**3.5.2 Mortality assesment in territorial T1D prevalence clusters**

To build the regression model we used 1925 deaths recorded among 27 896 patients. We have found that the patients living on the territory belonging to the maximal T1D prevalence cluster associated with increased risk of total mortality compared with the minimal prevalence cluster. In the minimal territorial cluster mortality was 15.68, and in the maximal -- 22.64 cases per 1000 person-years of follow up, p < 0.001. The risk (hazard ratio - HR) of death from all-cause mortality in patients from maximal in relation to the the minimal cluster was 1.5 (95% CI 1.31-1.79). Adjusting for gender had almost no effect on this risk: HRs standardized according to age, gender, and T1D duration for all cause mortality in

Prevalence of Type 1 Diabetes Correlates with Daily Insulin Dose, Adverse

maximal clusters of T1D prevalence (Khalangot et al., 2009c)

Outcomes and with Autoimmune Process Against Glutamic Acid Decarboxylase in Adults 75

Fig. 6. DM-related mortality represented by survival function in minimal, intermediate, and

Fig. 7. Mortality related to acute T1D complications (cumulative survival) in different

territorial clusters (Khalangot et al., 2010)

the maximal T1D prevalence cluster compared to the minimal made up 1.56 (95 % СІ 1.33- 1.81), р<0.001, whereas the same value for diabetes-related mortality was 1.5 (95 % СІ 1.14- 1.96), р<0.001. The risk of total mortality for patients from the intermediate cluster did not differ from the minimal one (fig. 5, 6).

During the whole period of observation, 57 cases of death from acute T1D complications among 27510 patients have been recorded. It has been established, that prevalence of T1D is directly associated with the increase of mortality from acute T1D complications (table 6, figure 7). Hazard ratios, determined using Cox model of regression, and standartized according to gender, duration, and age in maximal territorial cluster of T1D prevalence comparing to the minimal cluster, exceeded 5 : HR= 5.25 (95% CI 1.76-15.63), p<0.001.



Fig. 5. All cause mortality represented by survival function in minimal, intermediate, and maximal clusters of T1D prevalence (Khalangot et al., 2009c)

#### **3.5.3 Assesment of high blood pressure and proliferative retinopathy prevalence in territorial T1D prevalence clusters**

Assessment of arterial hypertension (AH) incidence among patients in regional clusters was performed using the same cohort of 27 896 patients. A total of 4159 hypertension cases, or

the maximal T1D prevalence cluster compared to the minimal made up 1.56 (95 % СІ 1.33- 1.81), р<0.001, whereas the same value for diabetes-related mortality was 1.5 (95 % СІ 1.14- 1.96), р<0.001. The risk of total mortality for patients from the intermediate cluster did not

During the whole period of observation, 57 cases of death from acute T1D complications among 27510 patients have been recorded. It has been established, that prevalence of T1D is directly associated with the increase of mortality from acute T1D complications (table 6, figure 7). Hazard ratios, determined using Cox model of regression, and standartized according to gender, duration, and age in maximal territorial cluster of T1D prevalence comparing to the minimal cluster, exceeded 5 : HR= 5.25 (95% CI 1.76-15.63), p<0.001.

Minimal 5 769 20 079,52 3.48 1.74 4 0.2 Intermedial 17 898 77 323,3 4.3 1.69 36 0.47 Maximal 3 919 17 974,66 4.59 1.79 17 0.95

Fig. 5. All cause mortality represented by survival function in minimal, intermediate, and

**3.5.3 Assesment of high blood pressure and proliferative retinopathy prevalence in** 

Assessment of arterial hypertension (AH) incidence among patients in regional clusters was performed using the same cohort of 27 896 patients. A total of 4159 hypertension cases, or

maximal clusters of T1D prevalence (Khalangot et al., 2009c)

**territorial T1D prevalence clusters** 

Mean Follow up, years

SD Death cases, n

Death cases per 1000 person-years

Follow up period, person years

Table 6. Mortality related to acute T1D complications (Khalangot et al., 2010)

differ from the minimal one (fig. 5, 6).

Patients, n

T1D prevalence cluster

Fig. 6. DM-related mortality represented by survival function in minimal, intermediate, and maximal clusters of T1D prevalence (Khalangot et al., 2009c)

Fig. 7. Mortality related to acute T1D complications (cumulative survival) in different territorial clusters (Khalangot et al., 2010)

Prevalence of Type 1 Diabetes Correlates with Daily Insulin Dose, Adverse

age of 30 in the same country.

severity of this autoimmune disease.

**5. Future studies** 

**Ukraine** 

Outcomes and with Autoimmune Process Against Glutamic Acid Decarboxylase in Adults 77

long been implementing public programs of relevant quality for treating diabetes (Asao et al., 2003). Comparison of our mortality data among patients with T1D in Ukraine (from 15.7 to 22.6 per 1000 person-years, respectively, in the minimal and maximal prevalence clusters) with mortality among patients with juvenile T1D in Japan and Finland (6.07 and 3.52 per 1000 person-years, respectively), demonstrates a considerably higher mortality in Ukraine and the presense of an opposing relationship between the frequency of T1D in compared countries and mortality in cohorts of patients with juvenile diabetes. Please note that cited Asao et al. study (2003) compared the mortality in cohorts of patients with infantile T1D from different countries, while our study compares T1D that develops in patients before the

**4. T1D sybtype may be responsible for the T1D territorial heterogenity in** 

Currently, researchers (eg. Dib & Gomes, 2009) distinguish such subtypes of T1D, as T1A (characterized by selective destruction of beta-cells by an autoimmune process that quickly leads to absolute insulin deficiency; most common among caucasians), LADA (Latent Autoimmune Diabetes in Adults with an onset usually after 35 years of age and characterized by slowly developing insulin deficit), and T1B, also called idiopathic (clinical course is similar to T1A, but without the autoimmune component). Fulminant diabetes is one of the subtypes of T1B. Its is common in asian countries, such as Japan, China, and Korea. It is characterized by a very quick progression of acute metabolic decompensation, damage of alpha and beta cells of pancreas, and absence of autoimmune disorders. The discovered positive relationship between T1D prevalence, exogenic insulin requirement level, development of diabetes complications, and mortality does not allow us to associate T1D territorial heterogenity with LADA. Furthermore, the increase of GADA persistence in T1D patients who reside in regions with higher prevalence of this disease does not allow to consider T1B as responsible for this phenomenon. Thus, T1A rather than T1B subtype of T1D determines the territorial differences in the risk of developing T1D as well as course

Causal link between the territorial distribution of autoimmune T1D in adults and the severity of its course and outcomes remains unknown. The recently discovered antibodies to the type 8 zinc transporter (ZnT8As) have substantially improved the clinical stratification of autoimmune diabetes in adults, demonstrating the link to a more severe insulin deficiency (Lampasone et al., 2010). Swedish researchers point out the possibility of low zinc content in drinking water as a possible T1D risk factor in children (Samuelsson et al., 2010; Haglund et al., 1996). Interestingly, in accordance with our preliminary results (unpublished data), there is no shortage of zinc in blood plasma in adults without diabetes, residing on territories with high prevalence of T1D, and we have even observed an increase of plasma zinc levels among adults with T1D comparing to similar patients from the minimal cluster. Plasma zink levels may be low (T2D) or high (T1D), zink supplementation may improve glycemic control in the two major types of diabetes, however the underlying molecular mechanisms have been elucidated very insignificantly (revieved by Jansen et al. , 2009). It is possible that the study of ZnT8As in

14.91%, were recorded. The minimal cluster included 691 AH cases (11.79%), maximal cluster had 570 cases (14.46%), and intermediate cluster included 2898 AH cases (16.02%). The prevalence of AH or proliferative retinopathy (PR) in the maximal or intermediale clusters is greater in relation to the minimal one (Table 7, Fig. 8). Hazard ratios were 1.36 and 1.46 for maximal and intermediale clusters in relation to the minimal cluster, the HR of which was considered as 1. Each year the T1D duration increases the risk of having hypertension. Adjusting according to gender, age and diabetes duration did not significantly change the risk of AH (table 6). Corresponding ORs for AH and PR were 1.36 (95% СІ 1.2-1.54), р<0,001 and 2.04 (95 % СІ 1.72-2.41), р<0.001. It was revealed that T1D prevalence is directly linked to the increase of all-cause and diabetes-related mortality risks, as well as to PR and AH prevalence.


Table 7. Prevalence of arterial hypertension in T1D patients in different territorial clusters (Khalangot et al., 2009c)

Fig. 8. Fraction (%) of patients with proliferative retinopathy (PR) in different clusters of T1D prevalene. The levels of PR prevalence (the dot within the box), its standart errors (the box height) and 95% CI (lines that emerge) are shown (Khalangot et al., 2009c).

We have found only one study that compared mortality between populations that differ in prevalence of T1D. This was a joint study of epidemiologists from Finland and Japan (Asao et al., 2003). Previously it was known that the incidence and prevalence of T1D in Finland is several times higher than in Japan, however mortality is higher among Japanese patients. The researchers explain this phenomenon by the fact that Finland was "disturbed" by its world's highest incidence of T1D, and because of that the Finnish health care system has long been implementing public programs of relevant quality for treating diabetes (Asao et al., 2003). Comparison of our mortality data among patients with T1D in Ukraine (from 15.7 to 22.6 per 1000 person-years, respectively, in the minimal and maximal prevalence clusters) with mortality among patients with juvenile T1D in Japan and Finland (6.07 and 3.52 per 1000 person-years, respectively), demonstrates a considerably higher mortality in Ukraine and the presense of an opposing relationship between the frequency of T1D in compared countries and mortality in cohorts of patients with juvenile diabetes. Please note that cited Asao et al. study (2003) compared the mortality in cohorts of patients with infantile T1D from different countries, while our study compares T1D that develops in patients before the age of 30 in the same country.
