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Marco Songini, Director Diabetes Unit - Azienda Ospedaliera “G.Brotzu” www.aob.it, marcosongini@aob.it Cagliari – Sardi

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

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Marco Songini, Director Diabetes Unit - Azienda Ospedaliera “G.Brotzu” www.aob.it, marcosongini@aob.it Cagliari – Sardi

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  1. 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

  2. Cagliari

  3. 10 42 T1D incidence* in the Mediterranean area (0-14yrs)* 36 21 26 20 23 10 * Per 100,000 6 22 8 7 13 13 6 19 13 6 12 7 10 15 High risk 12 7 8 9 8 Moderate risk 9 18 19 7 6 10 Low risk 19 11 9.8 12 7 8 14 5 7 12 8 15 4 6 42 6 9 12 10 6-9 6 15 18 8 *Adapted from EURODIAB and DiaMond 8 5 3 8

  4. T1D incidence in Italy(per 100.000,0-14 yrs, 2002) 19 13 7 11 9 11 10 12 10 9 10 High risk 9 8 Moderate risk 6 Low risk 42 12 some data courtesy of

  5. THE SARDINIAN MODEL: Geographical isolation Genetically homogenous population Registry for T1D operating since 1989 Epidemiology of T1D in Sardinia Sardinia: a beachside

  6. 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 Total41.7 32.9 43.7 46.6 Males47.6 35.9 48.4 55.7 Females35.4 29.7 38.6 36.9 M/F 1.3 1.2 1.2 1.5 Cases (%) 22 35 43 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

  7. 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 Total19.3 23.4 17.9 16.4 Males 23.0 28.1 19.7 21.1 Females 15.4 18.5 16.1 11.7 M/F1.5 1.5 1.2 1.8 Cases (%)38 32 30 N = 870 Completeness = 71%

  8. Epidemiology of T1D Temporal trend of T1D incidence (per 100.000) in Sardinia 0-14 yrs (1989-1999) N=1,214 P=0.002 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

  9. Epidemiology of T1D Temporal trend of T1D incidence (per 100.000) in Sardinia 15-29 yrs (1989-1999) N=870 P=0.5

  10. Epidemiology of T1D Age and sex specific incidence in Sardinia (Eurodiab 1989-1999) N=2,084 M F Stand. Incidence Casu Songini et al. Diabetes Care 2004

  11. Temporal trend 0-14 yrs

  12. Sardinian T1D Registry Temporal trend of T1D incidence by age 0-14 yrs (1989-1999) 10-14 5-9 0-4 N=1,214 No significant difference in the increasing incidences among the age groups was found Casu, Songini et al, Diabetes Care 2004

  13. The Sardinian Conscript T1D Registry Secular trend of T1D in Sardinia (1936-78 birth cohorts) 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 Male point prevalence at 18 years of age Casu, Songini et al, Pediatric Diabetes, 2004

  14. T1D incidencetemporal trend: Cagliari province 0-14 yrs (1959-1987) T1D incidence per 100,000 Province of Cagliari from Sardinian T1D Registry Modified from Paola Frongia, Paolo Pusceddu, Efisio Angius, personal communication

  15. Annual rate of increase of T1D incidence 0-14 years (1989-1998) The global incidence of childhood T1D will increase by 40% over 1998-2010! RIDI Study Group, unpublished Onkamo et al. 1999 Eurodiab Study Group 2001

  16. 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 1,00867%out of 601 i.v. fluids 57%out of 97527%out of 593 Onset mortality 0%out of 9420.2%out of 604 Autoim. Dis. 1.8%out of 9352%out of 548 Glycemia (mg/dl)364 out of 1,028302 out of 634 (median) No symptoms1.4%out of 9761.2%out of 595 Duration of 15 ggout of 97630 ggout of 595 symptoms (median)

  17. Epidemiology of T1D Family history of diabetes in newly T1D in Sardinia (1989-1999) 0-1415-29 Available data 947/1,209 595/868 Diabetes among61%62% relatives Diabetes in1st13%24% degree relatives Diabetes in 2nd52%42% degree relatives IDDM in 1st degree10%15% relatives

  18. Epidemiology of T1D T1D incidence under 1 year of age (1989-96) Comparison between Sardinian and Italian population Population Age group Number Incid. 95% C.I. (days) of cases rate 0-181 12 1.1 (0.6-2.0) Italian182-365 23 2.2 (1.4-3.3) 0-365 35 1.7 (1.2-2.3) 0-181 1 1.8 (0-10.2) Sardinian182-365 13 23.8 (12.7-40.7) 0-365 14 12.8 (7.0-21.5) Cherubini et al. 1999 Registries Insulin-dependent Diabetes mellitus Italy

  19. Epidemiology of T1D Onset seasonality in Sardinian pts aged 0-14 (1989-96) Age 0-4 c281= 66.6 p= 0.88 Age 5-9 c282= 72.8 p= 0.76 Incidence per 100.000 person/month Incidence per 100.000 person/month Time (days) Time (days) Registries Insulin-dependent Diabetes mellitus Italy Age 10-14 c283= 80.4 p= 0.56 Carle ,Songini et al. Submitted to Biometrics Incidence per 100.000 person/month Time (days)

  20. Epidemiology of T1D Birth seasonality in Sardinians T1D patients aged 0-14 years (1989-1998) T1D patients General population p=0.003 p=0.009 N=314,084 1979-1995 ISTAT p=0.01 N=1118 1989-1998 Songini,Casu, Laron et al. 2001

  21. Migrant studies

  22. 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 21 26 Canadians of Italian origin incidence 10.7/100,000 RR: 0.5 20 23 10 6 22 8 Sardinians migrated to Pavia: RR 3.0 7 13 13 6 Venetians migrated to Sardinia RR 0.2 19 13 6 12 7 10 15 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) Italians from Lazio and Lombardy migrated to Germany: incidence 7/100.000 RR 0.5 12 7 8 9 8 9 7 10 6 19 11 9.8 12 7 8 14 5 7 12 8 Moroccans (0-19) migrated to The Netherlands: Incidence 20/100.000 RR: 1.5 15 4 6 42 6 9 12 Turkish (0-19) migrated to The Netherlands: Incidence 4.5/100.000 RR: 0.3 10 6-9 6 15 18 8 8 5 3 8

  23. 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 T1D RR <0.95 0.95-1.00 1.00-1.05 1.05-1.10 >1.10 RR Carloforte: 0.999 (0.996-1.00) Incid. Liguria: 11.7 (7.6-16.2) T1D Relative Risk 0-14 yrs (1989-99) Casu, Songini et al, Diabetes Care 2004

  24. Incidence of type 1 diabetes Province of Oristano,1989-2001

  25. Annual incidences of type1 diabetes. Province of Oristano,1989-2001

  26. Cumulative incidences of type 1 diabetes. Oristano, Cabras and Italia

  27. Incidences (0-29) of type 1 diabetes province of Oristano,1989-2001

  28. Prevalences (0-29) of type 1 diabetes province of Oristano as 31/12/2000

  29. 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 Anthropological map of Sardinia T1D Relative Risk 0-14 yrs (1989-99)

  30. 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

  31. Epidemiology of pre-T1D Cagliari: main street

  32. 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

  33. 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 0.3% 4.5%* Moderate T1D risk Low T1D risk

  34. 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) 52.7 38.6 33.3 31.0 0.47 % SS NU 1.20 % OR 0.34 % CA 0.96 % Sardinia: 0.68% PPV = 32% N = 8.434 Age: 6-14

  35. Echological studies in Sardinia Cagliari: The old town skyline

  36. Echological studies Correlation with T1D risk in Sardinia • Birth seasonality YES • Onset seasonality YES/NO • Temp, pop. density, urban/rural NO • Average rainfall and sunligh (UVR) NO • Latitude NO • Time- and space-clustering MILD • Overlap with: - malaria NO • - talassemia NO • - G6PD deficiency NO • Nitrate intake (bottle and tap waters) NO • Cow’s and breast milk feeding NO • Gross domestic product NO • Coffee consumption NO

  37. 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

  38. Ecological studies Gross domestic product (1994) and T1D incidence (1989-1994) Patterson et al. 2001 Eurodiab ACE Study Group

  39. Ecological studies National coffee consumption and T1D incidence (1989-1994) Patterson et al. 2001 Eurodiab ACE Study Group

  40. Ecological studies Latitude and T1D incidence (1989-1994) Patterson et al. 2001 Eurodiab ACE Study Group

  41. Ecological studies 1) No correlation between nitrate level in tap water and T1D incidence among the 21 Sardinian health districts (1989-98) rp = -0.16 p = N.S. N = 1,118 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

  42. 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

  43. Ecological studies Breast feeding in Sardinia Influence of feeding habits on the risk of T1D in Sardinia T1D cases Controls OR (95% C.I.) Breast feeding Yes 84 70 1 (ref. cathegory) No 16 30 0.41(0.19-0.91) Meloni et al. 1997

  44. Ecological studies Cow’s milk consumption and T1D incidence Sardinia Sardinia Italy World Fava et al. 1994 Muntoni et al. 1994

  45. Ecological studies Cow’s milk and T1D -casein A1-B intake and T1D incidence Sardinia-actual (38.6) Sardinia-predicted (8.6) Elliott et al. 1999 Songini, Casu, Bottazzo, Elliott et al. 2001

  46. Ecological studies Cow’s milk consumption and T1D incidence Sardinia Sardinia Italy World Fava et al. 1994 Muntoni et al. 1994

  47. Ecological studies 1) No correlation between nitrate level in tap water and T1D incidence among the 21 Sardinian health districts (1989-98) rp = -0.16 p = N.S. N = 1,118 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

  48. 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

  49. Ecological studies Breast feeding in Sardinia Influence of feeding habits on the risk of T1D in Sardinia T1D cases Controls OR (95% C.I.) Breast feeding Yes 84 70 1 (ref. cathegory) No 16 30 0.41(0.19-0.91) • The ‘original’ ‘Accelerator’ hypothesis • Body weight • insulin secretion • expression of betacell-autoantigens betacell-autoimmunity High risk countries Finland:  body weight  T1D incidence Sardinia:  T1D incidence  body weight +IR (72% of obese children) Meloni et al. 1997

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