Aims/hypothesis
Secondary type 1 diabetes prevention trials require selection of participants with impending diabetes.
HLA-A
and -
B
alleles have been reported to promote disease progression. We ...investigated whether typing for
HLA-B*18
and
-B*39
may complement screening for
HLA-DQ8
,
-DQ2
and
-A*24
and autoantibodies (Abs) against islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) for predicting rapid progression to hyperglycaemia.
Methods
A registry-based group of 288 persistently autoantibody-positive (Ab
+
) offspring/siblings (aged 0–39 years) of known patients (Ab
+
against insulin, GAD, IA-2 and/or ZnT8) were typed for
HLA-DQ
, -
A
and -
B
and monitored from the first Ab
+
sample for development of diabetes within 5 years.
Results
Unlike
HLA-B*39
,
HLA-B*18
was associated with accelerated disease progression, but only in
HLA-DQ2
carriers (
p
< 0.006). In contrast,
HLA-A*24
promoted progression preferentially in the presence of
HLA-DQ8
(
p
< 0.002). In
HLA-DQ2
- and/or
HLA-DQ8
-positive relatives (
n
= 246),
HLA-B*18
predicted impending diabetes (
p
= 0.015) in addition to
HLA-A*24
,
HLA-DQ2/DQ8
and positivity for IA-2A or ZnT8A (
p
≤ 0.004).
HLA-B*18
interacted significantly with
HLA-DQ2/DQ8
and
HLA-A*24
in the presence of IA-2 and/or ZnT8 autoantibodies (
p
≤ 0.009). Additional testing for
HLA-B*18
and
-A*24
significantly improved screening sensitivity for rapid progressors, from 38% to 53%, among relatives at high Ab-inferred risk carrying at least one genetic risk factor. Screening for
HLA-B*18
increased sensitivity for progressors, from 17% to 28%, among individuals carrying ≥3 risk markers conferring >85% 5 year risk.
Conclusions/interpretation
These results reinforce the importance of HLA class I alleles in disease progression and quantify their added value for preparing prevention trials.
We aimed to investigate care processes and outcomes among children and adolescents with type 1 diabetes treated in hospital-based multidisciplinary paediatric diabetes centres. Our retrospective ...cross-sectional study among 12 Belgian centres included data from 974 patients with type 1 diabetes, aged 0–18 years. Questionnaires were used to collect data on demographic and clinical characteristics, as well as process of care completion and outcomes of care in 2008. Most patients lived with both biological or adoption parents (77 %) and had at least one parent of Belgian origin (78 %). Nearly all patients (≥95 %) underwent determination of HbA
1c
and BMI. Screening for retinopathy (55 %) and microalbuminuria (73 %) was less frequent, but rates increased with age and diabetes duration. Median HbA
1c
was 61 mmol/mol (7.7 %) interquartile range 54–68 mmol/mol (7.1–8.4 %) and increased with age and insulin dose. HbA
1c
was higher among patients on insulin pump therapy. Median HbA
1c
significantly differed between centres from 56 mmol/mol (7.3 %) to 66 mmol/mol (8.2 %). Incidence of severe hypoglycaemia was 30 per 100 patient-years. Admissions for ketoacidosis had a rate of 3.2 per 100 patient-years. Patients not living with both biological or adoption parents had higher HbA
1c
and more admissions for ketoacidosis. Parents' country of origin was not associated with processes and outcomes of care.
Conclusion
: Outcomes of care ranked well compared to other European countries, while complication screening rates were intermediate. The observed centre variation in HbA
1c
remained unexplained. Outcomes were associated with family structure, highlighting the continuing need for strategies to cope with this emerging challenge.
Aims To examine incidence and trends of Type 1 diabetes worldwide for the period 1990–1999.
Methods The incidence of Type 1 diabetes (per 100 000/year) was analysed in children aged ≤ 14 years from ...114 populations in 112 centres in 57 countries. Trends in the incidence of Type 1 diabetes were analysed by fitting Poisson regression models to the dataset.
Results A total of 43 013 cases were diagnosed in the study populations of 84 million children. The age‐adjusted incidence of Type 1 diabetes among 112 centres (114 populations) varied from 0.1 per 100 000/year in China and Venezuela to 40.9 per 100 000/year in Finland. The average annual increase in incidence calculated from 103 centres was 2.8% (95% CI 2.4–3.2%). During the years 1990–1994, this increase was 2.4% (95% CI 1.3–3.4%) and during the second study period of 1995–1999 it was slightly higher at 3.4% (95% CI 2.7–4.3%). The trends estimated for continents showed statistically significant increases all over the world (4.0% in Asia, 3.2% in Europe and 5.3% in North America), except in Central America and the West Indies where the trend was a decrease of 3.6%. Only among the European populations did the trend in incidence diminish with age.
Conclusions The rising incidence of Type 1 diabetes globally suggests the need for continuous monitoring of incidence by using standardized methods in order to plan or assess prevention strategies.
Type 1 diabetes arises from an interplay between environmental and genetic factors. The reported seasonality at diagnosis supports the hypothesis that currently unknown external triggers play a role ...in the onset of the disease. We investigated whether a seasonal pattern is observed at diagnosis in Belgian Type 1 diabetic patients, and if so whether seasonality varies according to age, sex and genetic risk, all known to affect the incidence of Type 1 diabetes.
The seasonal pattern at clinical diagnosis was assessed in 2176 islet antibody-positive diabetic patients aged 0 to 39 years diagnosed between 1989 and 2000. Additional stratification was performed for age, sex and HLA-DQ genotype.
Overall, a significant seasonal pattern at clinical diagnosis of diabetes was observed (p<0.001). More subjects were diagnosed in the period of November to February (n=829) than during the period of June to September (n=619) characterised by higher averages of maximal daily temperature and daily hours of sunshine. However, the seasonal pattern was restricted to patients diagnosed above the age of 10 (0-9 years: p=0.398; 10-19 years: p<0.001; 20-29 years: p=0.003; 30-39 years: p=0.015). Since older age at diagnosis is associated with a male to female excess and a lower prevalence of the genetic accelerator HLA-DQ2/DQ8, we further stratified the patients aged 10 to 39 years (n=1675) according to HLA-DQ genotype and sex, and we found that the seasonal pattern was largely restricted to male subjects lacking DQ2/DQ8 (n=748; p<0.00 vs all others: n=927; p=0.031).
In a subgroup of male patients diagnosed over the age of 10, the later stages of the subclinical disease process may be more driven by sex- and season-dependent external factors than in younger, female and genetically more susceptible subjects. These factors may explain the male to female excess in diabetes diagnosed in early adulthood.
Apart from genes in the HLA complex (IDDM1) and the variable number of tandem repeats in the 5′ region of the insulin gene (INS VNTR, IDDM2), several other loci have been proposed to contribute to ...IDDM susceptibility. Recently, linkage and association have been shown between the cytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) gene on chromosome 2q and IDDM. In a registry‐based group of 525 recent‐onset IDDM patients < 40 years old we investigated the possible interactions of a CTLA‐4 gene A‐to‐G transition polymorphism with age at clinical disease onset and with the presence or absence of established genetic (HLA‐DQ, INS VNTR) and immune disease markers (autoantibodies against islet cell cytoplasm (ICA); insulin (IAA); glutamate decarboxylase (GAD65‐Ab); IA‐2 protein tyrosine phosphatase (IA‐2‐Ab)) determined within the first week of insulin treatment. In new‐onset IDDM patients, G‐allele‐containing CTLA‐4 genotypes (relative risk (RR) = 1.5; 95% confidence interval (CI) = 1.2–2.0; P < 0.005) were not preferentially associated with age at clinical presentation or with the presence of other genetic (HLA‐DR3 or DR4 alleles; HLA‐DQA1*0301‐DQB1*0302 and/or DQA1*0501‐DQB1*0201 risk haplotypes; INS VNTR I/I risk genotype) or immune (ICA, IAA, IA‐2‐Ab, GAD65‐Ab) markers of diabetes. For 151 patients, thyrogastric autoantibodies (anti‐thyroid peroxidase, anti‐thyroid‐stimulating hormone (TSH) receptor, anti‐parietal cell, anti‐intrinsic factor) were determined, but association between CTLA‐4 risk genotypes and markers of polyendocrine autoimmunity could not be demonstrated before or after stratification for HLA‐ or INS‐linked risk. In conclusion, the presence of a G‐containing CTLA‐4 genotype confers a moderate but significant RR for IDDM that is independent of age and genetic or immune disease markers.
Multiple islet autoantibody positivity is currently believed to best predict progression to Type I (insulin-dependent) diabetes mellitus. We compared its predictive value with that of positivity for ...a particular type of islet autoantibody, directed against the IA-2 antigen.
Autoantibodies against islet cell cytoplasm (ICA), insulin (IAA), GAD (GADA) and IA-2 (IA-2A) were measured at initial sampling in 1724 non-diabetic siblings (median age range:16 0-39 years) of Type I diabetic patients with a median follow-up of 50 months.
On initial sampling 11% of siblings were positive for one antibody type or more and 2.1% for three of more types. During follow-up, 27 antibody-positive siblings developed diabetes. Using survival analysis, the risk for clinical onset within 5 years was 34% in subjects positive for three or more types compared with 13% in those with one type or more. Progression to diabetes amounted to 12% within 5 years among siblings positive for IAA, 20% for ICA, 19% for GADA but 59% for IA-2A (p<0.001 vs absence of the respective antibody). IA-2A were detected in 1.7% of all siblings and in 56% of the prediabetic subjects on first sampling. Initial positivity for two or three antibody markers was associated with a higher progression rate in IA-2A positive as compared to IA-2A negative siblings (p=0.001). In absence of IA-2A initial positivity for another antibody (IAA, ICA or GADA) conferred a low (<10% within 5 years) risk of diabetes compared to subjects lacking this antibody.
In siblings of Type I diabetic patients, IA-2A positivity is a more direct predictor of impending clinical onset than multiple antibody positivity per se. Assessment of IA-2A status allows us to select subjects with homogeneously high risk of diabetes for participation in prevention trials.
To compare the incidence rate of IDDM in the age-groups 0-14 and 15-39 years in Antwerp, Belgium, and to compare demographic, clinical, and biological data from Antwerp IDDM patients with 92% ...ascertainment with those from a larger Belgian patient group with 40% ascertainment.
Incident cases of IDDM were reported by physicians of the Belgian Diabetes Registry and in Antwerp by several other sources. In Antwerp, completeness of ascertainment was calculated by the capture-recapture method. Demographic and clinical data were collected by questionnaire. Blood was sampled for HLA-DQ genotyping and, in new-inset patients, for autoantibodies.
In Antwerp, the age- and sex-standardized IDDM incidence rates were similar in both age-groups (0-14 years: 11.8/100,000; 15-39 years: 8.9/100,000). The incidence rate decreased in girls above age 15 years (6.9/100,000; P = 0.003) but not in boys (11.0/100,000). Both in Antwerp and Belgium, IDDM was diagnosed more frequently in the 15-39 years age-group (60% of all cases) than under age 15 years, with a lower prevalence of acute symptoms, ketonuria, high-risk HLA-DQ genotype, and autoantibodies against insulin, islet cells, and IA-2, but with a higher prevalence of GAD65 autoantibodies.
In Antwerp, the incidence rate of IDDM under age 15 years is intermediately high compared with the rates in other European regions. It is similar in the 15-39 years age-group, but with a marked male predominance. Demographic, clinical, and biological data show the same age-dependent heterogeneity as the data collected nationwide, with 40% ascertainment indicating the representativeness of the latter.
Pancreatic amylase and lipase activities were measured in sera of 307 Caucasian insulin-dependent diabetes mellitus patients (IDDM) at clinical onset, 303 nondiabetic siblings of registered patients, ...and 207 control subjects under age 40 years. In all subject groups lipasemia and pancreatic (but not salivary) amylasemia increased with age and were significantly correlated. Using age-dependent reference ranges, reduced pancreatic enzyme levels were measured in 18% of patients, 6% of siblings, and only 2% of control subjects (p < 0.001). Increased lipase levels were noted in 10% of patients and in only 3% of siblings and 2% of control subjects (p < 0.001). Using both univariate and multivariate statistical analysis, elevated lipase activities at clinical onset were associated with higher titers of autoantibodies against islet cell cytoplasmic antigens and glucagon, but not against insulin or the 65-kDa isoform of glutamic acid decarboxylase (GAD65-Ab), or with markers of genetic predisposition or metabolic dysregulation. These findings indicate the presence of modest, but statistically significant, variations in circulating pancreatic enzyme levels in 28% of IDDM patients at clinical onset (p < 0.001 vs. 5% in control subjects). Increased lipase levels may express a form or a stage of the disease with exocrine cell damage; their association with higher titers of islet cell and glucagon autoantibodies is not yet explained. Lower lipase and isoamylase levels are thought to result from the reduced acinar cell function in the vicinity of insulin-depleted islets. It must be tested whether pancreatic enzyme activities in serum can also be altered during the preclinical stage and can thus be considered as an additional marker for the disease process in the pancreas.
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