Clinical Endocrinology 2009

Increased height and weight at 12 months only in siblings developing DM

Type 1 DiabetesType 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

SEARCH study “indicates” rise incidence vs.

CO registry

Diabetes in YouthDiabetes in Youthin the U.S.in the U.S.

170,000 patients younger than 20 y

1,500,000 patients with type 1 diabetes

all ages

Number of new patients annually has tripled in the past 20 years

REWERS

0

10

20

30

40

50

60

70

80

90

100

White Af Am Hispanic Asian AmericanIndian

Type 1 0-9 Type 2 0-9 Type 1 10-19 Type 2 10-19

Percent Type 1 versus Type 2 Diabetes by Age onset (0-9 versus 10-19)

Dabelea, SEARCH JAMA 2007; 297:2716-2724

BDA Cohort Study 1972-1993 All Cause Mortality

0

0.5

1

1.5

2

2.5

1-9 10-19 20-29

Age Cohort

Perc

ent D

ead

Per 1

0 ye

ars Diabetic

General

Extra 2.9% Dead by Age 30

Laing et al Diabetic Medicine 16, 459-465, 1999

Cause Specific Mortality rates

0

50

100

150

200

1-9 10-19 20-29

Age Groups

Mor

talit

y Ra

te p

er

100,

000

pers

on y

ears

Metabolic

Other

Laing et al Diabetic Medicine 16, 466-471, 1999

Of Diabetes Deaths 18% male hypo and 6% female not counting epilepsy and dead unattended

0

10

20

30

40

50

60

70

1950 1960 1970 1980 1990 2000

Finland

Sweden

Colorado

Germany

T1D incidence is rising 3-5% per year Due to environmental cause(s)

Incidence /100,000/ yr in children aged 0-14

REWERS

Accelerating Incidence Type 1 Diabetes Finland: Lancet 371:1778

Harjutsalo; Sjoberg; Tuomilehto May 2008

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

05

10

1520

2530

3540

4550

Yrs. 65-74 75-84 85-96

1-4 yrs5-9 yrs10-14 yrs

Diabetes Care: 22:1066-1070

Finland Type 1 Diabetes Incidence Finland Type 1 Diabetes Incidence 1965-1996 (32 years)1965-1996 (32 years)

Relative Percent IncreaseRelative Percent Increase

0

50

100

150

200

250

300

350

Age 1-4 Age 5-9 Age 10-14

Diabetes Care: 22:1066-1070

Incidence per 100,000 per yearIncidence per 100,000 per yearSwiss MalesSwiss Males

02468

101214161820

1940 1950 1960 1970 1980 1990 2000 2010

Year

Inci

den

ce/1

00,0

00 (

Ag

e 0-

4)

Schoenle et al. Diabetologia: 2,001, 44:286

Enterovirus Infection Finnish Enterovirus Infection Finnish DIPP StudyDIPP Study

26

18

57

31

4 3

29

6

0

10

20

30

40

50

60

%

Total 6 monthInterval

RNA total RNA 6month

Case (21)Control (104)

Hyoty et al Diabetes 49:1314, 2000

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

05

10

1520

2530

3540

Karvonnen et al., Diabetes Care, 23:1516, 2000

0 10 20 30 40 50

China, BeijingHong Kong

IsraelRomania

PolandHungaryGermanyDenmark

UK, OxfordUS BlackUS WhiteSardiniaFinland

Incidence (per 100,000/year)

Boys Girls

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 Relative Increase in Incidence of Type 1 Diabetes in Children < 14 Years1 Diabetes in Children < 14 Years

-2

0

2

4

6

8

10

Incr

ease

in I

ncid

ence

% p

er Y

ear UK

HungaryHawaiiChinaPoland, KrakowSlovakiaNorwayUSA, AlleghenySwedenLithuaniaEstoniaUSA, CO

Change globally: 2.5 % per year (2.32-2.66)

Onkamo et al, Diabetologia 42, 1999

Incidence of Type 1 Diabetes in Romania, by CountyAge < 14 years

Serban, et al, JPEM, 14 2001

Risk by the age of 20 years Risk by the age of 20 years

Risk group Autoimmunity T1 DM

Population 1:30 1:300

Maternal offspring 1:15 1:50

Paternal offspring Siblings HLA-DR3/4,DQB1*0302

1:5

1:15

Monozygotic twins 1:1 (?) 1:3

High Risk GroupsHigh 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

Promoters- genes?- virus?- diet ?

Natural history of type 1 diabetesNatural history of type 1 diabetes

Geneticsusceptibility

Initiators- virus?- diet?

No autoimmunity

Autoimmunity

Remission

Clinicaldiabetes

Genetic Susceptibility Genetic Susceptibility to T1 DM to T1 DM

Locus/Loci Unique Alleles/Haplotypes DRB1 34

DQB1 16

DPB1 23

A 33

B 52

DRB1-DQB1 57

DRB1-DQB1-DPB1 232

DRB1-DQB1-B 313

DPB1-DRB1-DQB1-B 558

DPB1-DRB1-DQB1-B-A 779

Alleles and Haplotypes in T1 DM FamiliesAlleles and Haplotypes in T1 DM Families

J. Noble , HBDI

IDDM risk by age 20 HLA-DR DQB1 Frequency %

High 1:15 3/4 0201/0302 2.4

Moderate 4/x 0302/ 12.71:60-1:200 4/4 0302/ 3.0

3/3 0201/0201 1.4

Average 1:300 3/x 0201/ 12.53/4 0201/not 0302 1.0

Lower than 1:300 4/x, 4/4 /not 0302 6.62/xothers

0602 60.4

HLA-Defined T1 DM Risk GroupsHLA-Defined T1 DM Risk GroupsDAISY, Denver Population, n=21,713DAISY, 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 syndromeCauses of congenital rubella syndrome

Hostembryo/fetusHLA-DR3/4

Agentrubella virus

Environmentunimmunized mother

Vectormaternal blood

Enteroviruses - recent studiesEnteroviruses - recent studies

Study Autoimmunity DiabetesFrisk 1992 CVB 1-5 IgM

Dahlquist 1995 CVB 2-4 IgM

Hyoty 1995 IgM, IgG CVB CVB IgM, IgG

Clements 1995 EV RNA

Graves (DAISY) 1996 no EV RNA ? EV IgM

Enterovirus Infection Finnish Enterovirus Infection Finnish DIPP StudyDIPP Study

26

18

57

31

4 3

29

6

0

10

20

30

40

50

60

%

Total 6 monthInterval

RNA total RNA 6month

Case (21)Control (104)

Hyoty et al Diabetes 49:1314, 2000

Interferon-alpha Therapy and Type 1 Interferon-alpha Therapy and Type 1 Diabetes MellitusDiabetes Mellitus

Fabris et al, Aliment Pharmacol Ther 2003: 18: 549-558Fabris 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 dietEarly childhood dietand T1 DM ?and T1 DM ?

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

0%

5%

10%

15%

20%

Cows MilkFormulaCaseinHydrolysate

p=0.043p=0.043

n=173n=173

Exposure to cow’s milk and islet autoimmunity

0.1

1

10

<3m

Norris et al., JAMA 1996

0.1

1

10

1-3m 4-6m 7+m

Norris, et al., JAMA 2003

N=1,181

Similar results:Hummel 2000Couper 1999

Odds Ratio Relative Risk

Rewers

Similar findings: Hummel et al. BABY-DIAB, Diabetes Care 1996

No association between immunizations and islet autoimmunity

Graves et al., DAISY, Diabetes Care 1999

Vaccine Cases of isletautoimmunity

N= 25

Controls

N= 292

p-value

HepB

Polio

DTP

Hib

40%

100%

100%

72%

37%

99%

99%

61%

0.765

0.678

0.611

0.275

•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

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

Where are We Today?Average A1c by Age, 2005-06

*11-18 yrs; ^the original 14 centers, unchanged compared to 1998

Age Intensive Rx Hvidoere N=1,295^

Sweden(80% of the nation)

Los AngelesN=1664

BDCDenverN=3910

DCCTN=195

EDICN=175

<6 

    7.5 8.0 7.8

6-12 

    7.9 7.8 8.2

13-18 8.1 8.4 8.6*^ 8.4 8.4* 8.6

>18 

7.1 7.9 8.0   7.8

REWERS

T1D patients diagnosed in childhoodlive longer

NishmuraR, et al. Diabetes Care 2001

Duration of diabetes (yrs)

0.5

0.6

0.7

0.8

0.9

1

0 5 10 15 20 25 30 35

1975-1970-

1965-

Duration of diabetes (yrs)

0.5

0.6

0.7

0.8

0.9

1

0 5 10 15 20 25 30 35

1970-74

1965-69

1975-79

REWERS

Incidence of microvascular complications is declining

Hovind P, et al. Diabetes Care 2003

1961-65

1966-70

1966-70

1971-751971-75

1976-80 1976-80

Diabetic nephropathyProliferative diabetic retinopathy1965-691965-69

1970-741970-74

1975-79

1975-79

1980-841980-84

30

20

10

40

REWERS

Poor control of hypertension and dyslipidemia in young adult patients with T1D

7%

10%

30%

53%

Normal Treated, controlled

Treated, uncontrolled Untreated

6%11%

16%

67%

Hypertension DyslipidemiaMaahs D, Diabetes Care 2005 Wadwa P, Diabetes Care 2005

REWERS

Type 2 DiabetesType 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 YouthReports of Type 2 Diabetes in Youth

Population-basedo Pimao Navajoo Cree & Ojibwayo NHANES III

School-basedo Japan

Clinic-based or Case serieso IHS

» AIo Cincinnati OH

» NHW and AAo Little Rock AK

o AA, NHWo Charleston SC

» AAo San Diego CA

» NHW, H, A, AAo Ventura CA

» Ho San Antonio TX

» H, NHW

A – Asian AmericansAI – American IndiansAA – African AmericansH - Hispanics NHW – non-Hispanic whites

Characteristics of Adolescents at Characteristics of Adolescents at Diagnosis with Type 2 Diabetes 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

The Changing Face of Diabetes in The Changing Face of Diabetes in YouthYouth

0

5

10

15

20

25

30

35

% w

ith ty

pe 2

87 88 89 90 91 92 93 94 95 96

Cincinnati <19 years Little Rock 8-21 years San Antonio <19 years

Type 2 by Ethnicity, Type 2 by Ethnicity, the Barbara Davis Center Experiencethe Barbara Davis Center Experience

0

20

40

60

Per

cen

t

NHW n=121 H n=12 AA n=9

Dabelea

Incidence of Type 2 Diabetes Incidence of Type 2 Diabetes in Japanese Children, in Japanese Children, 1976-19951976-1995

0

2

4

6

8

10

12

14

16In

cide

nce

per

100,

000/

year 1976-1980

1991-1995

Kitagawa et. al., Clinical Ped, 37, 1998

Age (years) 13-156-12

Prevalence of Type 2(?) DiabetesPrevalence of Type 2(?) Diabetesin Population-Based Studiesin Population-Based Studies

--per 1000 [95%CI]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

0

1

2

3

4

5

6

7

67-76 77-86 87-96

Examination time period (years)

Pre

vale

nce

%

Boys

0

1

2

3

4

5

6

7

67-76 77-86 87-96

Examination time period (years)

5-9 years

10-14 years

15-19 years

Girls

Prevalence of Type 2 DM in Pima Indian YouthPrevalence of Type 2 DM in Pima Indian Youth

Dabelea et al., Diabetologia, 41, 1998

Recent observationsRecent 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 Distribution of Body Mass Index by Type of DiabetesType of Diabetes

0

20

40

60

80

100

120

<19 19-21 22-24 25-27 28-30 31-33 34+

BMI

Num

ber

of s

ubje

cts

Type 2

Type 1

Age 10-19 years at diagnosisBarbara Davis Center for Childhood DiabetesDenver, CO

Dabelea

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

0

5

10

15

20

25

Type 1 Type 2

Inci

denc

e (p

er 1

00,0

00/y

ear)

NHW (1)

H (1)AA (2)

AA (3)

Pima (4)

NHW, H: 0-17 years AA Type 1: 0-14 yearsAA Type 2: 10-19 yearsPima: 10-19 years

*1. Kostraba, Epidemiology, 3, 19922. Libman, Diabetes Care, 16, 19933. Pinhas-Hamiel, J Pediatr, 128,19964. Unpublished data

Is it still so?

Types of Childhood Diabetes Types of Childhood Diabetes in Different Ethnic Groups: in Different Ethnic Groups:

Is This True?Is This True?

Type 1aType 1bType 2Known genetic mutationsSecondary

Whites

Other ethnicities

American Indians

Dabelea

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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

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