Aims/hypothesis
The aim of the study was to describe 20-year incidence trends for childhood type 1 diabetes in 23 EURODIAB centres and compare rates of increase in the first (1989–1998) and second ...(1999–2008) halves of the period.
Methods
All registers operate in geographically defined regions and are based on a clinical diagnosis. Completeness of registration is assessed by capture–recapture methodology. Twenty-three centres in 19 countries registered 49,969 new cases of type 1 diabetes in individuals diagnosed before their 15th birthday during the period studied.
Results
Ascertainment exceeded 90% in most registers. During the 20-year period, all but one register showed statistically significant changes in incidence, with rates universally increasing. When estimated separately for the first and second halves of the period, the median rates of increase were similar: 3.4% per annum and 3.3% per annum, respectively. However, rates of increase differed significantly between the first half and the second half for nine of the 21 registers with adequate coverage of both periods; five registers showed significantly higher rates of increase in the first half, and four significantly higher rates in the second half.
Conclusions/interpretation
The incidence rate of childhood type 1 diabetes continues to rise across Europe by an average of approximately 3–4% per annum, but the increase is not necessarily uniform, showing periods of less rapid and more rapid increase in incidence in some registers. This pattern of change suggests that important risk exposures differ over time in different European countries. Further time trend analysis and comparison of the patterns in defined regions is warranted.
Aims
C‐peptide secretion is currently the only available clinical biomarker to measure residual β‐cell function in type 1 diabetes. However, the natural history of C‐peptide decline after diagnosis ...can vary considerably dependent upon several variables. We investigated the shape of C‐peptide decline over time from type 1 diabetes onset in relation to age at diagnosis, haemoglobin A1c (HbA1c) levels and insulin dose.
Methods
We analysed data from 3929 type 1 diabetes patients recruited from seven European centres representing all age groups at disease onset (childhood, adolescence and adulthood). The influence of the age at onset on β‐cell function was investigated in a longitudinal analysis at diagnosis and up to 5‐years follow‐up.
Results
Fasting C‐peptide (FCP) data at diagnosis were available in 3668 patients stratified according to age at diagnosis in four groups (<5 years, n = 344; >5 years < 10 years, n = 668; >10 years < 18 years, n = 991; >18 years, n = 1655). FCP levels were positively correlated with age (p < 0.001); the subsequent decline in FCP over time was log‐linear with a greater decline rate in younger age groups (p < 0.0001).
Conclusions
This study reveals a positive correlation between age at diagnosis of type 1 diabetes and FCP with a more rapid decline of β‐cell function in the very young patients. These data can inform the design of clinical trials using C‐peptide values as an end‐point for the effect of a given treatment.
When using indirect ion-selective electrode (ISE) methods, hypertriglyceridemia leads to pseudohyponatremia due to water displacement artifacts. Multiple strategies exist to minimize this ...interference. Our objective was to create a patient-friendly one-tube-fits-all testing setup without compromising the method robustness.
Four strategies were evaluated in a single patient with hypertriglyceridemia. Additionally, the interchangeability between the Cobas 8000 and ABL Flex was evaluated on samples (n = 2274) with different total protein (TP) concentrations. Finally, a proof-of-concept (n = 40) was performed by re-measuring the routine sample with the ABL90 Flex.
ABL90 flex results and calculated sodium did not suffer from the presence of high triglyceride levels. We did not observe any significant differences between the three groups (P > 0.05) of sample types (arterial vs. venous plasma vs. venous whole blood after mixing up) nor for the analysers (Roche vs. ABL90 Flex). Passing-Bablok and Bland-Altman tests revealed interchangeability.
In future cases of hypertriglyceridemia, 1500 mg/dL will be used as a preliminary threshold for reliable sodium determination. Routine Li-heparin samples can be used for accurate sodium determination without any need for extra arterial or venous blood gas tubes, offering a patient-friendly test setup for similar cases.
ObjectiveBody weight-related insulin resistance probably plays a role in progression to type 1 diabetes, but has an uncertain impact following diagnosis. In this study, we investigated whether BMI ...measured at diagnosis was an independent predictor of C-peptide decline 1-year post-diagnosis.DesignMulticentre longitudinal study carried out at diagnosis and up to 1-year follow-up.MethodsData on C-peptide were collected from seven diabetes centres in Europe. Patients were grouped according to age at diagnosis (<5 years, n=126; >5 years <10 years, n=295; >10 years <18 years, n=421; >18 years, n=410). Linear regression was used to investigate whether BMI was an independent predictor of change in fasting C-peptide over 1 year. Models were additionally adjusted for baseline insulin dose and HbA1c.ResultsIn individuals diagnosed between 0 and 5 years, 5 and 10 years and those diagnosed >18 years, we found no association between BMI and C-peptide decline. In patients aged 10–18 years, higher BMI at baseline was associated with a greater decline in fasting C-peptide over 1 year with a decrease (β 95% CI; P value) of 0.025 (0.010, 0.041) nM/kg per m2 higher baseline BMI (P=0.001). This association remained significant after adjusting for gender and differences in HbA1c and insulin dose (β=0.026, 95% CI=0.0097, 0.042; P=0.002).ConclusionsThese observations indicate that increased body weight and increased insulin demand are associated with more rapid disease progression after diagnosis of type 1 diabetes in an age group 10–18 years. This should be considered in studies of β-cell function in type 1 diabetes.
Aims/hypothesis
We investigated whether screening for insulinoma-associated protein (IA-2) beta (IA-2β) autoantibodies (IA-2βA) and zinc transporter-8 (ZnT8) autoantibodies (ZnT8A) improves ...identification of first-degree relatives of type 1 diabetic patients with a high 5-year disease risk, which to date has been based on assays for insulin autoantibodies (IAA), GAD autoantibodies (GADA) and IA-2 autoantibodies (IA-2A).
Methods
IA-2βA and ZnT8A (using a ZnT8 carboxy-terminal hybrid construct, CW-CR, carrying 325Arg and 325Trp) were determined by radiobinding assay in 409 IAA
+
, GADA
+
and/or IA-2A
+
siblings or offspring (<40 years) of type 1 diabetic patients consecutively recruited by the Belgian Diabetes Registry. The median (interquartile range) age of the first-degree relatives was 12 (6–19) years.
Results
Of the first-degree relatives, 24% were IA-2A
+
(
n
= 97), 14% (
n
= 59) IA-2βA
+
and 20% (
n
= 80) ZnT8A
+
. IA-2βA and ZnT8A were significantly (
p
< 0.001) associated with IA-2A and prediabetes (
n
= 86); in IA-2A
−
first-degree relatives (
n
= 312) the presence of IA-2βA and ZnT8A was associated with an increased progression rate to diabetes (
p
< 0.001). Positivity for IA-2A and/or ZnT8A emerged as the most sensitive combination of two markers to identify first-degree relatives with a 5-year progression rate to diabetes of 45% (survival analysis) and as strongest predictor of diabetes (Cox regression analysis). Omission of first-degree relatives protected by
HLA-DQ
genotypes or maternal diabetes reduced the group to be followed from
n
= 409 to
n
= 246 (40%) with minor loss in the number of prediabetic IA-2A
+
or ZnT8A
+
first-degree relatives identified (
n
= 3).
Conclusions/interpretation
IA-2A
+
and/or ZnT8A
+
first-degree relatives may be the participants of choice in future secondary prevention trials with immunointervention in relatives of type 1 diabetic patients.
Background
The month of diagnosis in childhood type 1 diabetes shows seasonal variation.
Objective
We describe the pattern and investigate if year‐to‐year irregularities are associated with ...meteorological factors using data from 50 000 children diagnosed under the age of 15 yr in 23 population‐based European registries during 1989–2008.
Methods
Tests for seasonal variation in monthly counts aggregated over the 20 yr period were performed. Time series regression was used to investigate if sunshine hour and average temperature data were predictive of the 240 monthly diagnosis counts after taking account of seasonality and long term trends.
Results
Significant sinusoidal pattern was evident in all but two small centers with peaks in November to February and relative amplitudes ranging from ±11 to ±38% (median ±17%). However, most centers showed significant departures from a sinusoidal pattern. Pooling results over centers, there was significant seasonal variation in each age‐group at diagnosis, with least seasonal variation in those under 5 yr. Boys showed greater seasonal variation than girls, particularly those aged 10–14 yr. There were no differences in seasonal pattern between four 5‐yr sub‐periods. Departures from the sinusoidal trend in monthly diagnoses in the period were significantly associated with deviations from the norm in average temperature (0.8% reduction in diagnoses per 1 °C excess) but not with sunshine hours.
Conclusions
Seasonality was consistently apparent throughout the period in all age‐groups and both sexes, but girls and the under 5 s showed less marked variation. Neither sunshine hour nor average temperature data contributed in any substantial way to explaining departures from the sinusoidal pattern.
Summary
In first‐degree relatives of type 1 diabetic patients, we investigated whether diabetes risk assessment solely based on insulinoma antigen 2 (IA‐2) and zinc transporter 8 (ZnT8) antibody ...status (IA‐2A, respectively, ZnT8A) is as effective as screening for three or four autoantibodies antibodies against insulin (IAA), glutamate decarboxylase 65 kDa (GAD) glutamate decarboxylase autoantibodies (GADA) and IA‐2A with or without ZnT8A in identifying children, adolescents and adults who progress rapidly to diabetes (within 5 years). Antibodies were determined by radiobinding assays during follow‐up of 6444 siblings and offspring aged 0–39 years at inclusion and recruited consecutively by the Belgian Diabetes Registry. We identified 394 persistently IAA+, GADA+, IA‐2A+ and/or ZnT8A+ relatives (6·1%). After a median follow‐up time of 52 months, 132 relatives developed type 1 diabetes. In each age category tested (0–9, 10–19 and 20–39 years) progression to diabetes was significantly quicker in the presence of IA‐2A and/or ZnT8A than in their joint absence (P < 0·001). Progression rate was age‐independent in IA‐2A+ and/or ZnT8A+ relatives but decreased with age if only GADA and/or IAA were present (P = 0·008). In the age group mainly considered for immune interventions until now (10–39 years), screening for IA‐2A and ZnT8A alone identified 78% of the rapid progressors (versus 75% if positive for ≥ 2 antibodies among IAA, GADA, IA‐2A and ZnT8A or versus 62% without testing for ZnT8A). Screening for IA‐2A and ZnT8A alone allows identification of the majority of rapidly progressing prediabetic siblings and offspring regardless of age and is more cost‐effective to select participants for intervention trials than conventional screening.
Aims/hypothesis
The appearance of autoantibodies (Abs) before diabetes onset has mainly been studied in young children. However, most patients develop type 1 diabetes after the age of 15 years. In ...first-degree relatives aged under 40 years, we investigated the frequency of seroconversion to (persistent) Ab positivity, progression to diabetes and baseline characteristics of seroconverters according to age.
Methods
Abs against insulin (IAA), glutamate decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A) and zinc transporter 8 (ZnT8A) were measured during follow-up of 7,170 first-degree relatives.
Results
We identified 379 (5.3%) relatives with positivity for IAA, GADA, IA-2A and/or ZnT8A (Ab
+
) at first sampling and 224 (3.1%) at a later time point. Most seroconversions occurred after the age of 10 years (63%). During follow-up, Abs persisted more often in relatives initially Ab
+
(76%) than in seroconverters (53%;
p
< 0.001). In both groups diabetes developed at a similar pace and almost exclusively with Ab persistence (136 of 139 prediabetic individuals). For both groups, progression was more rapid if Abs appeared before the age of 10 years. Baseline characteristics at seroconversion did not vary significantly according to age.
Conclusions/interpretation
Seroconversion to (persistent) Ab
+
occurs regardless of age. Although the progression rate to diabetes is higher under age 10 years, later seroconverters (up to age 40 years) have similar characteristics when compared with age-matched initially Ab
+
relatives and generate an important minority of prediabetic relatives, warranting their identification and, eventually, enrolment in prevention trials.
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.
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