. The epidemiologic patterns of type 1 diabetes regarding geographic differences, gender and age of the patients, as well as seasonal and ethnic factors in populations are summarized. The expected changes in type 1 diabetes epidemiology and its implications on future research directions and health care are mentioned.
lation-based EURODIAB registers in 17 countries registered 29,311 new cases of type 1 diabetes in children before their 15th birthday (Patterson, Dahlquist et al. 2009). The World Health Organization program, Multinational Project for Childhood Diabetes (Diabetes Mondiale or DIAMOND), has been developed to investigate and characterize global incidence and mortality of type 1 diabetes and the health care provided for type 1 diabetic patients. Both projects used similar ascertainment methodologies. However, DIAMOND ascertained some data retrospectively. This may have led to some underestimation of incidence rates. The completeness of case ascertainment varied from 35 to 100% in DIAMOND. Most European nations in DIAMOND had comparable (> 90%) rates of ascertainment to EURODIAB (Vehik and Dabelea 2010). DIAMOND reached the lowest completeness rates in Africa, Central and South America. This reflects a general problem when assessing type 1 diabetes epidemiology: data from developing countries are scarce and may not be fully representative due to low rates of completeness.

The incidence of type 1 diabetes mellitus
This section provides a comprehensive description of type 1 diabetes incidence, its changes over the last years, and its variability in populations and patient subgroups.

Geographic differences
Mean incidence rates of type 1 diabetes vary considerably depending on the geographic region (Galler, Stange et al. 2010). The worldwide incidence of type 1 diabetes is described to vary by at least 100-to 350-fold among different countries (Karvonen, Viik-Kajander et al. 2000). The highest incidence rates are found in Finland and Sardinia (Italy) and the lowest in South American countries, e.g. Venezuela and Brazil, and Asian countries, e.g. China or Thailand ( . Apart from regions with low to intermediate incidence rates ranging between 5 and 20 per 100,000 children or adolescents per year, there are areas with incidence rates as high as 27 to 43 per 100,000 children or adolescents per year. Canada and Northern European countries, such as Finland and Sweden, have the highest incidence rates ranging between 30 and 40 per 100,000 children/ adolescents per year. Incidence rates of countries in Central Europe (with the exception of Sardinia) vary from 8 to 18 per 100,000 children/adolescents per year. The incidence for type 1 diabetes in German children aged 0 to 14 years was estimated at 13 per 100,000 per year for 1987-1998 and at 15.5 per 100,000 per year for 1999-2003. The registry of the former German Democratic Republic, which was kept from 1960 until 1989, reported incidence rates between 7 and 14 per 100,000 children/adolescents per year (Galler, Stange et al. 2010). In Mediterranean countries, the incidence rates of type 1 diabetes also show wide variations, although for some of them, there are still no relevant and reliable data (Muntoni 1999). Summarizing the data on type 1 diabetes incidence, the polar-equatorial gradient does not seem to be as strong as previously assumed. The incidence of type 1 diabetes among different countries is presented in Table 1 and Table 2. When comparing the incidence of type 1 diabetes between countries, it is important to keep the size of the sample and the area of sampling in mind. This is because the incidence of type 1 diabetes may show strong variations among different regions from many countries as United States or Italy. Also a Romanian study revealed a wide geographic variation (6.71-fold) between the highest and the lowest incidence rates in different districts of the country (Ionescu-Tirgoviste, Guja et al. 2004).
While genetic factors are thought to explain some of the geographic variability in type 1 diabetes occurrence, they cannot account for its rapidly increasing frequency. Instead, the declining proportion of newly diagnosed children with high-risk genotypes suggests that environmental pressures are now able to trigger type 1 diabetes in genotypes that previously would not have developed the disease during childhood (Borchers, Uibo et al. 2010). The importance of environmental factors towards manifestation of type 1 diabetes is also supported by migration studies: For example a recently published study revealed that being born in Sweden, a country with high type 1 diabetes incidence, increases the risk for type 1 diabetes in children with a genetic origin in low-incidence countries (Soderstrom, Aman et al. 2012

Changes over the last years
A global rise in the incidence of type 1 diabetes in children and adolescents has been reported over the past decades ( For Europe, data from the EURODIAB-register suggest an annual increment of incidence of about 0.6-15% (see Table 2 for details; Patterson, Dahlquist et al. 2009). Earlier data regarding type 1 diabetes incidence from all 36 EURODIAB-centers were published by Green and Patterson (2001).
Regarding the strong differences in the annual increase in the incidence of type 1 diabetes between the countries, it must be mentioned that, besides the geographic differences, the incidence trend was found not to be continuously linear. Furthermore, the incidence trend increases exponentially. Predictions made by Onkamo et al. for the incidence rates in 2010 pointed to large increases, but, in retrospect, were too conservative, especially regarding younger children (Knip 2012).

Sex-dependent differences of type 1 diabetes mellitus incidence
Despite matched-pair investigations suggested that for some early childhood risk factors the odds ratio in boys were different from those in girls ( ter also found the average annual increase of incidence to be significantly higher in boys (3.8% vs. 1.9%, p = 0.046).
Taken together the reported studies suggest no sex-dependent differences in the incidence of type 1 diabetes. Type 1 diabetes can be assumed to be the only major organ-specific autoimmune disease not to show a strong female bias. The overall sex ratio is roughly equal in children diagnosed under the age of 15 years (Gale and Gillespie 2001). After the age of puberty, males are more frequently affected than females (Nystrom, Dahlquist et al. 1992).

Age-dependent differences of type 1 diabetes mellitus incidence
The following sections are intended to answer two questions: 1) does the incidence of type 1 diabetes differ between distinct age groups, and 2) what changes of the incidence of type 1 diabetes within these age groups occurred over the last years.

The age-dependent pattern of type 1 diabetes mellitus incidence
The incidence of type 1 diabetes shows an age-dependent pattern. It was reported to be significantly lower in the 0-to 4-year-old group than in the other groups (Bizzarri, Patera et al. 2010). Many studies from different countries reported an increase of the incidence with increasing age. The highest incidences were found in the 10 to 14-year-old age group

The increase of incidence in different age groups
The increasing incidence of type 1 diabetes is evident. Although some groups found no age-dependent differences in the annual increment of type 1 diabetes incidence (

Seasonal differences of type 1 diabetes mellitus incidence
When discussing seasonal differences in the epidemiology of type 1 diabetes, two different aspects must be mentioned: 1) different frequency of type 1 diabetes regarding the season of birth, and 2) the changing onset or diagnosis of type 1 diabetes through the year.

Seasonal changes in the incidence of type 1 diabetes mellitus
The seasonality of onset or diagnosis of type 1 diabetes has been extensively studied and the results, so far, are conflicting (Moltchanova, Schreier et al. 2009). However, an increment of type 1 diabetes incidence during the winter has been reported by manifold studies (for details:  2009) analyzed data from 105 centers in 53 countries: however, only 42 centers exhibited significant seasonality (p < 0.05) in the incidence of type 1 diabetes when the data were pooled for age and sex (Moltchanova, Schreier et al. 2009). Centers further away from the equator were on average more likely to exhibit seasonality (p < 0.001). Although the majority of the published data suggests seasonal-dependent changes in the incidence of type 1 diabetes mellitus, further research is needed to complete the picture. Especially populations living below the 30th parallel north should be studied, the populations themselves should be investigated more deeply, and the sample sizes should be increased to gain adequate power to detect seasonal changes in low-incidence populations.
According to the published literature, the seasonal changes in the incidence of type 1 diabetes are likely to be caused by changes of the (auto-)immune activity. The first point is that a reduced ultraviolet radiation exposure during the winter months may lead to reduced vitamin D levels. Thereby, the inhibitory effect of vitamin D on Th1-lymphocytes decreases. The second point is the stimulation of the immune system especially by viral infections during the winter months. The result of both could be a higher (auto-)immune activity that causes ß-cell destruction.

Effects of the season of birth on the incidence of type 1 diabetes mellitus
Possible influences of the season of birth are discussed for many autoimmune diseases, e.g. multiple sclerosis, Hashimoto thyreoditis, or Grave's disease (Krassas, Tziomalos et al. 2007). Spring births were associated with increased likelihood of type 1 diabetes, but possibly not in all United States regions (Kahn, Morgan et al. 2009). An Egyptian group reported that 48.3% of diabetic children were delivered during summer months (Ismail, Kasem et al. 2008). A German investigation showed children and adolescents with diabetes being significantly less often born during the months April-June and July-September (Neu, Kehrer et al. 2000). This seasonality pattern was different from those registered in Israel, Sardinia and Slovenia, in which the population with dia-betes type 1 had most births during these months (1972; Neu, Kehrer et al. 2000). A Ukrainian group found that type 1 diabetes was some 30% more common among persons born in April than among persons born in December ( Authors describing a relationship between season of birth and susceptibility for type 1 diabetes have attributed this to intrauterine infections, dietary intake of certain nutrients and possible toxic food components, short duration of breastfeeding, early exposure to cows' milk proteins, and vitamin D deficiency (Vaiserman, Carstensen et al. 2007). Since most of these factors vary with season, one would expect a difference in the seasonal birth pattern between the general population and those children who develop diabetes. A possible link between environmental factors and type 1 diabetes mellitus manifestation was provided by Badenhoop et al. They found HLA susceptibility genes to be in different proportions of patients either born in different seasons of the year or having manifested their disease in different historical periods over time (Badenhoop, Kahles et al. 2009).

Ethnic differences
It has been proposed that much of the current variation in the incidence of type 1 diabetes is due in part to differing distributions of ethnicity throughout the world. Many large studies of type 1 diabetes have provided evidence that the ethnic background is one of the most important risk factors for type 1 diabetes (Vehik and Dabelea 2010). It can be assumed that there is a genetically founded -and thereby ethnically associated -varying susceptibility for type 1 diabetes. The onset of the disease is then triggered by ubiquitous environmental factors (Knip, Veijola et al. 2005;Knip and Simell 2012). In general, susceptibility to type 1 diabetes is attributable to genes that link disease progression to distinct steps in immune activation, expansion, and regulation (Nepom and Buckner 2012).
One half of the genetic susceptibility for type 1 diabetes is explained by the HLA (human leukocyte antigen) genes (Knip and Simell 2012). It becomes conclusive that the main research focus is on ethnic variances in HLA-haplotypes and its association with type 1 diabetes (Lipton, Drum et al. 2011;Noble, Johnson et al. 2011). Based on the presence of two highrisk HLA-DQA1/B1 haplotypes, an investigation in the United States revealed that Caucasians are at the highest and Latinos are at the second-highest risk for developing type 1 diabetes compared to all other ethnic groups (Lipton, Drum et al. 2011). However, there is accumulating evidence that the proportion of subjects with newly diagnosed type 1 diabetes and high-risk HLA genotypes has decreased over the last decades, whereas the proportion of those with low-risk or even protective HLA genotypes has increased (Hermann, Knip et al. 2003;Gillespie, Bain et al. 2004).
The second half of the genetic susceptibility for type 1 diabetes is caused by more than 50 non-HLA genetic polymorphisms (Knip and Simell 2012). Nowadays, there are more than 60 gene loci contributing to the susceptibility of developing type 1 diabetes (Morahan 2012), but this overwhelming list of type 1 diabetes risk genes exerts little influence on the clinical management of children that are at high risk. Conclusively, it is necessary to place the genetics of type 1 diabetes in a more amenable clinical context (Morahan 2012).
Despite the fact that there is consensus about the different genetic type 1 diabetes susceptibility among different ethnic groups, these differences cannot explain the complete variance of type 1 diabetes incidence and prevalence. Furthermore, the annual increment of type 1 diabetes incidence cannot be explained by changing genetic susceptibility. Together with the fact that many individuals are genetically highly susceptible for type 1 diabetes, it becomes conclusive that environmental factors play a crucial role in the onset of the disease and its epidemiology (Knip and Simell 2012).

The prevalence of type 1 diabetes mellitus
This section provides a comprehensive description of the type 1 diabetes prevalence, current prevalence trends, and its variability depending among populations and individuals of different age. In accordance with incidence rates differing regionally within countries and also among different countries, the prevalence of type 1 diabetes mellitus varies in a broad range. The prevalence of type 1 diabetes in different countries is summarized in Table 3.

The age-related differences of type 1 diabetes mellitus prevalence
Regarding age dependents phenomena of type 1 diabetes incidence (see section 3.4) it becomes conclusive that 1) the prevalence of type 1 diabetes shows no sex-related differences and increases with age due to accumulation of individuals suffering from the disease and 2) the age-dependent increment of prevalence is not just linear but more likely exponential due to an age-dependent increment of type 1 diabetes incidence. These assumptions have been confirmed for example by the findings of the Australian Institute of Health and Welfare (see Table 4) that were based on the Australian National Diabetes Register.

What the changing epidemiology implies for future research
The number of investigations concerning the epidemiology of type 1 diabetes is extensive. However, the published results are controversial or even contradictory. There is consensus about fundamental aspects, such as the increasing incidence and prevalence of type 1 diabetes. Thereby, it becomes clear that type 1 diabetes will become more and more of a burden. Although most investigations and publications have been of high methodological quality, they lack exact explanations of the described phenomena, and understanding the mechanisms and triggers of type 1 diabetes remains a mystery.
Future research should lead to improved methods of estimating the epidemiology of type 1 diabetes. Like this, more valid and thereby comparable data on type 1 diabetes epidemiology and risk factors have to be gained, but also more data on the epidemiology of type 1 diabetes over the whole lifespan are definitely needed (Knip 2012). Furthermore, future research may lead to a better understanding of the underlying pathogenesis of type 1 diabetes by complementing the results of descriptive epidemiology with those of 'aetiological' epidemiology (Knip 2012) including the assessment of suspected environmental triggers and risk factors as well as genetic background of the assessed individuals. Conclusively, future research on type 1 diabetes cannot exclusively be performed with population-based approaches. Individualized approaches, e.g. metabolic profiling in both the pre-autoimmune period and the preclinical period (Oresic, Simell et al. 2008), may provide clues to environmental triggers, such as infections or dietary changes, which likely cause disturbances in the intestinal microbiota and the immune system and contribute to the onset of type 1 diabetes. Thereby, children/adolescents at a high risk may be identified and possibilities for prevention of type 1 diabetes may be detected.
In part promising therapeutic approaches to type 1 diabetes as immunotherapy, stem cell-, β-cell-or islet of Langerhans-transplantation have to be assessed in future studies to find causal therapeutic strategies (

What the changing epidemiology implies for future health care
Until now, the treatment of type 1 diabetic patients has been the duty of pediatricians, internal specialists, or diabetologists. The consultation prevalence of type 1 diabetic patients in the general practitioners' consultation hour was low (Frese, Sandholzer et al. 2008). However, if the present trends continue, a doubling of new cases of type 1 diabetes in European children younger than 5 years is predicted between 2005 and 2020, and prevalent cases younger than 15 years will rise by 70% (Patterson, Dahlquist et al. 2009). Adequate health-care resources to meet these children's needs should be made available (Patterson, Dahlquist et al. 2009). It is important to ensure appropriate planning of services and that resources are in place to provide high-quality care for the increased numbers of children who will be diagnosed with diabetes in future years (Patterson, Dahlquist et al. 2009).
In Germany, the costs of pediatric diabetes care exceeded €110 million in 2007. Compared with estimates from the year 2000, average costs per patient had increased by 20% and direct total costs for German pediatric diabetes care by 47% (Bachle, Holl et al. 2012). The treatment costs rose because of new therapeutic strategies and an increase in diabetes prevalence. This illustrates that type 1 diabetes will be an increasing challenge for future health care.
Regarding future health care, it should be kept in mind that elderly and old patients with type 1 diabetes represent a growing population that requires thorough diabetes care. Especially type 1 diabetic patients older than 60 years will suffer from a longer diabetes duration, a doubled risk for severe hypoglycemia, and a higher percentage of cardiovascular complications (Schutt, Fach et al. 2012). In order to provide an adequate health care service, treatment strategies for adults and elderly persons suffering from type 1 diabetes have to be implemented in practice and the knowledge of involved physicians, especially general practitioners, has to be enhanced.

Summary
Data on the epidemiology of type 1 diabetes are based on standardized registry data, such as the Diabetes Mondiale (DIAMOND) Project worldwide and The Epidemiology and Prevention of Diabetes (EURODIAB) study in Europe. Some countries provide national registers. Regional or loco-regional registers as well as (cross-sectional) studies have added further data to the current knowledge. Epidemiologic data from developing countries are scarce and may not be fully representative.
The incidence of type 1 diabetes varies up to 100-fold among different countries. The highest incidences are found in northern countries, especially Finland. The lowest incidence rates were recorded in South American and Asian countries. When discussing type 1 diabetes incidence, also strong variations within countries have to be regarded and care should be taken when generalizing results from a regional sample to a general population. The incidence of type 1 diabetes increases worldwide exponentially. The mean of increment is 3.0% per year. Some assume that the incidence of type 1 diabetes in 2020 will be twice that of the year 2000. Before the age of puberty type 1 diabetes there is no sex-related difference in the incidence of type 1-diabetes. However some early childhood risk factors show different odds for boys and girls and after puberty males are more frequently affected by new onset of type 1 diabetes than females. Type 1 diabetes incidence increases with the age of the children/adolescents, but the annually increase of incidence is higher in younger children and those with moderate genetic susceptibility. There is evidence for a circannular variation with a peak of type 1 diabetes incidence during the winter months. Possible effects of the season of birth have to be further investigated with attention to the genetic background of assessed individuals. Genetic susceptibility explains some of the variation of type 1 diabetes incidence and prevalence with the highest risk in individuals with Caucasian or Latino background. As supported by migration studies, the increasing incidence of type 1 diabetes illustrates the importance of environmental risk factors as triggers of the disease.
Future research should focus on indentifying environmental and genetic risk factors of type 1 diabetes and its complications, preventive strategies and causal treatment options. The prevalence, which doubled worldwide over the last decades, will increase further and type 1 diabetes will shift more and more into the focus of general practitioners. It becomes conclusive that type 1 diabetes will be a burden for more and more patients and for the majority of health care systems.