MSc in DiabetesA population approach

Ross LawrensonPostgraduate Medical SchoolUniversity of Surrey

Epidemiology of Type 1 Diabetes

UniS

Type 1 Diabetes

• An auto immune disorder characterised by islet cell destruction

• Used to equate to insulin dependent diabetes mellitus (IDDM)

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

Prevalence

Prevalence of Type 1 diabetes per 1000

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0 10 20 30 40 50 60 70 80 90

MaleFemale

Incidence

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)

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0-4 5 10 15

Type 1 in older patients

• Both these ladies developed diabetes at the age of 48 years.

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.

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.

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

Type 1 Diabetes

• Increasing incidence

Increasing incidence

• 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.

Type 1 diabetes is becoming commoner in children

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1978 1983 1988 1993 1998

0 to 45 to 910 to 14

Williams R. 2001

Geographical Variation

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

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

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.

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 .

Seasonal variation

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

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35

Cases

Ethnicity and genetics

Ethnicity - incidence per 100,000 in different ethnic groups

• US Virgin Islands– Hispanics 7.2– Whites 28.9– Blacks 5.9

• Hokkaido 1.7

• Aust Euro 13.2

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

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

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

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

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)

Cows milk

Incidence of Type 1 diabetes in relation to mean yearly consumption of cows milk

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0 100 200 300Yearly consumption of milk

person/litre

Incidence of Type 1

diabetes

Countries

Linear (Countries)

Diabetes Care Nov 1991

Finland

JapanFrance

Sweden

UK

NZNetherlands

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

Maternal age

Maternal age

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

Cumulative risk of developing diabetes in siblings of children with Type 1 diabetes in quintiles (median age range 21 -34 years)

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1 2 3 4 5

% developingdiabetes

I.F. Douek, P.J. Bingley, E.A.M. Gale. EASD Suppl 1999

Viruses

• Coxsackievirus and cytomegalovirus have both been implicated.

• Multiple infections in early infancy seem to be protective

Mortality and Morbidity

Mortality

• Mortality in UK patients with Type 1 diabetes

SMR by age and sex for people with Type 1 diabetes

Age at death Male Female

1-19 2.3 3.6

20-39 3.1 5.4

40-59 3.3 3.9

Laing et al BDA cohort study. Diabetic medicine 1999: 16;1-7

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Non-diabetic males Males type 1Non-diabetic females Females type 1

Survival (all causes of death): type 1 diabetes

Age

Probability of survival (%)

Mortality in Type 1 diabetes over time

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1940-49 1950-59 1960-69 1970-79 1980-89

MaleFemale

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

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?

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