RESUMO
Environmental agents are proposed to play a role in triggering or exacerbating pancreatic islet autoimmunity in people genetically predisposed to type 1 diabetes. However, with few exceptions, these agents remain enigmatic. Clues to environmental agents may be found by investigating population/geographic clusters or 'hotspots' of high disease incidence. We were alerted to a small community where the incidence of type 1 diabetes appeared to be five-fold higher than expected. Because type 1 diabetes is now recognized to have a subclinical phase during which anti-islet antibodies can be detected, we aimed to identify and characterize a reservoir of children with subclinical disease in this community. Venous blood samples were collected from 1906/2347 (81%) local school children during one week. Islet cell antibodies (ICAs) were detected in 122 (6.4%) children, 18 (0.9%) being high titer (> or = 20 Juvenile Diabetes Foundation units (JDFu)). On retest, 15 months later, the majority of low titer ICAs were undetectable, whereas high-titer ICAs persisted. The latter were found in two distinct age-related, ethnically similar groups. The younger group, aged 6-9 yr, had antibodies to insulin (IAAs), glutamic acid decarboxylase (GAD) and tyrosine phosphatase IA2 in addition to ICA, human leukocyte antigen (HLA) genes associated with susceptibility to type 1 diabetes, and lower first-phase insulin responses (FPIRs) to intravenous glucose. The older group, aged 13-16 yr, the age cohort of the index clinical cases, had few antibodies other than ICA, non-susceptibility HLA genes and normal FPIRs. During follow-up, three children, all from the younger group with multiple antibodies and FPIRs less than the first percentile, developed diabetes 4, 6 and 7 yr after screening. The finding of two age groups of subclinical disease suggests that if environmental agents triggered islet autoimmunity they did not act constantly on the community. Furthermore, the absence of multiple autoantibodies and/or HLA susceptibility genes in the older group, the source of index clinical cases, implies they are a residual subgroup with slow or absent progressive beta-cell destruction. This study illustrates that the natural history of type 1 diabetes may be elucidated by analyzing age-related subclinical disease in the general population.
RESUMO
Insulin-dependent diabetes mellitus (IDDM) is preceded by the presence of antibodies against islet proteins including a protein tyrosine phosphatase (PTP) designated IA-2. Recently, we cloned a novel PTP named IAR which shares 43% sequence identity with IA-2 and is recognised by antibodies from a majority of patients with IDDM. The aim of the present study was to determine whether IAR antibodies (IAR Ab) or IA-2 antibodies (IA-2 Ab) are associated with progression to IDDM in first-degree relatives "at-risk" for IDDM (operationally defined as those with islet cell antibodies [ICA] > or = 20JDFU or insulin autoantibodies [IAA] > or = 100 nU/ml), and to examine combinations of IAR Ab and IA-2 Ab in these subjects. The sensitivity and specificity of these antibodies were also examined in patients with recent-onset IDDM. Using Cox's Proportional Hazards Model, the number of siblings with IDDM was associated with progression to IDDM in "at-risk" relatives, but other covariables (age, sex, number of affected offspring or parents) were not significantly associated. Using number of affected siblings as a covariable, both IAR and IA-2 antibodies were significantly associated with progression to IDDM (p < 0.005). Combinations of both antibodies, however, did not result in a significantly stronger association with progression to IDDM. The threshold of positivity for IAR Ab (0.5 units) and IA-2 Ab (3.0 units) assays was adjusted to give the same specificity (97.9%) for each assay in 144 healthy control subjects, to allow standardised comparisons. Levels of IAR Ab and IA-2 Ab were strongly correlated in 53 recent-onset IDDM patients (r = 0.70, p < 0.0001) but 11.3% had IAR Ab in the absence of IA-2 Ab and 16.9% had IA-2 Ab in the absence of IAR Ab. The sensitivity for IDDM (defined as the proportion of IDDM patients positive) was 56.6% for IAR Ab and 62.3% for IA-2 Ab. We conclude that there is considerable overlap in IA-2 Ab and IAR Ab positivity, although either antibody can occur independently in IDDM patients. Both IAR Ab and IA-2 antibodies are associated with progression to IDDM in first-degree relatives at-risk of IDDM, but the use of IAR and IA-2 antibodies in combination are not significantly more strongly associated with progression than single antibodies. IAR Ab may play an important role in the prediction of IDDM.
