The Center for Immunology and Transplantation
University of Florida, Gainesville, July 5th, 2005
type 1 diabetes and related ADs in
Sardinia
Marco Songini, Director
Diabetes Unit - Azienda Ospedaliera “G.Brotzu”
www.aob.it, marcosongini@aob.it
Cagliari – Sardinia, Italy
Cagliari
10
42
T1D incidence* in the
Mediterranean area
36
21
(0-14yrs)*
20 23
* Per 100,000
7
Low risk
13
13
13
7
10 15
8
18
19
11
14
12
15
6
7
9
8
19
6
10
12 8 9.8
7
8
6
12
6-9
6
6
12
12
42
*Adapted from EURODIAB
and DiaMond
10
8
6
22
19
High risk
Moderate risk
26
9
7
7
5
4
6
9
10
18
8
8
15
8
5
3
T1D incidence in Italy
(per 100.000,0-14 yrs, 2002)
19
7
9
10
13
11
11
12
10
10
High risk
Moderate risk
8
9
9
6
Low risk
42
12
some data courtesy of
Epidemiology of T1D in Sardinia
THE SARDINIAN MODEL:
Geographical isolation
Genetically homogenous population
Registry for T1D operating since 1989
Sardinia: a beachside
Sardinian T1D Registry
T1D incidence (per 100,000) in Sardinia (1989-2002)
age group 0-14 yrs (N = 1,576)
SIR 0-14
0-4
5-9
10-14
Total
41.7
32.9
43.7
46.6
Males
47.6
35.9
48.4
55.7
Females
35.4
29.7
38.6
36.9
1.3
1.2
1.2
1.5
22
35
43
M/F
Cases (%)
Completeness = 91%
In Sardinia the prevalence of any DM 20-59yrs is 3.75% in M and 2.74% in F;
M/F = 1.37; 16% were insulin treated ( from Muntoni et al, 1988)
Casu, Songini et al, Diabetes Care 2004
Epidemiology of T1D
T1D incidence (per 100,000) in Sardinia (1989-1999)
Age Group 15-29 yrs
SIR 15-29
15-19
20-24
25-29
Total
19.3
23.4
17.9
16.4
Males
23.0
28.1
19.7
21.1
Females
15.4
18.5
16.1
11.7
1.5
1.5
1.2
1.8
38
32
30
M/F
Cases (%)
N = 870
Completeness = 71%
Epidemiology of T1D
Temporal trend of T1D incidence (per
100.000) in Sardinia 0-14 yrs (1989-1999)
60
49.3
SIR (per 100.000)
50
40
44.3
39.8
37.7
43.5
38.1
40.0
39.5
33.0
30
33.2
32.0
20
N=1,214
10
P=0.002
0
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
Anno
Yearly incr. incidence: 0.81 (Fin 0.67, DK 0.80, NZ 0.59)
Yearly incr. rate: 2.8% (Europe: 3.4%, NZ 5%, WW 3%)
Predicted incidence rate year 2010 : 55 (Fin 50.2, NZ 26, China 1.7)
Casu Songini et al. Diabetes Care 2004
Epidemiology of T1D
Temporal trend of T1D incidence (per
100.000) in Sardinia 15-29 yrs (1989-1999)
Incidence (per 100,000)
30
25
20.47
21.07
20,20
23.91
21.68
20
20.02
18.36
15
17.32
16.52
16.64
15.51
10
N=870
5
P=0.5
0
1989
1990
1991
1992
1993
1994
Year
1995
1996
1997
1998
1999
Epidemiology of T1D
Age and sex specific incidence in Sardinia
(Eurodiab 1989-1999)
80
N=2,084
Incidence per 100.000
70
60
50
40
30
20
10
0
<1 1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
year
M
Casu Songini et al. Diabetes Care 2004
F
Stand. Incidence
Temporal trend 0-14 yrs
Sardinian T1D Registry
Temporal trend of T1D incidence by age
0-14 yrs (1989-1999)
70
60
SIR (per 100.000)
10-14
50
5-9
40
30
0-4
20
10
N=1,214
0
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
year
No significant difference in the increasing incidences
among the age groups was found
Casu, Songini et al, Diabetes Care 2004
1999
The Sardinian Conscript T1D Registry
Secular trend of T1D in Sardinia
(1936-78 birth cohorts)
Prevalence (per 1000)
7,00
6,00
5,00
4,00
3,00
2,00
1,00
Birth cohorts
Male point prevalence at 18 years of age
Casu, Songini et al, Pediatric Diabetes, 2004
1978
1976
1974
1972
1970
1968
1966
1964
1962
1960
1958
1956
1954
1952
1950
1948
1946
1944
1942
1940
1938
1936
0,00
T1D incidence
temporal trend: Cagliari province 0-14 yrs (1959-1987)
T1D incidence per 100,000
60
50
40
Males
Females
Total
30
20
10
0
1958-67
1968-77
1978-87
1989-00
Province of Cagliari from
Sardinian T1D Registry
Modified from Paola Frongia, Paolo Pusceddu, Efisio Angius, personal
communication
Annual rate of increase of T1D incidence 0-14 years (19891998)
The global incidence of childhood T1D will increase by 40% over 1998-2010!
5.3
Centr-East.Europe
3.9
3.9
3.6
3.4
Centr-Western Europe
Atlantic Europe
Mainland Italy
Finland
3.0
2.9
2.8
WW
Baltics
Sardinia
2.3
Balkans
2
Mediterranean Europe
-0.2
Northern Europe
-1
0
1
2
3
4
5
increase %
Eurodiab Study Group 2001
RIDI Study Group, unpublished
Onkamo et al. 1999
6
Epidemiology of T1D
Some of the clinical characteristics of Sardinian
patients at diabetes onset (1989-1999)(p<0.001)
0-14 (n=1,209)
15-29 (n=868)
Ketonuria
75%
out of 1,008
67%
out of 601
i.v. fluids
57%
out of 975
27%
out of 593
0%
out of 942
0.2%
out of 604
Autoim. Dis.
1.8%
out of 935
2%
out of 548
Glycemia (mg/dl)
(median)
364
out of 1,028
302
out of 634
No symptoms
1.4%
out of 976
1.2%
out of 595
Duration of
symptoms
(median)
15 gg
out of 976
30 gg
out of 595
Onset mortality
Epidemiology of T1D
Family history of diabetes in newly T1D in Sardinia
(1989-1999)
0-14
15-29
947/1,209
595/868
Diabetes among
relatives
61%
62%
Diabetes in 1st
degree relatives
13%
24%
Diabetes in 2nd
degree relatives
52%
42%
IDDM in 1st degree
relatives
10%
15%
Available data
Epidemiology of T1D
T1D incidence under 1 year of age (1989-96)
Comparison between Sardinian and Italian population
Population
Age group
(days)
Number
of cases
Incid.
rate
95% C.I.
Italian
0-181
182-365
0-365
12
23
35
1.1
2.2
1.7
(0.6-2.0)
(1.4-3.3)
(1.2-2.3)
Sardinian
0-181
182-365
0-365
1
13
14
1.8
23.8
12.8
(0-10.2)
(12.7-40.7)
(7.0-21.5)
Cherubini et al. 1999
Registries
Insulin-dependent
Diabetes mellitus
Italy
Epidemiology of T1D
10
c281= 66.6
p= 0.88
Age 0-4
9
8
7
6
5
4
3
2
1
0
0
30
60
90
120
150
180
210
240
270
300
330
360
Incidence per 100.000 person/month
Time (days)
10
c282= 72.8
p= 0.76
Age 5-9
9
8
7
6
5
4
3
2
1
0
0
30
60
90
120
150
180
210
240
270
300
330
360
Time (days)
10
c283= 80.4
p= 0.56
Age 10-14
9
Incidence per 100.000 person/month
Incidence per 100.000 person/month
Onset seasonality in Sardinian pts aged 0-14 (1989-96)
8
7
Registries
Insulin-dependent
Diabetes mellitus
Italy
6
Carle ,Songini et al. Submitted to Biometrics
5
4
3
2
1
0
0
30
60
90
120
150
180
210
Time (days)
240
270
300
330
360
Epidemiology of T1D
Birth seasonality in Sardinians T1D patients
aged 0-14 years (1989-1998)
T1D patients
General population
16
2000
1800
14
Mean number of births/month
Mean number of births/month
1600
12
10
8
6
4
1400
1200
1000
800
600
400
2
200
0
0
Jan-March
Apr-June
p=0.003
July-Sept
Oct-Dec
Jan-March
Apr-June
July-Sept
Oct-Dec
p=0.009
p=0.01
N=1118
1989-1998
Songini,Casu, Laron et al. 2001
N=314,084
1979-1995
ISTAT
Migrant studies
Effect of migration
on T1D RR
10
42
RR (relative risk) = migrated pop./host pop.
Canadians of French origin:
incidence 8.2/100,000
RR: 0.4
36
21Canadians of Italian origin
26
incidence 10.7/100,000
10
RR: 0.5
6
20 23
Sardinians migrated to
Pavia: RR 3.0
7
22
13
19
Offspring of both (one) Sardinian
parents migrated to:
Turin: RR 3.2 (2.1)
Lombardy: RR 3.3 (2.0)
Lazio: RR 4.3 (2.0)
Moroccans (0-19) migrated
to The Netherlands:
Incidence 20/100.000
RR: 1.5
13
13
7
10 15
12
8
8
19
11
14
12
15
42
6
8
Venetians
6 migrated
to Sardinia
6
RR 0.2
12
7
9
10
6
12 8 9.8
7
8
6
6-9
Italians from Lazio and
Lombardy migrated to
9Germany:
7 7/100.000
incidence
RR 0.5
7
5
4
6
9
12(0-19) migrated
Turkish
to The Netherlands:
18
Incidence 4.5/100.000
RR:
8 0.3
10
15
8
85 3
Sardinian T1D Registry
Geographical distribution of T1D (0-14) RR
RR Alghero: 0.986 (0.979-0.993)
Incid. Catalunia : 11.5 (10.6-12.4)
RR Arborea: 0.2
Incid. Veneto 0-29: 10.9
RR Carloforte: 0.999 (0.996-1.00)
Incid. Liguria: 11.7 (7.6-16.2)
T1D RR
<0.95
0.95-1.00
1.00-1.05
1.05-1.10
>1.10
T1D Relative Risk 0-14 yrs (1989-99)
Casu, Songini et al, Diabetes Care 2004
Incidence of type 1 diabetes
Province of Oristano,1989-2001
70
M
F
ratesx100.000
60
50
40
30
20
10
0
0-4
5-9
10-14
15-19
age
20-24
25-29
Annual incidences of type1 diabetes. Province of
Oristano,1989-2001
ratesx100.000
120
100
0-14
15-29
80
60
40
20
0
89 90 91 92 93 94 95 96 97 98 99 00 01
years
cum.Inc. x 1000
Cumulative incidences of type 1 diabetes.
Oristano, Cabras and Italia
18
16
14
12
10
8
6
4
2
0
Oristano
Italia
Cabras
0-4
5-9
10-14
15-19
age classes
20-24
25-29
Incidences (0-29) of type 1 diabetes
province of Oristano,1989-2001
Prevalences (0-29) of type 1 diabetes province of
Oristano as 31/12/2000
Epidemiology of T1D
Geographical distribution of T1D
Relative Risk
<0.95
0.95-1.00
1.00-1.05
1.05-1.10
>1.10
Archaic area
boundaries
Proto-Sardinian
area
Vona et al. 1996
T1D Relative Risk 0-14 yrs (1989-99)
Anthropological map of Sardinia
Echological studies
Malaria and T1D in Sardinia
Relative risk of T1D due to past malaria in all Sardininan areas with
low and high morbidity for malaria (Fermi, 1938)
Songini, Bernardinelli, Bottazzo et al. 1998
Epidemiology
of pre-T1D
Cagliari: main street
Prediction study-neonates
Prevalence of islet-related Abs among Sardinian
newborns
The Sardinian Newborn – IDDM Study (SNI)
Unselected children aged 1:
2,959
• ICA  5 JDFu:
0.17%
• GADA  10 AU (98.5th percentile):
0.69%
• IA-2icA  4 AU (98.5th percentile):
1.38%
These results are comparable to those obtained from high risk
selected population ( Finnish newbors, O. Simell et al. 1998)
Bottazzo, Songini, Casu, Cirillo et al. 1998
Prediction study
young ages
4.1%
Prevalence of ICA among
European Schoolchildren (SC)
3%
2.7%
0.3%
0.9%
1.5%
High T1D risk
Moderate T1D risk
Low T1D risk
0.3%
4.5%*
Prediction study-young ages
Prevalence of 2-3 islet-related Abs in SC from 36 villages
of the four Sardinian provinces (1986-95)
T1D risk
(/100,000)
0.47 %
SS
52.7
38.6
33.3
31.0
1.20 %
0.96 %
N = 8.434
Age: 6-14
OR
NU
0.34 %
CA
Sardinia: 0.68%
PPV = 32%
Echological studies in Sardinia
Cagliari: The old town skyline
Echological studies
Correlation with T1D risk in Sardinia













Birth seasonality
Onset seasonality
Temp, pop. density, urban/rural
Average rainfall and sunligh (UVR)
Latitude
Time- and space-clustering
Overlap with: - malaria
- talassemia
- G6PD deficiency
Nitrate intake (bottle and tap waters)
Cow’s and breast milk feeding
Gross domestic product
Coffee consumption
YES
YES/NO
NO
NO
NO
MILD
NO
NO
NO
NO
NO
NO
NO
Ecological studies
Correlation with T1D risk in Sardinia
Temperature
NO
(North-South)
Precipitation
NO
(North-South)
G6PD-
NO
(whole island)
G6PD- *
YES
(Central-West)
Population density
NO
(whole island)
Urban/rural
NO
(whole island)
Songini,Bottazzo et al. 1999
* Mastinu F. 1999
Ecological studies
Standardized incidence rate (per
100.000)
Gross domestic product (1994) and T1D incidence
(1989-1994)
45
40
35
30
25
20
15
10
5
0
0
5000
10000
15000
20000
25000
30000
Gross Domestic Products (US$ per head)
Patterson et al. 2001
Eurodiab ACE Study Group
35000
40000
Ecological studies
Standardised incidence rate (per
100.000)
National coffee consumption and T1D incidence
(1989-1994)
45
40
35
30
25
20
15
10
5
0
0
50
100
150
200
Coffee consumption (60 Kg bags per 1000 heads)
Patterson et al. 2001
Eurodiab ACE Study Group
250
Ecological studies
Standardised incidence rate (Per
100.000)
Latitude and T1D incidence (1989-1994)
45
40
35
30
25
20
15
10
5
0
30
35
40
45
50
Latitude (°N)
Patterson et al. 2001
Eurodiab ACE Study Group
55
60
65
70
Ecological studies
T1D incidence 0-14 yrs (/100,000)
1) No correlation between nitrate level in tap water and T1D incidence
among the 21 Sardinian health districts (1989-98)
65
60
55
50
45
40
35
30
25
20
15
10
5
0
rp = -0.16
p = N.S.
N = 1,118
0
2
4
6
8
10
12
14
16
18
Median nitrate concentration (mg/l)
2) No association between the consumption of bottled waters with
different concentration of nitrates and the incidence of T1D
Casu, Bottazzo, Songini et al. 2000
Ecological studies
Malaria and T1D in Sardinia
Relative risk of T1D due to past malaria in all Sardininan areas with
low and high morbidity for malaria (Fermi, 1938)
Songini, Bernardinelli, Bottazzo et al. 1998
Ecological studies
Breast feeding in Sardinia
Influence of feeding habits on the risk of T1D in
Sardinia
T1D cases
Breast feeding
Yes
No
Meloni et al. 1997
84
16
Controls
70
30
OR (95% C.I.)
1
(ref. cathegory)
0.41(0.19-0.91)
Ecological studies
Cow’s milk consumption and T1D incidence
50
T1D incidence (per 100,000)
T1D incidence (per 100,000)
35
Sardinia
30
25
20
15
10
5
45
40
35
30
Sardinia
25
20
15
10
5
0
0
70
75
80
85
90
95
Cow's milk consumption (litres/person/yr)
Italy
Fava et al. 1994
Muntoni et al. 1994
100
0
50
100
150
200
Cow's milk consumption (litres/person/yr)
World
250
Ecological studies
Cow’s milk and T1D
-casein A1-B intake and T1D incidence
40
Sardinia-actual (38.6)
T1D incidence (per 100,000)
35
30
25
20
15
10
Sardinia-predicted (8.6)
5
0
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
casein A1-B consumption (g/person/day)
Elliott et al. 1999
Songini, Casu, Bottazzo, Elliott et al. 2001
4.00
4.50
Ecological studies
Cow’s milk consumption and T1D incidence
50
T1D incidence (per 100,000)
T1D incidence (per 100,000)
35
Sardinia
30
25
20
15
10
5
45
40
35
30
Sardinia
25
20
15
10
5
0
0
70
75
80
85
90
95
Cow's milk consumption (litres/person/yr)
Italy
Fava et al. 1994
Muntoni et al. 1994
100
0
50
100
150
200
Cow's milk consumption (litres/person/yr)
World
250
Ecological studies
T1D incidence 0-14 yrs (/100,000)
1) No correlation between nitrate level in tap water and T1D incidence
among the 21 Sardinian health districts (1989-98)
65
60
55
50
45
40
35
30
25
20
15
10
5
0
rp = -0.16
p = N.S.
N = 1,118
0
2
4
6
8
10
12
14
16
18
Median nitrate concentration (mg/l)
2) No association between the consumption of bottled waters with
different concentration of nitrates and the incidence of T1D
Casu, Bottazzo, Songini et al. 2000
Ecological studies
Malaria and T1D in Sardinia
the Hygiene hypothesis: might it play a role?
Decrease prevalence of parasite infections
Disruption/malfunction of the immune system
 autoimmunity
Relative risk of T1D due to past malaria in all Sardinian areas
with low and high morbidity for malaria (Fermi, 1938)
Songini, Bernardinelli, Bottazzo et al. 1998
Ecological studies
Breast feeding in Sardinia
Influence of feeding habits on the risk of T1D in Sardinia
T1D cases
Breast feeding
Yes
No
Controls
84
16
The ‘original’ ‘Accelerator’ hypothesis
Body weight
 insulin secretion
expression of betacell-autoantigens
betacell-autoimmunity
Meloni et al. 1997
70
30
OR (95% C.I.)
1
(ref. cathegory)
0.41(0.19-0.91)
High risk countries
Finland:  body weight
 T1D incidence
Sardinia:  T1D incidence
 body weight +IR (72%
of obese children)