Marco Songini

1
Marco Songini on behalf of the Sardinian IDDM
Study Groups The Type 1 Diabetes Sardinia
(HotCold Spot) Project what did we learn so
far?
2
History of the HotCold Spot Project
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
The Environmental/Veterinarian/Ecological studies
- first results
1996
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
Schoolchildren IDDM Study (SSI)
1990
Eurodiab-Ace Sardinia is an hot spot for Type
1 diabetes in Europe
1989
3
Time trends in Type 1 Diabetes incidence ( 0 - 14
years)
45
Finland (40.2)
40
Sardinia (35.9)
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
4
The Sardinian Schoolchildren IDDM Study (SSI) (1)
Survival Function
1,0
,9
,8
Number of Abs
,7
3
2
,6
Cum Survival
1
,5
0
100
80
60
40
20
0
LATENCY (months)
5
The Sardinian Schoolchildren IDDM Study (SSI) (2)

10
9
8
7
6
5
4
3
2
1
0
1 Ab
gt 2 Abs
6
The Sardinian Newborn-IDDM Study (SNI) (1)
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
7
The Sardinian Newborn-IDDM Study (SNI) (2)
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 ????
8
Prevalence of islet-related autoantibodies (ICA,
GADA and IA-2icA) according to the different age
(from the Sardinian Newborn and the Sardinian
School Children Studies)

7
6
5
4
prevalence
3
2
1
0
cord blood
2
3
6
7
8
9
10
11
12
13
14
15
1
age (years)
ICA ????JDF-u
GADA ????
IA-2icA ??10
9
The COELIAC DISEASE study (1)
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
10
Coeliac Disease and pre-Type 1 Diabetes in
Sardinian schoolchildren (2)
Islet-related Abs
CD-related Abs
11
79
126

ICA IgG-AGA 8 GADA IgG-AGA 1 GADA
IgG/IgA-AGA AEA 2
11
The MILITARY SERVICE approach
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
1938
1940
1942
1944
1946
1948
1950
1952
1954
1956
1958
1960
1962
1964
1966
1968
1970
1972
1974
1976
1978
Birth cohorts
12
The ENVIRONMENTAL and ECHOLOGICAL studies
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) Cows and breast milk feeding
YES YES NO NO YES NO NO NO NO NO
13
The GESTATIONAL DIABETES (GDM) Study
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)
14
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
15
ATA and ICA in Sardinian school children (2)
ICA 325
ATA 211
16
16
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 ()
17
The SARDINIAN MIGRANTS study
the prevalence of type 1 diabetes was
assessed in 2,200 born in Sardinia and migrated
to Pavia
In 10 individuals the diagnosis of type 1
diabetes 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. Three subjects were already
diabetic at the time of migration, and 7
developed the disease after the migration to Pavia
35
30
25
Age at onset of type 1 diabetes (years)
20
15
10
5
0
Before migration (Nr3)
After migration (Nr7)
18
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. 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.
19
What did we learn so far? (2)
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.
20
What we are doing now
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.).
Broadening the original investigation for type 1
diabetes on the prevalence of coeliac disease and
autoimmune thyroid diseases and to study their
associations.
Comparig data from Sardinia and other areas
(continental Italy, Finland, Sweden, Spain) by
new collaborative studies.
Investigating LADA within the Sardinian type 2
patients.
21
Cost of predicting T1-DM from birth andin school
children background population
Individualc cost for T1-DM care per year

• 12,500

• DIPP (Finnish IDDM Prediction and Prevention
  Project)
• individual cost for 10 year preventive
  strategies 733 245

Strategy 2
Strategy 1

Birth
Birth
250,000
20
225,000
18
100
100
200,000
16
GeneticAbs screening
Abs screening
175,000
14
150,000
12
years
13
100
125,000
10
Abs follow up counselling
cost saved
100,000
8
Abs follow up
75,000
6
50,000
4
25,000
2
0
0
individual cost for T1-DM care per 20 years
estimated cost to identify 1 school children
developing T1-DM in 5 years (cumulative risk
0.32, PPV 35)
modified from Hahl et al. Diabetologia (1998)
4179-85
22
Cost of predicting T1-DM from birth andin school
children background population
individual cost for T1-DM care per 20 years
estimated cost to identify 1 school children
developing T1-DM in 5 years (cumulative risk
0.32, PPV 35)
modified from Hahl et al. Diabetologia (1998)
4179-85
23
Benefits of a predictive screening for Type 1
diabetes in the general population
24
IDDM-Sardinia Study Groups
Scientific Committee
G. Benaggiano, S. Carta, S. Del Giacco, A. Maida,
F. Oleari, G. Pirone, G. Pozza, G. Vicari .


The migrant Study Group
Responsible
M.T Tenconi 10 co-workers
ASRIS
President GF. Bottazzo
Vice-president M. Songini
Secretary M. Porceddu
Administrator P. Cocco
ADCT
Patron M. Coen
MedicalScientific Director GF. Bottazzo
Secretary M. Cooper Freeman
Trustees The Hon Olga Polizzi di Sorrentino CBE
25
In spite of Gian Francos breakthrough
twenty-five years ago with the ICA, the mystery
of Type 1 diabetes still remains deeply hidden
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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