Characterization of rapid progression to type 1

diabetes in children with genetic disease

susceptibility
Petra Maria Pllnen
University of Helsinki, Finland

Presenter Disclosure Information

No conflict of interest

Objective of the study

To assess the characteristics of

rapid progression to type 1 diabetes (T1D)
in children with genetic disease susceptibility
recruited from general population

Prediabetic period is highly variable in

duration

Prediabetic period: autoantibodies against beta-cells appear into

the circulation
Islet cell autoantibodies (ICA), autoantibodies to insulin (IAA),
glutamic acid decarboxylase (GADA), islet antigen 2 (IA-2A), and
zinc transporter 8 (ZnT8A)
According to observations on prediabetic individuals, the duration
of the prediabetic period is highly variable

Individuals with aggressive islet autoimmunity

might benefit from early intensive treatment

Characterization of individuals with rapid progression to T1D might

enable us to identify T1D at an earlier stage
We might be able to prevent these individuals from developing
severe diabetic ketoacidosis at diagnosis
Individuals with rapid progression might benefit from more intensive
immunomodulatory interventions

Subjects and methods

7410 children (52.6% males) with HLA-conferred disease risk for

development of islet autoimmunity and progression to T1D followed
from birth (the Finnish DIPP Study)
The median follow-up time 13.2 years (range 0.9-18.2)
The highest genetic disease risk in the Finnish population: HLADQB1*02/*03:02 genotype
Moderate disease risk: HLA-DQB1*03:02/x genotype, where x is not
DQB1*02, *03:01, *06:02, *06:03, *06:04 or any other protective allele

Subjects and methods

Islet cell autoantibodies (ICA) were the primary tool for

screening for -cell autoimmunity
If a child tested positive for ICA or progressed to T1D, all his/her
prior samples were analyzed also for IAA, GADA, and IA-2A
Since 2003, all samples have been tested for all mentioned
autoantibodies, except ZnT8A

Subjects and methods

Rapid progression was defined as progression to clinical T1D

within one year after seroconversion to autoantibody positivity

Results: Development of prediabetic

autoantibodies and progression to T1D

Among the 7410 genetically susceptible children, 1563 (21%) tested

positive for at least one autoantibody by the end of 2012
221 (14% of the seroconverters) progressed to T1D
36 (16% of the progressors) were rapid progressors
The median delay from seroconversion to diagnosis 0.27 years
(range 0.02-0.96) in rapid progressors, while 4.04 years (1.02-15.81)
in slower progressors

Results: Rapid progressors vs. individuals

with slower disease development

Compared to individuals with slower disease development,

rapid progressors
Had higher levels of ICA (13.5 vs. 5 JDFU, P=0.004)
Were more often ICA positive (72 vs. 54%, P=0.04)

Had higher frequency of multipositivity (81 vs. 55%, P=0.004)

At seroconversion

Results: Rapid progressors vs. individuals

with slower disease development

No significant effect on progression rate:

Gender (53 vs. 58% males, P=0.58)
Age at seroconversion (median 1.8 vs. 1.5 years, P=0.53)
High-risk HLA genotype (44 vs. 41%, P=0.72)

Results: Rapid progressors vs. individuals

with slower disease development

Rapid progressors

Non-rapid progressors

P value

ICA

26 (72%)

100 (54%)

0.04

IAA

30 (83%)

125 (68%)

0.06

GADA

19 (54%)

83 (45%)

0.31

IA-2A

11 (31%)

42 (23%)

0.27

ICA, JDFU

13.5

5.0

0.004

IAA, RU

4.4

3.6

0.48

GADA, RU

5.8

3.2

0.66

IA-2A, RU

0.11

0.10

0.12

AAB positivity n (%)

AAB levels (median)

JDFU=Juvenile Diabetes Foundation Unit, RU=Relative Unit

Results: Rapid progressors vs.

autoantibody positive non-progressors

Compared to autoantibody positive non-progressors, rapid progressors

Were younger at seroconversion (1.8 vs. 5.5 years, P<0.001)
Carried more often the high-risk genotype HLA-DQB1*02:0302
(44 vs. 26%, P=0.03)
Had higher frequency of multipositive seroconversions (81 vs. 6%,
P<0.001)

Results: Rapid progressors vs.

autoantibody positive non-progressors

Had higher levels of ICA, IAA, GADA, and IA-2A at seroconversion

Rapid progressors

Autoantibody positive
non-progressors

P value

ICA, JDFU

13.5

4.0

< 0.001

IAA, RU

4.4

0.0

< 0.001

GADA, RU

5.8

0.1

< 0.001

IA-2A, RU

0.11

0.08

< 0.001

AAB levels (median)

JDFU=Juvenile Diabetes Foundation Unit, RU=Relative Unit

Results: Rapid progressors vs.

autoantibody positive non-progressors

No significant effect on rapid progression:

Gender (53 vs. 52%, P=0.95)
ICA positivity at seroconversion (72 vs. 80%, P=0.24)

Summary

At seroconversion, young age, high-risk HLA genotype, higher

levels of ICA, IAA, GADA, and IA-2A, and multipositivity are
characteristic of individuals with rapid progression to type 1
diabetes
Compared to individuals with slower disease progression, rapid
progressors have higher frequency of ICA positivity and
multipositivity, and higher levels of ICA at seroconversion

Conclusion

Young children with a high-risk HLA genotype

and fierce initial autoimmune responses
should be considered as a target for
intensive immunomodulation and early
efficient treatment

Collaborators

Prof. Mikael Knip, MD, PhD. Heli Siljander, Prof. Jorma Ilonen, Prof.
Olli Simell, Prof. Jorma Toppari, Prof. Riitta Veijola
Universities of Helsinki, Turku, Tampere, Kuopio, and Oulu, Finland

Thank you!