INCIDENCE OF CHILDHOOD TYPE 1 DIABETES IN 14 EUROPEAN COUNTRIES INCLUDING ALL NORDIC COUNTRIES

Transcription

1 INCIDENCE OF CHILDHOOD TYPE 1 DIABETES IN 14 EUROPEAN COUNTRIES INCLUDING ALL NORDIC COUNTRIES FINLAND Sardinia SWEDEN NORWAY UK DENMARK ICELAND Estonia France Greece Italy Lithuania Latvia Romania Incidence/100,000 children < 15 years of age EURODIAB ACE

2 INCIDENCE OF T1D AMONG CHILDREN < 15 YEARS OF AGE IN FINLAND Incidence/100, , Harjutsalo et al., submitted for publication

3 PATHOGENESIS OF TYPE 1 DIABETES Insulin secretory capacity, % Exogenous factors 100 Clinical diabetes II. III. I. Age Exogenous factors Beta-cell autoimmunity (autoantibodies) Genetic susceptibility

4 THE BOTTOM LINE: GENETIC DISEASE SUSCEPTIBILITY HLA region - chromosome 6 (6p21.3), IDDM1 Class II HLA-DQ, HLA-DR Other HLA Class I, Class III Non-HLA genes (polymorphisms in more than 40 non-hla genes) Insulin gene region, 11p15.5, IDDM2 PTPN22, 1p13, encoding the LYP protein ITPR3, 6p21, encoding the inositol 1,4,5-triphosphate receptor, type 3 Cytotoxic T-lymphocyte associated antigen 4, CTLA4, 2q33, IDDM7 IFIH1, 6p21, encodes interferon-induced helicase 1, which functions as an enterovirus receptor IL2RA/CD25, 10p15.1, encodes a subunit of the high-affinity interleukin-2 receptor

5 HLA CLASS II ALLELES AND TYPE 1 DIABETES Allele Relative risk DR2 = DQ6 0.1 DR3 = DQ2 3-5 DR 4 = DQ8 5-8 DR3/DR4 = DQ2/DQ

6 INCIDENCE OF TYPE 1 DIABETES IN CHILDREN < 15 YEARS OF AGE IN RUSSIAN KARELIA AND FINLAND IN I 50 Incidence, /100,000/year Karelia Finland Kondrashova et al. Ann Med 2005; 37: 67-72

7 INCIDENCE OF TYPE 1 DIABETES IN CHILDREN < 15 YEARS OF AGE IN RUSSIAN KARELIA AND FINLAND IN II 50 Incidence, /100,000/year Finns/Carelians Russians Others Finland Kondrashova et al. Ann Med 2005; 37: 67-72

8 FREQUENCY OF SUSCEPTIBLE AND PROTECTIVE HLA DQB1 GENOTYPES IN KARELIANS, RUSSIANS AND FINNS Frequency, % 100 Karelians Russians Finns 10 1 High risk Moderate risk Low risk Protective Kondrashova et al. Ann Med 2005; 37: 67-72

9 ARGUMENTS IN FAVOR OF OF A PIVOTAL ROLE OF ENVIRONMENTALFACTORS IN THE ETIOPATHOGENESIS OF TYPE 1 DIABETES Only one out of individuals carrying increased HLA-defined genetic susceptibility to type 1 diabetes does progress to clinical disease The concordance rate for type 1 diabetes has been reported to range from 20 to 40% in monozygotic twins Migrant studies indicating that the incidence in a population is modified by the incidence rate in the new location/country Rapid increase in incidence in most Western countries after World War II

10 POTENTIAL ENVIRONMENTAL FACTORS IN TYPE I DIABETES INFECTIONS - enterovirus infections? - other infections? DIETARY FACTORS - cow s milk proteins e.g. bovine insulin? - vitamin D? LIFE STYLE INDUCING BETA-CELL STRESS - high intake of energy in relation to consumption? - accelerated linear growth and weight gain?

11 Seasonal variation in the emergence of the first autoantibodies number of cases Jan F eb M ar Apr M ay Jun J ul Aug Se p Oct Nov Dec month The majority of autoantibodies appeared in the fall or winter, from September to February (30/38; 76.3%) vs. (8/38; 23.7%) in the spring or summer, from March to August (p < 0.001). Kimpimäki et al. J Clin Endocrinol Metab 2001; 86:

12 Enteroviruses Several serotypes: 3 poliovirus serotypes 23 coxsackie A serotypes 6 coxsackie B serotypes 31 echovirus serotypes Primary replication: lymphoid tissues in pharynx and in gut Infections common, usually minor febrile illness but also CNS infections, carditis, paralysis etc. Neonatal infections

13 Enterovirus infections 0-6 months prior to appearance of autoantibodies OR % 31 % 0 cases Lönnrot et al. Diabetes 2000; 49: controls DIPP

14 Detection of enterovirus RNA 0-6 months prior to appearance of autoantibodies OR % 10 0 cases Lönnrot et al. Diabetes 2000; 49: % controls DIPP

15 Current hypothesis Enterovirus infections may initiate and accelerate the beta-cell damaging process Serial infections by different enterovirus serotypes may lead to progressive beta-cell damage Etiological fraction might be larger than previously estimated Hyöty et al. 2011

16 RELATIVE RISK OF TYPE 1 DIABETES IN RELATION TO EARLY EXPOSURE TO COW S MILK AND SHORT DURATION OF BREAST- FEEDING Odds ratio 2,4 2 1,6 1,2 0,8 0,4 0 Exposure to cow s milk < 4 mo of age Breast-feeding < 3 mo Gerstein, Diabetes Care 1994;17:13-19

17 Insulin as an autoantigen in type 1 diabetes the only beta-cell specific autoantigen IAA appear as the first antibody in most cases [in 22/25 infants (88%) with at least two autoantibodies in the DIPP study] IAA are common in young children with type 1 diabetes

18 Hypothesis I Does exposure to cow s milk formula in early infancy induce an immune response to insulin? Vaarala et al. Diabetes 1999; 48:

19 IgG antibodies to bovine insulin in formula-fed and breastfed infants at the age of 3 months 2.0 p< IgG-antibodies to BI (OD) Group I Formula introduced < 3 mo of age Group II Exclusive BF > 3 mo Vaarala et al. Diabetes 1999; 48:

20 IgG antibodies to bovine insulin at the age of 3, 12 and 18 months in three groups of infants 1.0 IgG-antibodies to BI (OD) Infants with beta-cell autoimmunity Formulafed infants Breast-fed infants Age (months) Vaarala et al. Diabetes 1999; 48:

21 HYPOTHESIS II Could bovine insulin work in type 1 diabetes as glutein in celiac disease?

22 COW S MILK CONSUMPTION IN LATER CHILDHOOD AS A RISK FACTOR FOR AUTOANTIBODY SEROCONVERSION AND CLINICAL TYPE 1 DIABETES Odds Hazard Odds Hazard ratio 1 ratio 1 ratio 2 ratio 2 Ratios 1 adjusted for age, sex, maternal age and maternal education Ratios 2 adjusted in addition for infant nutrition variables Seroconversion Type 1 diabetes Virtanen et al. Diabetic Med 1999; 15:

23 COMPARISON BETWEEN TYPE 1 DIABETES AND CELIAC DISEASE Characteristic Type 1 diabetes Celiac disease Exogenous factor Bovine insulin? Gluten Genetics DQ8 DQ2 DQ2 (DQ8) Non-HLA genes 50% Non-HLA genes 50% Self structures DQ8 - insulin, IA-2 Tissue transglutami- DQ2 - GAD nase (ttg) Autoantibodies IAA, IA-2A, GADA TGA, reticulin AB, endomycium AB Trigger of target cell Enteroviral infections, Nonspecific? damage other infections? Infections?

24 EARLY WEIGHT GAIN AND RISK OF TYPE 1 DIABETES Highest quartile vs. others Age 3 mo 6 mo 9 mo Hyppönen et al. Diabetes Care 1999; 22:

25 CORRELATION BETWEEN THE INCIDENCE OF TYPE 1 DIABETES AND THE BODY MASS INDEX IN FINNISH 15-YEAR-OLD ADOLESCENTS OVER A 12 YEAR PERIOD Incidence(/100,000) 38,0 36,0 y = 4.82x r = 0.87 p = , , , ,0 19,8 20,0 20,2 20,4 20,6 20,8 21,0 21,2 21,4 BMI (kg/m 2 ) 2

26 INCIDENCE OF TYPE 1 DIABETES vs GROSS NATIONAL PRODUCT (GNP) IN FINLAND Incidencw/ < 15-yera-old children Incidence = BKT r = 0.94 R 2 = Gross national product

27 Incidence, /100,000/year IS THERE A TRUE INCREASE IN INCIDENCE OR A SHIFT TO YOUNGER AGE AT DIAGNOSIS? A. INCIDENCE IN 0-34-YEAR-OLD SUBJECTS IN SWEDEN B. AGE AT DIAGNOSIS, years Males Females Males Females p<0.001 p< Pundziute-Lyckå et al. Diabetologia 2002; 45:

28 TEMPORAL SHIFT IN THE DISTRIBUTION OF HLA GENOTYPES AMONG PATIENTS WITH NEWLY DIAGNOSED TYPE I DIABETES Frequency, % p=0.007 p= High risk Moderate risk Low risk Protective HLA-DQB1 genotypes Hermann et al. Diabetologia 2003;46:

29 VITAMIN D SUPPLEMENTS IN EARLY INFANCY AS A FACTOR PROTECTING FROM THE DEVELOPMENT OF TYPE 1 DIABETES Austria Bulgaria Latvia Lithuania Luxem- Romania Northern All bourg Ireland together EURODIAB Study Group, Diabetologia 1999; 42: 51-54

30 VTAMIN D AND RISK OF TYPE 1 DIABETES Rate ratio Regular vs. no Irregular vs. no Suspected rickets supplementation supplementation Hyppönen et al. Lancet 2001; 358:

31 CONCLUSIONS I the incidence of type 1 diabetes has increased substantially in most developed countries after World War II among children younger than 15 years of age at the same time there have been a shift to a younger age at diagnosis and to weaker HLA DQB1-conferred susceptibility among the patients with newly diagnosed disease implying an increased environmental load

32 CONCLUSIONS II enterovirus infections are temporally associated with seroconversion to positivity for type 1 diabetes related autoantibodies in a substantial poportion of prediabetic subjects suggesting that diabetogenic enteroviruses are capable of triggering beta-cell autoimmunity young children who develop signs of beta-cell autoimmunity seem to lack ability to normal tolerization to bovine insulin indicating that bovine insulin might qualify as a driving nutritional antigen in type 1 diabetes

33 CONCLUSIONS III The enhanced burden of type 1 diabetes must reflect changes in life style and environment that have occurred over the last 50 years and are related to the increased wealth characterizing the socioeconomic development in industrilized countries Candidates for contributing factors: - increase in early enterovirus infections due to decreasing maternal antibody levels? - increased exposure to bovine insulin as a consequence of the industrilized processing of milk? - accelerated growth and increased body mass among children? - improved standard of hygiene resulting in reprogramming of the immune system?

34 PATHOGENESIS OF TYPE 1 DIABETES (T1D) Genetic predisposition Primary trigger of beta- Driving exogenous Outcome cell damage antigen Protective genotype No diabetogenic enterovirus Bovine insulin No T1D Protective genotype Diabetogenic enterovirus Bovine insulin No T1D Protective genotype No diabetogenic enterovirus Bovine insulin No T1D Protective genotype Diabetogenic enterovirus Bovine insulin No T1D Susceptible genotype No diabetogenic enterovirus Bovine insulin No T1D Susceptible genotype Diabetogenic enterovirus Bovine insulin No T1D Susceptible genotype No diabetogenic enterovirus Bovine insulin No T1D Susceptible genotype Diabetogenic enterovirus Bovine insulin T1D

35 PATHOGENESIS OF TYPE 1 DIABETES Insulin secretory capacity, % Modyfying factors 100 Clinical diabetes II. Trigger IV. III. I. Driving antigen Beta-cell autoimmunity Genetic susceptibility Age

36 IMPLICATIONS FOR THE HEALTH CARE SYSTEM increased number of patients with type 1 diabetes increased duration of type 1 diabetes increased number of patients with microvascular complications including retinopathy