Chapter9

Type 1 Diabetes: 

Type 1 Diabetes The incidence of childhood type 1 diabetes varies with geographic location, age, sex, ethnicity and time period. Increase in Type 1 incidence worldwide Limited US data but SEARCH study “indicates” rise incidence vs. CO registry

Slide2: 

Percent Type 1 versus Type 2 Diabetes by Age onset (0-9 versus 10-19) Dabelea, SEARCH JAMA 2007; 297:2716-2724

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Extra 2.9% Dead by Age 30 Laing et al Diabetic Medicine 16, 459-465, 1999

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Laing et al Diabetic Medicine 16, 466-471, 1999 Of Diabetes Deaths 18% male hypo and 6% female not counting epilepsy and dead unattended

Type 1 DM incidence is rising 3-5% /year: 

Type 1 DM incidence is rising 3-5% /year Incidence /100,000/ yr children age 0-14 1.4 million patients in the U.S. Rewers

Type 1 diabetes in Finland: 

Type 1 diabetes in Finland Incidence /100,000 children age 0-14

Finland Incidence Type 1 DM/100K 1965-1996: 

Finland Incidence Type 1 DM/100K 1965-1996 Diabetes Care: 22:1066-1070

Finland Type 1 Diabetes Incidence 1965-1996 (32 years)Relative Percent Increase: 

Finland Type 1 Diabetes Incidence 1965-1996 (32 years) Relative Percent Increase Diabetes Care: 22:1066-1070

Incidence per 100,000 per yearSwiss Males: 

Incidence per 100,000 per year Swiss Males Schoenle et al. Diabetologia: 2,001, 44:286

Enterovirus Infection Finnish DIPP Study: 

Enterovirus Infection Finnish DIPP Study Hyoty et al Diabetes 49:1314, 2000

Incidence Type 1 Diabetesper 100,000 per year Children <=14: 

Incidence Type 1 Diabetes per 100,000 per year Children <=14 Karvonnen et al., Diabetes Care, 23:1516, 2000

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Worldwide Incidence of Type 1 Diabetes in Children < 14 Years, by Sex Karvonen et al., Diabetes Care, 23, 2000

Relative Increase in Incidence of Type 1 Diabetes in Children < 14 Years: 

Relative Increase in Incidence of Type 1 Diabetes in Children < 14 Years Change globally: 2.5 % per year (2.32-2.66) Onkamo et al, Diabetologia 42, 1999

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Incidence of Type 1 Diabetes in Finnish Children Aged < 14 Years -1987 to 1996- Tuomilehto et al, Diabetologia 42, 1999

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Incidence of Type 1 Diabetes in Romania, by County Age < 14 years Serban, et al, JPEM, 14 2001

Risk by the age of 20 years : 

Risk by the age of 20 years

High Risk Groups: 

High Risk Groups Scandinavia - < 5% IDDM cases worldwide Relatives - only about 10% of the cases Children - < 40% of the cases HLA-DR3/4 - about 30-40% of childhood cases

Natural history of type 1 diabetes: 

Promoters - genes? - virus? - diet ? Natural history of type 1 diabetes Genetic susceptibility Initiators - virus? - diet? No autoimmunity Autoimmunity Remission Clinical diabetes

Genetic Susceptibility to T1 DM : 

Genetic Susceptibility to T1 DM

IDDM Loci Confirmed in Recent Genome Screens: 

IDDM Loci Confirmed in Recent Genome Screens Concannon 768 families: Julier 485 sib pairs*

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The HLA Region (6p21.31) DP DQ DR B C A Class II (1.1 Mb) Class III Class I (2.2Mb) Complement and Cytokines Class I-like genes and pseduogenes Frequent Recombination Recombination is Rare Telomere Centromere Recombination is Rare (0.7Mb)

Which HLA Loci Are Involved ?: 

DP DQ DR B C A +++ + +++ ? ? + Which HLA Loci Are Involved ?

Alleles and Haplotypes in T1 DM Families: 

Alleles and Haplotypes in T1 DM Families J. Noble , HBDI

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HLA-Defined T1 DM Risk Groups DAISY, Denver Population, n=21,713

Congenital Rubella Syndrome : 

Congenital Rubella Syndrome 30% diabetic usually early IDDM, some NIDDM incubation period 5-20 yrs ICA, IAA in up to 80% of those with diabetes HLA-DR3 or 3/4 in those with diabetes other autoimmune diseases (thyroid, AD) molecular mimicry with a 52kD autoantigen animal model - Syrian hamsters no diabetes after postnatal infection or MMR vacc.

Causes of congenital rubella syndrome : 

Causes of congenital rubella syndrome

Enteroviruses - recent studies: 

Enteroviruses - recent studies

Enterovirus Infection Finnish DIPP Study: 

Enterovirus Infection Finnish DIPP Study Hyoty et al Diabetes 49:1314, 2000

Interferon-alpha Therapy and Type 1 Diabetes MellitusFabris et al, Aliment Pharmacol Ther 2003: 18: 549-558: 

Interferon-alpha Therapy and Type 1 Diabetes Mellitus Fabris et al, Aliment Pharmacol Ther 2003: 18: 549-558 Review: 31 cases type 1 diabetes Hepatitis C- 3% islet ab+, increase to 7% 9/18 cases type 1 diabetes had anti-islet antibodies (ab+) prior to interferon Rx 23/30 (77%) ab+ at diagnosis 8 cases transient insulin dependence Consider Islet Ab Testing Interferon Rx

Early childhood dietand T1 DM ?: 

Early childhood diet and T1 DM ?

Infant diet and beta-cell autoimmunity: 

Infant diet and beta-cell autoimmunity Hazard Ratio Norris et al. DAISY 2000 Adjusted for HLA-DR,DQ and relationship to type 1 diabetic person Prospective cohort study 27 cases and 1,022 controls

TRIGR 3-yr Follow-up Results Seroconversion to 1+ Autoantibody: 

TRIGR 3-yr Follow-up Results Seroconversion to 1+ Autoantibody p=0.043 n=173

Exposure to cow’s milk and islet autoimmunity: 

Exposure to cow’s milk and islet autoimmunity Norris et al., JAMA 1996 Norris, et al., JAMA 2003 N=1,181 Similar results: Hummel 2000 Couper 1999 Odds Ratio Relative Risk Rewers

No association between immunizations and islet autoimmunityGraves et al., DAISY, Diabetes Care 1999: 

Similar findings: Hummel et al. BABY-DIAB, Diabetes Care 1996 No association between immunizations and islet autoimmunity Graves et al., DAISY, Diabetes Care 1999 No difference in % vaccinated before 9 months of age No difference in the median age at the first dose of DTP, Hib, Polio, HepB No difference in the % receiving HepB at birth No difference in the median number of doses of Polio, DTP Rewers

Slide36: 

Do environmental agents cause type 1 diabetes? YES Can can autoimmune diseases, including T1 DM be prevented by modification of environment ? YES Is this the “easiest” way to prevention? PROBABLY

Type 2 Diabetes: 

Type 2 Diabetes Apparent increase in 2 diabetes in youth in several populations – especially American Indians, Hispanics and African Americans Lack of population based studies Undiagnosed cases Cases with severe acute symptoms misclassified Cases reported mainly by pediatric endocrinologists

Reports of Type 2 Diabetes in Youth: 

Reports of Type 2 Diabetes in Youth Population-based Pima Navajo Cree & Ojibway NHANES III School-based Japan Clinic-based or Case series IHS AI Cincinnati OH NHW and AA Little Rock AK AA, NHW Charleston SC AA San Diego CA NHW, H, A, AA Ventura CA H San Antonio TX H, NHW A – Asian Americans AI – American Indians AA – African Americans H - Hispanics NHW – non-Hispanic whites

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Characteristics of Adolescents at Diagnosis with Type 2 Diabetes Most are minority children (AA, AI, H) More girls than boys (F:M ratio = 1.7-3.0) Mean age: 13 years > 80% have a history of diabetes in a first degree relative Obese (Average BMI > 30) > 60% have acanthosis nigricans

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The Changing Face of Diabetes in Youth

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Type 2 by Ethnicity, the Barbara Davis Center Experience Dabelea

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Incidence of Type 2 Diabetes in Japanese Children, 1976-1995 Kitagawa et. al., Clinical Ped, 37, 1998 Age (years) 13-15 6-12

Prevalence of Type 2(?) Diabetesin Population-Based Studies-per 1000 [95%CI]-: 

Prevalence of Type 2(?) Diabetes in Population-Based Studies -per 1000 [95%CI]- New Mexico (1991-1992) Navajo Indians 12-19 years 14.1 [0-33.5] Arizona (1992-1996) Pima Indians 10-14 years 22.3 [11.1-33.5] Manitoba (1996-1997) Cree & Ojibway Indians 4-19 years 11.1[5.4-18.8] NHANES III (1988-1994) NHW, AA, H 12-19 years 4.1 [0-8.6] Fagot-Campagna, et al., J Pediatr,136, 2000

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Prevalence of Type 2 DM in Pima Indian Youth Dabelea et al., Diabetologia, 41, 1998

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Recent observations Possible change in the phenotype of “typical” Type 1 diabetes in youth – to more obese, with less severe clinical onset Reports of “atypical” diabetes with mixed phenotypes in youth

Distribution of Body Mass Index by Type of Diabetes: 

Distribution of Body Mass Index by Type of Diabetes Age 10-19 years at diagnosis Barbara Davis Center for Childhood Diabetes Denver, CO Dabelea

Incidence of Diabetes in U.S. Children, by ethnicity*: 

Incidence of Diabetes in U.S. Children, by ethnicity* NHW (1) H (1) AA (2) AA (3) Pima (4) NHW, H: 0-17 years AA Type 1: 0-14 years AA Type 2: 10-19 years Pima: 10-19 years * 1. Kostraba, Epidemiology, 3, 1992 2. Libman, Diabetes Care, 16, 1993 3. Pinhas-Hamiel, J Pediatr, 128,1996 4. Unpublished data Is it still so?

Types of Childhood Diabetes in Different Ethnic Groups: Is This True?: 

Types of Childhood Diabetes in Different Ethnic Groups: Is This True? Whites Other ethnicities American Indians Dabelea

Slide49: 

Instructions for obtaining article and slideset: Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. Ziegler AG, Schmid S, Huber D, Hummel M, Bonifacio E. JAMA 2003 Oct 1;290(13):1721-8 Go to http://www.biocritique.com/ Sign in or register. Select the Diabetes Forum from the drop down list. Click on the Selected Articles link. In the chronological list, scroll to Oct. 6th, 2003 articles. Select Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. Ziegler AG, Schmid S, Huber D, Hummel M, Bonifacio E. JAMA 2003 Oct 1;290(13):1721-8: The abstract will appear. Choose from many options, including Download Article & Download Slides.