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Marco Songini on 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)

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Marco Songini

on behalf of the Sardinian IDDM Study Groups

The Type 1 Diabetes

Sardinia (Hot&Cold Spot) Project:

what did we learn so far?


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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)


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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.


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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.


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History of the Hot&Cold Spot Project (1) 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.

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

1995

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

1994

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

1993

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)

1990

1989

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


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History of the Hot&Cold Spot Project (2) 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.

1999

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

the Post-partum Thyroiditis and Neonatal Hypothyiroidism studies

1998

the Gestational Diabetes (GDM) Study

1998

Coeliac Disease in the Northern Sardinia school children

1997

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

1997

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

1997

1996

The Environmental / Veterinarian / Ecological studies - first results


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Time trends in Type 1 Diabetes incidence 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.

( 0 - 14 years)

45

Finland (40)

40

Sardinia (35)

35

30

Sweden (25.8)

25

Incidence (per 100,000)

Norway (21.2)

20

Denmark (16.4)

15

10

Hungary (8.8)

5

0

1960

1965

1970

1975

1980

1985

1990

1994

Calendar year


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The Sardinian Schoolchildren IDDM Study (SSI) (1) 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.

Survival Function

1,0

,9

Number of Abs

,8

,7

3

Cum Survival

2

,6

1

0

,5

0

20

40

60

80

100

LATENCY (months)


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Oristano 45/100,000/year 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.

Cagliari 38/100,000/year

Nuoro 35/100,000/year

Sassari 30/100,000/year

The Sardinian Schoolchildren IDDM Study (SSI) (2)

%

10

9

8

7

6

5

4

3

2

1

0

>= 2 Abs

1 Ab


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

18 Centres from the 4 Sardinian provinces involved in the Study

Number recruited ~ 19,000

ICA tested = 15,509

(cord blood)

ICA JDF-u

2.3%

ICA 6-19 JDF-u

1.7%

ICA JDF-u

0.6%


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The Sardinian Newborn-IDDM Study (SNI) (2) 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.

FOLLOW UP

%

2.0

1.6

prevalence

1.2

0.8

0.4

0.0

2,959

2,125

2,117

1,148

399

399

388

1st YEAR

2nd YEAR

3rd YEAR

ICA JDF-u

GADA 

IA-2icA 


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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

(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)

7

%

6

5

prevalence

4

3

2

1

0

cord

blood

1

2

3

6

7

8

9

10

11

12

13

14

15

age (years)

ICA JDF-u

GADA 

IA-2icA 10


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The COELIAC DISEASE study (1) t o a n t i b o d i e s

~ 1,600 Sardinian school children

investigated for AGA-IgG, AGA-IgA and AEA

Prevalence of coeliac disease

(confirmed by intestinal biopsy)

10.5/1000 children

the highest reported so far in a background population


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Coeliac Disease and pre -Type 1 Diabetes t o a n t i b o d i e s

in Sardinian schoolchildren (2)

Islet-related Abs

CD-related Abs

11*

126

79

*

ICA + IgG-AGA = 8

GADA + IgG-AGA = 1

GADA + IgG/IgA-AGA + AEA = 2


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The MILITARY SERVICE approach t o a n t i b o d i e s

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

7,00

6,00

5,00

4,00

Prevalence (per 1000)

3,00

2,00

1,00

0,00

1936

1940

1944

1950

1954

1958

1962

1964

1966

1968

1972

1976

1938

1942

1946

1948

1952

1956

1960

1970

1974

1978

Birth cohorts


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The ENVIRONMENTAL and ECHOLOGICAL studies t o a n t i b o d i e s

Birth seasonality

Onset seasonality

Temp, pop. density, urban/rural

Average rainfall

Time- and space-clustering

overlap with: - malaria

- talassemia

- G-6-P-D deficiency

Nitrate intake (bottle and tap waters)

Cow’s and breast milk feeding

YES

YES

NO

NO

YES

NO

NO

NO

NO

NO


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The GESTATIONAL DIABETES (GDM) Study t o a n t i b o d i e s

~ 100 Sardinian mothers with GDM

investigated 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)


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6 t o a n t i b o d i e s

5

ATA pos (%)

4

Males

3

Females

2

1

0

6-7

7-8

8-9

9-10

10-11

11-12

12-13

13-14

>14

Age (years)

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


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ATA and ICA in Sardinian school children (2) t o a n t i b o d i e s

ICA +

325

ATA +

211

16


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40 t o a n t i b o d i e s

35

100

30

80

25

60

20

15

40

10

20

5

0

0

OR

CA

NU

SS

ATA at low titers

ICA*

 20

JDFu

ICA

5-19

JDFu

ICA

< 5

JDFu

ATA at high titers

AUTOIMMUNE THYROIDITIS and PREGNANCY (3)

~ 2,500 Sardinian mothers at delivery time

were investigated for ATA and ICA

At the time of delivery, the prevalence of ATA and ICA

was 11.8 and 2.6%, respectively

(0.4% with both specificities)

Prevalence of ATA (%)


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The SARDINIAN MIGRANTS study t o a n t i b o d i e s

the prevalence of type 1 diabetes was assessed

in ~ 2,200 born in Sardinia and migrated to Pavia

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.

35

30

25

20

Age at onset of T1D (years)

15

10

5

0

Before migration (Nr=3)

After migration

(Nr=7)


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What did we learn so far? (1) t o a n t i b o d i e s

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.


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What did we learn so far? (2) t o a n t i b o d i e s

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.


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What did we learn so far? (3) t o a n t i b o d i e s

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.


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What we are doing now (1) t o a n t i b o d i e s

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.

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.).


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What we are doing now (2) t o a n t i b o d i e s

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.


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$ t o a n t i b o d i e s

250,000

20

225,000

18

200,000

16

175,000

cost saved

14

150,000

12

years

125,000

10

cost saved

cost saved

100,000

8

75,000

6

50,000

4

25,000

2

0

0

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

1

2

3

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

4


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1. t o a n t i b o d i e s

Early diagnosis / Early insulin treatment

(In U.S.A. about 50 deaths yearly from DKA)

2.

? Prevention and/or delay of diabetic complications

3.

Prevention of the onset of type 1 diabetes in

‘at risk’ individuals (? magic bullet)

4.

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

Benefits of a predictive screening for Type 1

diabetes in the general population


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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.

?

?

?

?

The IDDM-Sardinia Study Groups


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