Abstract
The purpose of this research was to assess the role of antibodies
to glutamic acid decarboxylase (GAD) in children with newly diagnosed
type 1 diabetes in relation to other disease-associated autoantibodies
and HLA-defined genetic disease susceptibility, to evaluate the
role of GAD antibodies (GADA) in relation to clinical characteristics
at the diagnosis of type 1 diabetes and to compare the frequency
and levels of GADA between adult and childhood onset type 1 diabetes.The
study population comprised altogether 999 children and adolescents
with type 1 diabetes, 100 affected adult subjects and more than
370 non-diabetic controls. GADA were measured with a liquid radioligand
assay, and a similar assay was used for the analysis of antibodies
to the islet antigen 2 (IA-2) molecule. Islet cell antibodies (ICA)
were determined with conventional immunofluorescence and insulin
autoantibodies (IAA) with a liquid phase radioimmunoassay either in
a tube or a plate format (microassay).
GADA were detected at diagnosis in 68 to 73% of the
children and adolescents with type 1 diabetes. GADA were more frequent
in girls and in those older than 10 years of age at clinical disease manifestation.
Subjects testing positive for GADA had higher levels of ICA and
IAA than those negative for GADA. Multiple antibodies ( 2) were
observed more often in girls and in children under the age of 5
years.
Children with the HLA DR3/non-DR4 phenotype had the
highest GADA levels, significantly higher than those seen in children
with the DR4/non-DR3 combination. The highest prevalence
of multiple autoantibodies was seen in subjects heterozygous for
DR3/4. When studying HLA DQB1 genotypes those with the
DQB1*02/y (y = other than *0302)
genotype had the highest GADA levels as expected since DQB1*02
and DR3 are in strong linkage disease equilibrium. The same group
had the lowest frequency of multiple antibodies among the children
younger than 10 years of age.Patients diagnosed with type 1 diabetes
before the age of 20 had a higher frequency of all four autoantibodies
analysed than those presenting with clinical disease after the age
of 20. The proportion of subjects testing negative for all four
antibodies was substantially higher among adults than in those under
the age of 20. The smallest age-related difference in antibody frequencies
was observed for GADA, and the GADA-positive adult patients had
on an average about three times higher antibody levels than the
GADA-positive children.
No association was observed between positivity for GADA and
the degree of metabolic decompensation at the clinical presentation
of type 1 diabetes. No significant differences were either seen
between the subjects who tested positive for GADA at diagnosis and
those who were negative in serum C-peptide concentrations, metabolic
control or exogenous insulin requirement over the first 2 years
of observation. The proportion of children in clinical remission
was, however, lower among GADA-positive subjects than in GADA-negative
patients at 18 months after the clinical manifestation. Positivity
for multiple antibodies was associated with accelerated beta-cell
destruction and increased exogenous insulin requirements over the
2-year observation period.
The observations that GADA are related to female gender, older
age and the HLA-DR3/ DQB1*02 haplotype suggest
that a strong humoral immune response to GAD may reflect a propensity
to general autoimmunity rather than specific beta-cell destruction.
| Identifer | oai:union.ndltd.org:oulo.fi/oai:oulu.fi:isbn951-42-5628-X |
| Date | 05 May 2000 |
| Creators | Sabbah, E. (Emad) |
| Publisher | University of Oulu |
| Source Sets | University of Oulu |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis, info:eu-repo/semantics/publishedVersion |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess, © University of Oulu, 2000 |
| Relation | info:eu-repo/semantics/altIdentifier/pissn/0355-3221, info:eu-repo/semantics/altIdentifier/eissn/1796-2234 |
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