Aims/hypothesis: We investigated whether random proinsulin levels and proinsulin:C-peptide ratio (PI:C) complement immune and genetic markers for identifying relatives at high risk of type 1 diabetes. Materials and methods: During an initial sampling, random glycaemia, proinsulin, PI:C and HLA DQ genotype were determined in 561 non-diabetic first-degree relatives who had been positive for islet autoantibodies on one or more occasions and in 561 age-and sex-matched persistently antibodynegative relatives. Results: During follow-up (median 62 months), 46 relatives with antibodies at entry developed type 1 diabetes. At baseline, antibody-positive relatives (n=338) had higher PI:C values (p<0.001) than antibodynegative subjects with (n=223) or subjects without (n=561) later seroconversion. Proinsulin and PI:C were graded according to risk of diabetes as expressed by positivity for (multiple) antibodies or IA-2 antibodies, especially in persons carrying the high-risk HLA DQ2/DQ8 genotype and in prediabetic relatives. In the presence of multiple or IA-2 antibodies, a PI:C ratio exceeding percentile 66 of all antibody-negative relatives at entry (n=784) conferred a 5-year diabetes risk of 50% and 68%, respectively (p<0.001 vs 13% for same antibody status with PI:C

Aims/hypothesis: Prevention trials in first-degree relatives of type 1 diabetic patients are hampered by large interindividual differences in progression rate to diabetes. We investigated whether specific combinations of immune and genetic markers can identify subgroups with more homogeneous progression to clinical onset. Methods: Antibodies against islet cell cytoplasm (ICA), insulin (IAA), glutamate decarboxylase (GADA) and IA-2 protein (IA-2A) were measured in 790 non-diabetic control subjects and 4,589 first-degree relatives under age 40. Results: On first sampling, 11.1% of the siblings presented at least one antibody type (p<0.001 vs other relatives). During follow-up (median 52 months) 43 subjects developed type 1 diabetes (31 siblings, ten offspring of a diabetic father, two offspring of a diabetic mother). Using Kaplan-Meier survival analysis and Cox regression, IA-2A conferred the highest 5-year diabetes risk (>50%) irrespective of the number of antibodies present. In initially IA-2A-positive relatives (n=58) progression to hyperglycaemia depended more on HLA DQ status than on type of kinship (84% progression in the presence of DQ2/DQ8 vs 32% in its absence; p<0.003). In IA-2A-negative relatives (n=4,531) 5-year progression to diabetes increased with the number of other antibodies (ICA, GADA and/or IAA) (p<0.001) but overall did not exceed 10% even for two or more antibodies. Among relatives initially positive for one or more antibody type other than IA-2A (n=315), there was significantly more progression to diabetes (overall still <10%) in carriers of DQ2 (p<0.001 vs no DQ2), regardless of DQ8 status. Conclusions/interpretation: These observations suggest that the HLA-DQ-inferred risk of diabetes can proceed through two distinct pathways distinguished by IA-2A status. Combined positivity for DQ2/DQ8 and IA-2A defines a more homogeneous high-risk population for prevention trials than those used so far.

BACKGROUND: When the concentrations of 2 or more substances are measured separately, their molar ratios are subject to the additive imprecisions of the different assays. We hypothesized that the cumulative error for concentration ratios of peptides containing a common sequence might be minimized by measuring the peptides simultaneously with a "trefoil-type" immunoassay.

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Aims/hypothesis: The incidence of type 1 diabetes varies according to age, sex and season of diagnosis. We investigated whether these and other clinical, biological and anthropometric parameters were correlated with residual beta cell function in newly diagnosed patients, since it is possible that the nature of external and/or genetic disease accelerators may be (partly) reflected in the inaugural disease presentation. Materials and methods: The correlates of random Cpeptide levels sampled shortly after diagnosis (median [interquartile range]: 3 [0-14] days) were studied by multivariate analysis in 1,883 islet-antibody-positive diabetic patients aged <40 years who were diagnosed between 1989 and 2000. Results: Higher C-peptide levels (above percentile 50 of patients) were associated with older age at diagnosis, female sex, diagnosis in the high-incidence season (October to March), less-decreased BMI (expressed as a standard deviation score), lower insulin requirements after stabilisation, lower prevalence of ketonuria and a less-increased glycaemia at diagnosis (all p<0.001). C-peptide levels were not correlated with calendar year at diagnosis, duration of symptoms prior to diagnosis, HLA-DQ2/DQ8 genotype or islet antibody status.Conclusions/interpretation: Sex-and seasondependent differences in residual functional beta cell mass and/or insulin resistance have been identified at diagnosis of type 1 diabetes. They may reflect differences in disease-precipitating external or lifestyle factors and should be further investigated longitudinally in prediabetes to further identify putative aetiological factors, which may provide targets for prevention.