1. MSc in Diabetes A population approach Ross Lawrenson Postgraduate Medical School University of Surrey Epidemiology of Type 1 Diabetes UniS

2. Type 1 Diabetes An auto immune disorder characterised by islet cell destruction Used to equate to insulin dependent diabetes mellitus (IDDM)

3. Diagnosis? Insulin dependent diabetes associated with auto antibodies e.g Islet Cell Antibodies (ICA) Insulin Autoantibodies (IAA) and Glutamic Acid Decarboxylase Antibodies (GADA) - 90% of white children with newly diagnosed diabetes have auto antibodies Some apparent type 1 diabetics have no demonstrable auto antibodies - 10% Epidemiological definition is IDDM developing in people before age of 35 years Atkinson MA, Eisenbarth GS. Lancet 2001; 358: 221-9

4. Prevalence

5. Prevalence of Type 1 diabetes per 1000

6. Incidence

7. Incidence of Type 1 Diabetes - new cases for every 100,000 per year by age groups 0-4, 5-9,10-14,15-19 (1992)

8. Type 1 in older patients Both these ladies developed diabetes at the age of 48 years.

9. Type 1 in older patients A study Danish adults over the age of 30 has found an incidence rate of type 1 diabetes of 8.2 cases/100,000/year. This rate is lower than that found in Danish children (21.5 cases/100,000/year) Assuming that all type 1 diabetes is incident in children might lead to an underestimation the incidence of type 1 diabetes in the population as a whole. Molbak AG. Incidence of insulin-dependent diabetes mellitus in age groups over 30 years in Denmark. Diabet.Med. 1994; 11: 650-655.

10. Gender With the exception of one study from America, no difference in incidence of type 1 diabetes in children has been observed between males and females. The American study suggested a male excess Allen C et al. Incidence and differences in urban-rural seasonal variation of type 1 (insulin-dependent) diabetes in Wisconsin. Diabetologia 1986; 29: 629-633.

11. Gender No sex-specific significant difference is apparent in the prevalence of type 1 diabetes in children, In adults appears more prevalent in men, with a prevalence of 0.42% of men aged 25-29, but 0.19% of women. This male excess disappears in older age groups - above 65 years of age the prevalence is 0.11% in men and 0.08% in women. Waugh NR et al.The Dundee prevalence study of insulin-treated diabetes; intervals between diagnosis and start of insulin therapy. Diabet.Med. 1989; 6: 346-350

12. Type 1 Diabetes Increasing incidence

13. UK –1951-60: 3.8 per 100,000 –1961-70: 5.3 per 100,000 –1971-80: 10.6 per 100,000 –1985-95: 18.6 per 100,000 Gardner et al. BMJ 1998 showed a 4% annual increase in incidence since 1985 and in the under fives this was an 11% increase.

14. Type 1 diabetes is becoming commoner in children Williams R. 2001

15. Geographical Variation

16. Adjusted incidence per 100,000 person year of Type 1 diabetes under 15 yr (1980) Finland Sweden Scotland England Netherlands France 29.5 22.4 19.9 15.6 9.7 4.4

17. Adjusted incidence per 100,000 person year of Type 1 diabetes under 15 yr (1980) Canada PEI Minnesota Colorado California Cuba 25.5 20.8 15.1 9.4 2.6

18. Geographical Variation A variation in incidence of type 1 diabetes in the British Isles has been observed. Rates in Scotland (20 cases/100,000/year), Wessex (17.1 cases/100,000/year) and East Anglia (17.7 cases/100,000/year), whilst significantly lower rates were found in the Thames region (8-12 cases/100,000/year), Northern Ireland (10.9 cases/100,000/year) and Eire (6.8 cases/100,000/year). No geographical pattern is apparent within the variation, and the hypothesis of a North-South difference is not supported.

19. Geographical variation Statistically significant clustering of incidence has been noted in Yorkshire, even at the ward level, as well as in Northern Ireland and Scotland. The clustering of incident cases of type 1 diabetes has been linked with deprivation and household crowding and suggest environmental, rather than genetic, components. A role for ecological factors, such as nitrates in drinking water, cannot be excluded. Geographical variation is not unique to Britain: in Finland regional differences have been observed, with an inverse correlation between population density and incidence of type 1 diabetes.

20. Seasonal variation

21. Number of cases per month of Type 1 diabetes (n=226)

23. Ethnicity and genetics

24. Ethnicity - incidence per 100,000 in different ethnic groups US Virgin Islands –Hispanics7.2 –Whites28.9 –Blacks5.9 Hokkaido1.7 Aust Euro13.2

25. Genetics If an identical twin has Type 1 diabetes then in 50% of cases the other twin will also develop Type 1 diabetes. If the twins are not identical then less than 10% chance. Kyvik,K. BMJ 1995;311:913-7

26. Genetic susceptibility HLA-DR3 and HLA-DR4 are more likely to develop Type 1 diabetes HLA-DR2 seems protective Genetics cannot be specified on classical lines of dominant, recessive or intermediate genes

27. Risk of Type 1 diabetes in siblings. 4% developed Type 1 diabetes by age 22 years. 12% risk in those with HLA DR3 or DR4 56% with raised Islet Cell Antibodies went on to diabetes. Deschamps I. Diabetologia 1992

28. Use of nicotinamide in children with high levels of circulating ICA. 8 children who were 1 st degree relatives of Type 1 diabetics with ICA levels above 80 units were followed for 5 years. All became diabetic after a mean 17 months. 14 other children who were 1 st degree relatives and had raised ICA were given 150 - 300 mg Nicotinamide and followed for 5 years. 1 became diabetic after 25 months Has led to a major RCT (report in 2003) Elliott R. Diabetologia 1991

29. Nicotinamide DENIS (Deutsche Nicotinamide Intervention Study) showed no difference in randomised trial involving 55 children for 3 years. (Lampeter EF. Klinghammer A. Scherbaum WA. Heinze E. Haastert B. Giani G. Kolb H. The Deutsche Nicotinamide Intervention Study: an attempt to prevent type 1 diabetes. DENIS Group. Diabetes. 1998; 47(6):980-4) Much larger multi national randomised trial (ENDIT) will report in 2003 (Gale et al)

30. Cows milk

31. Incidence of Type 1 diabetes in relation to mean yearly consumption of cows milk Diabetes Care Nov 1991 Finland Japan France Sweden UK NZ Netherlands

32. Cows milk Exclude cows milk from rats diet and the incidence of diabetes falls. Children with diabetes have been breast fed for a shorter period than controls. Western Samoan children did not get Type 1 diabetes until they moved to New Zealand

33. Maternal age

34. Recent study have suggested Type 1 diabetes in children maybe associated with maternal age

35. Cumulative risk of developing diabetes in siblings of children with Type 1 diabetes in quintiles (median age range 21 -34 years) I.F. Douek, P.J. Bingley, E.A.M. Gale. EASD Suppl 1999

36. Viruses Coxsackievirus and cytomegalovirus have both been implicated. Multiple infections in early infancy seem to be protective

37. Mortality and Morbidity

38. Mortality Mortality in UK patients with Type 1 diabetes

39. SMR by age and sex for people with Type 1 diabetes Laing et al BDA cohort study. Diabetic medicine 1999: 16;1-7

40. Survival (all causes of death): type 1 diabetes Age Probability of survival (%)

41. Mortality in Type 1 diabetes over time McNally P et al. Trends in mortality of childhood-onset insulin- dependent diabetes mellitus in Leicestershire: 1940-1991. Diabet.Med. 1995; 12: 961-966.

42. Summary of aetiological findings Type 1 diabetes is increasing Probably caused by a combination of genetic and environmental influences Role of cows milk? Nicotinamide? Seasonal variation –Diet? –Viruses?

43. Conclusion Incomplete information on aetiological factors A number of possibilities for prevention have been raised but have yet to lead to a worthwhile population approach Still great potential for preventing increase in developed communities