**Altering Trends in the Epidemiology of Type 1 Diabetes Mellitus in Children and Adolescents**

Elisavet Efstathiou and Nicos Skordis

*Paediatric Endocrine Unit, Department of Paediatrics, Makarios Hospital, Nicosia Cyprus* 

#### **1. Introduction**

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Diabetes mellitus is a group of metabolic diseases characterised by chronic hyperglycemia resulting from defects in insulin secretion and/or insulin action, or both [1]. The history of diabetes dates back to 1550 BC as the polyuric states were described in an Egyptian papyrus, where treatment was given with a four day decoction of bones, wheat, grain, grit and earth. The term diabetes was coined by Aretaeus of Cappadocia in the 2nd century AD for conditions causing increased urine output. The sweet taste of diabetic urine was noted in the 5th century AD by Indian physicians and in 1776, Matthew Dobson confirmed that diabetic serum and urine contained sugar. The revolution in the history of Diabetes was the discovery of insulin by Banting, Best and colleagues in 1922 (http://wwunix.oit.umass.edu /~abhu000/diabetes/index.html).

Type 1 diabetes mellitus (T1DM) is one of the most common endocrine metabolic disorders in children and adolescence worldwide with serious acute and chronic complications. It has been proven that T1DM represents the ending result of an autoimmune destruction of the pancreatic islet beta cells in genetically susceptible individuals exposed to certain but still unclear environmental factors. The precise cause of T1DM is not known. However, multiple genetic and environmental risk factors seem to play an important role in the genesis of the disease. The genetic background is complex and difficult to be explained by the involvement of HLA gene region alone. On the other hand viral and nutritional factors changing continuously from country to country, may contribute to the etiology of T1DM. There is no doubt that monitoring temporal trends and incidence of T1DM contribute to the international effort to determine the exact pathogenesis of the disease and it is of critical public health importance. All these temporal trends in the incidence of T1DM have provided significant clues for understanding the disease, most likely reflecting environmental changes more than genetic changes and detecting the factors that implicated in this increase.

In this chapter we review the changing trends in the epidemiology of T1DM and we present data on the rising incidence of T1DM in Greek Cypriot population.

#### **2. Incidence-changing trends**

The prevalence of T1DM greatly varies between different countries, within countries, and between different ethnic populations. The global variation of the incidence of T1DM is

Altering Trends in the Epidemiology of Type 1 Diabetes Mellitus in Children and Adolescents 325

Fig. 1. Mean Annual Incidence rates for T1DM comparing different countries in the world as

Furthermore one of the most notable and recent, in the United States, includes a populationbased study of incidence rates of T1DM from 10 study locations by The SEARCH for Diabetes in Youth Study. The Search Group found an overall incidence of T1DM in children 0–19 of 24.3 per 100,000 person years with the highest rates observed among the 5–9 and 10–

A recent study from Saudi Arabia over an 18 year period, has shown an average incidence of 27.52/100000/year increasing from 18.05/100000/year in the first 9 years of the study period to 36.99/100000/year in the next 9 years [12]. Significant increase in incidence of T1DM was also observed in Lower Silesia during the period 2000-2005 with an increase

Additionally in Scotland two studies by Patterson and co-workers [14-15] have shown an increasing incidence from 13, 8/100000/year between 1968 and 1976 and up to

14 age groups with rates of 22.9 and 33.9 per 100,000 respectively [11].

from 10.43/100000 in 2000 to 13.49/100000 in 2005 [13].

seen in reference 1.

evaluated by grouping the populations with very low (<1/100.000 per yr), low (1-4/100.000 per yr), intermediate (5-9.99/100.000 per yr), high (10-19.99/100.000 per yr) and very high (>20/100.000 per yr) incidence [2]. The different annual incidence rates of T1DM comparing different countries of the world (0.1 to 57.6 per 100000) are displayed in figure 1 [1]. The highest incidence is observed in the Scandinavian countries, where Finland has the highest one reported while there is a gradual decrease in countries located closer to equator [3]. However in some areas such as Puerto Rico, Kuwait and Sardinia there is an unexplained highly increased incidence [4]. The lowest incidence in the world is observed in China, where an enormous geographic variation in the development risk is observed [5]. A long time ago, during the 5th century BC, Hippocrates described diabetes as a 'rare condition' while later on Arataeus the Cappadocian described it as 'not being frequent among men' (http://wwunix.oit.umass.edu/~abhu000/diabetes/index.html). Nowadays the incidence of T1DM increases dramatically throughout the world and it is estimated that it may reach the status of an epidemic in the 21st century [6].

A number of 37 studies from 27 countries confirmed the increased incidence for the period 1960-96 in T1DM with an upward tendency in another 12 countries. The global average annual increase was 3.0% per year with a more pronounced relative increase in the populations with lower incidence [7]. If these trends continue, the number of new cases T1DM in children younger than five years of age may double in some regions between 2005 and 2020 and prevalent cases in children under 15 years will rise by 70 % [8].

The need for rigorous epidemiological studies to monitor the trends of T1DM in children less than 15 year of age led to the creation of the World Health Organization ( WHO) sponsored Diabetes Mondiale (DIAMOND) [2] Project and the EURODIAB study [9].

The data from the WHO project for the incidence of T1DM worldwide DIAMOND showed a large geographic variability. This study group was based on 43,013 cases of T1DM from a study population of 84 million children aged 14 year old or less during the period 1990-1999 in 114 populations from 57 countries. During this time the average annual increase in incidence was 2.8% (95% CI 2.4%–3.2%) with a slightly higher rate during 1995 to 1999, 3.4% (95% CI 2.7%–4.3%) than during 1990 to 1994, 2.4% (95% CI 1.3%–3.4%). An increase in the incidence of T1DM was observed in the populations studied (4.0% in Asia, 3.2% in Europe, and 5.3% in North America) with the exception of Central America and the West Indies, where T1D is less prevalent, and where the trend was a decrease of 3.6% [10].

 It is of interest that several reports have shown an increase in the incidence of T1DM worldwide. This tendency implicates an increasing influence of environmental trigger factors against a background of genetic susceptibility. The geographic and ethnic variations mirror the prevalence of susceptibility genes or that of contributing environmental factors, or both. Nevertheless this increasing incidence rate in such a short period cannot be solely attributed to genetic shifts.

The EURODIAB ACE study group examined the trends in the incidence of T1DM from 1989 to 1994. The study was based on 16,362 cases of T1D in 44 European centres and Israel covering a population of 28 million children [9]. There were enormous variations in the annual incidence rate with 3.2/100,000 person-years in the Former Yugoslav Republic of Macedonia to 40.2/100,000 person-years in two regions of Finland. During this time the annual increase in the incidence rate of T1D was 3.4% (95% CI 2.5%–4.4%) although the rate of increase was noted to be higher in some central European countries. The rates of increase were found to be the highest in the youngest age group: ages 0 to 4 years (6.3%, 95% CI 1.5%–8.5%), 5 to 9 years (3.1%, 95% CI 1.5%–4.8%), and 10 to 14 years (2.4%, 95% CI 1.0%–3.8%).

evaluated by grouping the populations with very low (<1/100.000 per yr), low (1-4/100.000 per yr), intermediate (5-9.99/100.000 per yr), high (10-19.99/100.000 per yr) and very high (>20/100.000 per yr) incidence [2]. The different annual incidence rates of T1DM comparing different countries of the world (0.1 to 57.6 per 100000) are displayed in figure 1 [1]. The highest incidence is observed in the Scandinavian countries, where Finland has the highest one reported while there is a gradual decrease in countries located closer to equator [3]. However in some areas such as Puerto Rico, Kuwait and Sardinia there is an unexplained highly increased incidence [4]. The lowest incidence in the world is observed in China, where an enormous geographic variation in the development risk is observed [5]. A long time ago, during the 5th century BC, Hippocrates described diabetes as a 'rare condition' while later on Arataeus the Cappadocian described it as 'not being frequent among men' (http://wwunix.oit.umass.edu/~abhu000/diabetes/index.html). Nowadays the incidence of T1DM increases dramatically throughout the world and it is estimated that it may reach

A number of 37 studies from 27 countries confirmed the increased incidence for the period 1960-96 in T1DM with an upward tendency in another 12 countries. The global average annual increase was 3.0% per year with a more pronounced relative increase in the populations with lower incidence [7]. If these trends continue, the number of new cases T1DM in children younger than five years of age may double in some regions between 2005

The need for rigorous epidemiological studies to monitor the trends of T1DM in children less than 15 year of age led to the creation of the World Health Organization ( WHO) sponsored Diabetes Mondiale (DIAMOND) [2] Project and the EURODIAB study [9]. The data from the WHO project for the incidence of T1DM worldwide DIAMOND showed a large geographic variability. This study group was based on 43,013 cases of T1DM from a study population of 84 million children aged 14 year old or less during the period 1990-1999 in 114 populations from 57 countries. During this time the average annual increase in incidence was 2.8% (95% CI 2.4%–3.2%) with a slightly higher rate during 1995 to 1999, 3.4% (95% CI 2.7%–4.3%) than during 1990 to 1994, 2.4% (95% CI 1.3%–3.4%). An increase in the incidence of T1DM was observed in the populations studied (4.0% in Asia, 3.2% in Europe, and 5.3% in North America) with the exception of Central America and the West Indies,

 It is of interest that several reports have shown an increase in the incidence of T1DM worldwide. This tendency implicates an increasing influence of environmental trigger factors against a background of genetic susceptibility. The geographic and ethnic variations mirror the prevalence of susceptibility genes or that of contributing environmental factors, or both. Nevertheless this increasing incidence rate in such a short period cannot be solely

The EURODIAB ACE study group examined the trends in the incidence of T1DM from 1989 to 1994. The study was based on 16,362 cases of T1D in 44 European centres and Israel covering a population of 28 million children [9]. There were enormous variations in the annual incidence rate with 3.2/100,000 person-years in the Former Yugoslav Republic of Macedonia to 40.2/100,000 person-years in two regions of Finland. During this time the annual increase in the incidence rate of T1D was 3.4% (95% CI 2.5%–4.4%) although the rate of increase was noted to be higher in some central European countries. The rates of increase were found to be the highest in the youngest age group: ages 0 to 4 years (6.3%, 95% CI 1.5%–8.5%), 5 to 9 years

and 2020 and prevalent cases in children under 15 years will rise by 70 % [8].

where T1D is less prevalent, and where the trend was a decrease of 3.6% [10].

(3.1%, 95% CI 1.5%–4.8%), and 10 to 14 years (2.4%, 95% CI 1.0%–3.8%).

the status of an epidemic in the 21st century [6].

attributed to genetic shifts.

Furthermore one of the most notable and recent, in the United States, includes a populationbased study of incidence rates of T1DM from 10 study locations by The SEARCH for Diabetes in Youth Study. The Search Group found an overall incidence of T1DM in children 0–19 of 24.3 per 100,000 person years with the highest rates observed among the 5–9 and 10– 14 age groups with rates of 22.9 and 33.9 per 100,000 respectively [11].

A recent study from Saudi Arabia over an 18 year period, has shown an average incidence of 27.52/100000/year increasing from 18.05/100000/year in the first 9 years of the study period to 36.99/100000/year in the next 9 years [12]. Significant increase in incidence of T1DM was also observed in Lower Silesia during the period 2000-2005 with an increase from 10.43/100000 in 2000 to 13.49/100000 in 2005 [13].

Additionally in Scotland two studies by Patterson and co-workers [14-15] have shown an increasing incidence from 13, 8/100000/year between 1968 and 1976 and up to

Altering Trends in the Epidemiology of Type 1 Diabetes Mellitus in Children and Adolescents 327

Additionally this rising incidence was more pronounced among children who manifested the disease before the age of 5yr. Table 1 shows the percentage of newly diagnosed T1DM

1990-1999 31 19.0 (13.0-25.0) 66 40.5 (33.0-48.0)\*\* 66 40.5 (33.0-48.0)\*\* 2000-2009 55 26.4 (20.4-32.4) 77 37.0 (30.4-43.6)\* 76 36.5 (30.0-43.0)\* *1990-2009 86 23.2 (18.9-27.5) 143 38.5 (33.5-43.5)\*\* 142 38.3 (33.4-43.2)\*\** 

Table 1. Age of diagnosis in total and in the three age groups. Binomial test performed to

T1DM formerly called as juvenile diabetes it is one of the most common chronic disease of youth as 80% of individuals with T1DM are younger than 20 year of age [20-21]. The age of manifestation of childhood onset T1DM has a bimodal allotment with one peak at 4 to 6 years of age and a second in early puberty (10 to 14 years of age) [22-23]. Recent studies report a higher rate of increase among children younger than 5 years than in children between 5 and 15 years of age [24-25]. This may be related to an earlier onset of clinical

Although the clinical appearance occurs at all ages [21] one fourth of individuals with T1DM are diagnosed as adults [26]. Up to 10% of adults primarily supposed to have type 2 diabetes are found to have antibodies associated with T1D [27] and beta cell destruction in adults seems to take place at a much slower rate than in young T1D cases, often delaying the

Although most autoimmune diseases are more common in females, there appears to be no

However, a gender influence on the age of onset has been reported, in select populations. Some data reported from Europe suggest a female predominance in lower risk populations, and slight male excess in the high risk groups [3]. Furthermore many reports showed that older male adults of European origin (≥15 to 40 years of age) are more likely to develop T1DM than females of similar age and geographic location with an approximate 3:2 male to female ratio [28-30]. The same 3:2 male to female ratio also was reported in children younger than 6 years of age in an observational study from Boston [31]. Based on our data it seems that more males develop T1DM at younger age, whereas female predominate during the

The first report of seasonal variation in the manifestation of T1DM was presented by Franklin Adams in 1926[32] although a consistent picture on the real seasonality of the disease has not been established. The increased incidence of T1DM diagnosis during

**Age Group (years) 0-4 5-9 10-14 n % n % n %** 

cases expressed as age group in accordance with the international standards.

compare proportions compared to "0-4 year" age group: \* p<0.01, \*\*p<0.001

manifestation or to a true increase in the causative factors of the disease.

gender difference in the overall incidence of childhood T1DM [11].

**Period at Diagnosis** 

**3. Age of onset** 

need for insulin therapy after diagnosis.

peripubertal period as shown in figure 3.

**5. Seasonal variation at onset and birth** 

**4. Gender differences** 

21,0/100000/year from 1977 to 1983 for children aged less than 19 year old. Another study for the same population found that the incidence of T1DM had increased from 22,7/100000 in 1984 to 26,0/100000 in 1993 and this increase of about 2% a year, though small, is statistically significant and the effect over 10 years is a large increase [16]. An important increase in incidence of T1DM was also observed in Saxony between the five year periods 1999-2003 and 2004-2008 with estimated rates 15.7/100000 and 19.2/100000 respectively [17].

Ιn our study we have ascertained the mean annual incidence on T1DM in the Greek Cypriot population during the period 1990 - 1999 in children younger than 15 years of age. During this period the incidence of T1DM was 10.76 /100000[18]. In order to identify an increase in the incidence of T1DM in our country, as occurred in the majority of the populations worldwide, we had performed an analysis of the newly diagnosed cases until the end of the year 2004. There was a statistically significant increase in the incidence during the period 2000-2004 with an estimated mean overall incidence 11.9/100000[19]. We had subsequently extended this work by adding the new cases of the five year period 2005 – 2009 in order to document this rising trend by comparing the incidence between the two decades (1990-1999 vs 2000-2009). We have observed a rising trend of the mean incidence from 10.76/100.000 at the first decade (1990-1999) of the study up to 14.4/100.000 at the second decade (2000-2009). According to Wilcoxon two-sample test this increasing trend of incidence during the 20 years analysed is statistically significant (p-value=0.0091). The mean incidence rate for each 5 year- period in accordance with the population data (population below the age of 15yr) is presented in figure 2. The overall mean incidence of T1DM, in the Greek Cypriot population was 12.46/100000 during the twenty-year period 1990-2009. This raised incidence classifies Cyprus among the countries with high incidence of T1DM.

Fig. 2. Different annual incidence rates during five year periods.


Additionally this rising incidence was more pronounced among children who manifested the disease before the age of 5yr. Table 1 shows the percentage of newly diagnosed T1DM cases expressed as age group in accordance with the international standards.

Table 1. Age of diagnosis in total and in the three age groups. Binomial test performed to compare proportions compared to "0-4 year" age group: \* p<0.01, \*\*p<0.001
