Marco Songinion behalf of the Sardinian IDDM Study Groups

The Type 1 Diabetes

Sardinia (Hot&Cold Spot) Project:

what did we learn so far?

Dr. Marco Songini is the director of the Diabetes Unit at the S. Michele Hospital in Cagliari (Sardinia- Italy)

He is also the vice-president of ASRIS (Association for the Study of Type 1 Diabetes in Sardinia)

The island of Sardina has the second highest incidence of type 1 diabetes in the world and a high prevalence of other autoimmune diseases (celiac disease, thyroid autoimmune diseases) has been reported.

The type 1 diabetes prevalence has rapidly increased after the second world war.

The island also offers a relatively small population with a homogenous genetic background selected by centuries of isolation.

Immune markes of type 1 diabetes (ICA, GADA, IA2, IAA) appear several years before the clinical onset of the disease, as was seen in family members of diabetic patients, but relatively little is know about the prevalence and prognosis of such markers in the general population. The aim of the Hot and Cold Spot Project is to investigate the prevalence of immune markers in Sardinian population and to evaluate their prognostic significance to develop a screening procedure.

History of the Hot&Cold Spot Project (1)

Eurodiab - Ace: Sardinia is an ‘hot spot’ for Type 1 diabetes in Europe

first recruitment of newborn from the general population: launch of the Sardinian Newborn IDDM study (SNI)

ICA assay in 1,800 serum samples of school children from the general population enrolled for an epidemiological study of goitre prevalence in Sardinia;first milestone of the Sardinian School children IDDM Study (SSI)

the Military Service approach (secular trend of type 1 diabetes among Sardinians)

ending of the recruitment of the SSI (total cohort 10,000 children)

1995

1994

1993

1990

1989

History of the Hot&Cold Spot Project (2)

stop of recruitment of SNI (total cohort 19,000 children)

The Sardinian Migrants IDDM study (SMI) in the province of Pavia

Coeliac Disease in the Northern Sardinia school children

the Post-partum Thyroiditis and Neonatal Hypothyiroidism studies

the Gestational Diabetes (GDM) Study

The Environmental / Veterinarian / Ecological studies - first results

1996

1997

1997

1997

1998

1998

1999 HLA typing in ‘immunologically at risk’ children for type 1 diabetes

0

5

10

15

20

25

30

35

40

45

Time trends in Type 1 Diabetes incidenceTime trends in Type 1 Diabetes incidence( 0 - 14 years)( 0 - 14 years)

1960 1965 1970 1975 1980 1985 1990 1994

Calendar yearCalendar year

Inci

den

ce (

per

100

,000

)In

cid

ence

(p

er 1

00,0

00)

Finland (40)Finland (40)Sardinia (35)Sardinia (35)

Sweden (25.8)Sweden (25.8)Norway (21.2)Norway (21.2)Denmark (16.4)Denmark (16.4)

Hungary (8.8)Hungary (8.8)

The Sardinian Schoolchildren IDDM Study (SSI) (1)

Survival Function

LATENCY (months)100806040200

Cu

m S

urv

ival

1,0

,9

,8

,7

,6

,5

Number of Abs

3

1 0

2

The Sardinian Schoolchildren IDDM Study (SSI) (2)

Oristano 45/100,000/yearCagliari 38/100,000/year

Nuoro 35/100,000/yearSassari 30/100,000/year

0123456789

10

1 Ab >= 2 Abs

%

The Sardinian Newborn-IDDM Study (SNI) (1)The Sardinian Newborn-IDDM Study (SNI) (1)

Number recruited ~ 19,000Number recruited ~ 19,000

ICA tested = 15,509ICA tested = 15,509(cord blood)(cord blood)

18 Centres from the 4 Sardinian provinces involved in the Study18 Centres from the 4 Sardinian provinces involved in the Study

ICA ICA JDF-u JDF-u

2.3%2.3%ICA 6-19 ICA 6-19 JDF-uJDF-u

1.7%1.7%ICA ICA JDF-u JDF-u

0.6%0.6%

The Sardinian Newborn-IDDM Study (SNI) (2)The Sardinian Newborn-IDDM Study (SNI) (2)FOLLOW UPFOLLOW UP

ICA ICA JDF-uJDF-u GADA GADA IA-2icA IA-2icA

%%p

reva

len

cep

reva

len

ce

0.00.0

0.40.4

0.80.8

1.21.2

1.61.6

2.02.0

11stst YEAR YEAR 22ndnd YEAR YEAR 33rdrd YEAR YEAR

2,9592,959 2,1252,125 2,1172,117 1,1481,148 399399 399399 388388

00

11

22

33

44

55

66

77

cordcordbloodblood

11 22 33 66 77 88 99 1010 1111 1212 1313 1414 1515

%%

pre

vale

nce

pre

vale

nce

age (years)age (years)ICA ICA JDF-uJDF-u GADA GADA IA-2icA IA-2icA

P r e v a l e n c e o f i s l e t - r e l a t e d a u t o a n t i b o d i e s P r e v a l e n c e o f i s l e t - r e l a t e d a u t o a n t i b o d i e s (ICA, GADA and IA - 2icA) according to the different age (ICA, GADA and IA - 2icA) according to the different age

(from the S a r d i n i a n N e w b o r n and the S a r d i n i a n S (from the S a r d i n i a n N e w b o r n and the S a r d i n i a n S c h o o l C h i l d r e n S t u d i e s)c h o o l C h i l d r e n S t u d i e s)

The COELIAC DISEASE study (1)

~ 1,600 Sardinian school childreninvestigated for AGA-IgG, AGA-IgA and AEA

Prevalence of coeliac disease (confirmed by intestinal biopsy)

10.5/1000 childrenthe highest reported so far in a background

population

79 12611*

Coeliac Disease and pre -Type 1 Diabetesin Sardinian schoolchildren (2)

Islet-related

Abs

CD-related Abs

ICA + IgG-AGA = 8GADA + IgG-AGA = 1GADA + IgG/IgA-AGA + AEA = 2

*

The MILITARY SERVICE approach

Secular trend of type 1 diabetes prevalence at 19 years among male conscripts in Sardinia

0,00

1,00

2,00

3,00

4,00

5,00

6,00

7,00

1936

1938

1940

1942

1944

1946

1948

1950

1952

1954

1956

1958

1960

1962

1964

1966

1968

1970

1972

1974

1976

1978

Birth cohorts

Pre

vale

nce

(p

er 1

000)

The ENVIRONMENTAL and ECHOLOGICAL studies

Birth seasonalityOnset seasonalityTemp, pop. density, urban/ruralAverage rainfallTime- and space-clusteringoverlap with: - malaria

- talassemia - G-6-P-D deficiency

Nitrate intake (bottle and tap waters)Cow’s and breast milk feeding

YESYESNONOYESNONONONONO

The GESTATIONAL DIABETES (GDM) Study

~ 100 Sardinian mothers with GDMinvestigated for ICA, GADA and IA-2icA

8 women resulted positive for at least 1 islet-related autoantibody at the time of OGTT

After a follow up of 4 yrs, 5 became diabetic(3 insulin-dependent and 2 non insulin-dependent)

AUTOIMMUNE THYROIDITIS in Sardinian school children (1)~ 8,000 Sardinian schoolchildren from the general population

investigated for ATA

Overall, the prevalence of ATA was 3.7% and the prevalence of a subclinical thyroiditis was about 0.9%

No correlations were found between prevalence of ATA and urinary iodine excretion or prevalence of goitre

0

1

2

3

4

5

6

6-7 7-8 8-9 9-1010-1111-12 12-13 13-14 >14

MalesFemales

Age (years)

AT

A p

os (

%)

ATA and ICA in Sardinian school children (2)

ICA +ICA +

325325ATA +ATA +

2112111616

AUTOIMMUNE THYROIDITIS and PREGNANCY (3)

At the time of delivery, the prevalence of ATA and ICAwas 11.8 and 2.6%, respectively

(0.4% with both specificities)

0

20

40

60

80

100

OR CA NU SS

ATA at low titersATA at high titers

05

10152025303540

ICA* 20

JDFu

ICA5-19

JDFu

ICA< 5

JDFu

~ 2,500 Sardinian mothers at delivery timewere investigated for ATA and ICA

Prevalence of ATA (%)

The SARDINIAN MIGRANTS study

In 10 individuals the diagnosis of T1D has been confirmed giving a prevalence (4/1000) similar to that registered in the

island and 3 times higher than the ones registered in Northern Italy. 3 subjects were already diabetic at the time of migration,

and 7 developed the disease after the migration to Pavia.

the prevalence of type 1 diabetes was assessedin ~ 2,200 born in Sardinia and migrated to Pavia

0

5

10

15

20

25

30

35

Age

at

onse

t of

T

1D (

year

s)

Before migration (Nr=3)

After migration(Nr=7)

What did we learn so far? (1)

Islet-related autoantibodies can appear very early in life (with particular reference to GADA) and they play a predictive role towards the future onset of type 1 diabetes.

The appearance of islet-related autoantibodies progressively increases in the first years of life.

The combination of more than 1 islet-related autoantibody (rather than which autoantibody) is the best predictor for the development of type 1 diabetes in the Sardinian school children population.

What did we learn so far? (2)

Even though some epidemiological evidences suggest a role of the environment on the etiopathogenesis of type 1 diabetes, none of the variables considered so far have shown their influence; however other variables need to be further investigated.

Coeliac disease shows an high prevalence among Sardinian school children and then it deserves more large investigations. It seems not to play a relevant role on the etiopathogenesis of type 1 diabetes in Sardinia instead.

The prevalence of thyroid-related autoantibodies seems not to be as much as high among Sardinian school children, even though they live in an Island at high risk for other autoimmune diseases.

The same findings appear among the pregnant mothers, in whom the prevalence of ATA is not significantly higher than the ones registered in other matched populations. However, the possible immunosuppressive role of pregnancy on these parameters needs to be further investigated.

What did we learn so far? (3)

Trying to further improve the prediction of type 1 diabetes in the general population by carrying out HLA genetic typing in children found ‘at immunological risk’ during the screening.

What we are doing now (1)

Studying the immunological and genetic markers for type 1 diabetes and other autoimmune diseases in Sardinian migrants and their relatives.Investigating other putative environmental factors which can play a role towards the etiopathogenesis of type 1 diabetes (e.g., chemicals, toxins, vaccinations, viral infections, etc.).

What we are doing now (2)

Broadening the original investigation for type 1 diabetes on the prevalence of coeliac disease and autoimmune thyroid diseases and to study their associations.

Comparing data from Sardinia and other areas (continental Italy, Finland, Sweden, Spain) by new collaborative studies.

Investigating LADA within the Sardinian type 2 patients.

025,00050,00075,000

100,000125,000150,000175,000200,000225,000250,000

0

2

4

6

8

10

12

14

16

18

20

years

$

cost

sav

ed

cost

sa

ved

cost

sav

ed

Cost of predicting T1-DM from birth andin school children background population

modified from Hahl et al. Diabetologia (1998) 41:79-85

1234

Benefits of a predictive screening for Type 1 Benefits of a predictive screening for Type 1 diabetes in the general populationdiabetes in the general population

Early diagnosis / Early insulin treatmentEarly diagnosis / Early insulin treatment(In U.S.A.(In U.S.A. about 50 deaths yearly from DKA about 50 deaths yearly from DKA))

1.

? Prevention and/or delay of diabetic complications? Prevention and/or delay of diabetic complications2.

Prevention of the onset of type 1 diabetes inPrevention of the onset of type 1 diabetes in‘‘at risk’ individuals (? at risk’ individuals (? magic bullet)magic bullet)

3.

Identification of ‘non at-risk’ individuals (>99%)Identification of ‘non at-risk’ individuals (>99%)4.

In spite of Gian Franco’s breakthrough twenty-five years ago with the ICA, the mystery of Type 1 diabetes still remains deeply hidden ...

… but we strongly believe that along with him in this beautiful Island, we have a very good chance to unravel the causes of the autoimmune diseases.

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The IDDM-Sardinia Study Groups

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