Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2beta) and zinc transporter-8 to select first-degree relatives of type 1 diabetic patients with risk of rapid progression to clinical onset of the disease: implications for prevention trials.

AIMS/HYPOTHESIS: We investigated whether screening for insulinoma-associated protein (IA-2) beta (IA-2beta) autoantibodies (IA-2betaA) 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-2betaA 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-2betaA(+) and 20% (n = 80) ZnT8A(+). IA-2betaA 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-2betaA 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.

Adiponectin levels do not predict clinical onset of type 1 diabetes in antibody-positive relatives.

AIMS/HYPOTHESIS: Insulin resistance has been proposed as a risk factor for type 1 diabetes. We investigated whether adiponectin, an insulin sensitiser, can serve as an additional predictive marker for type 1 diabetes in first-degree relatives of known patients. METHODS: Adiponectin was followed in 211 persistently islet antibody-positive (Ab+) first-degree relatives of type 1 diabetic patients and in 211 age- and sex-matched persistently antibody-negative relatives, and correlated with antibody status, random proinsulin:C-peptide ratio and HLA-DQ genotype. During follow-up, 37 Ab+ relatives developed type 1 diabetes. RESULTS: In the group of 422 relatives, baseline adiponectin correlated inversely with age and BMI and was lower in male than in female participants, especially after 15 years of age (p < 0.001). There was no correlation with antibody status or later development of diabetes. In 24 Ab+ relatives sampled fasted, adiponectin levels correlated significantly with homeostasis model assessment of insulin sensitivity (p = 0.006). In Ab+ relatives (n = 211), adiponectin levels could not predict type 1 diabetes nor complement risk assessment based on islet antibodies, HLA-DQ genotype and pancreatic hormones in Cox regression analysis. CONCLUSIONS/INTERPRETATION: Adiponectin levels do not contribute to the prediction of type 1 diabetes in Ab+ relatives.

Identification of prediabetes in first-degree relatives at intermediate risk of type I diabetes.

Prevention trials of type I diabetes are limited by recruitment of individuals at high risk of the disease. We investigated whether demographic and biological characteristics can identify rapid progressors among first-degree relatives of known patients at intermediate (< 10%) 5-year risk. Diabetes-associated antibodies, random proinsulin : C-peptide (PI/C) ratio and HLA DQ genotype were determined (repeatedly) in 258 islet antibody-positive IA-2Antibody-negative (Abpos/IA-2Aneg) normoglycaemic first-degree relatives. During follow-up (median 81 months), 14 of 258 Abpos/IA-2Aneg relatives developed type I diabetes; 13 (93%) of them had persistent antibodies conferring a 12% [95% confidence interval (CI): 5-19%] 5-year risk of diabetes. In Abpos/IA-2Aneg relatives with persistent antibodies (n = 126), the presence of >/= 1 HLA DQ susceptibility haplotype in the absence of a protective haplotype (P = 0.033) and appearance on follow-up of a high PI/C ratio (P = 0.007) or IA-2A-positivity (P = 0.009) were identified as independent predictors of diabetes. In persistently antibody-positive relatives with HLA DQ risk a recurrently high PI/C ratio or development of IA-2A identified a subgroup (n = 32) comprising 10 of 13 (77%) prediabetic relatives and conferred a 35% (95% CI: 18-53%) 5-year risk. Under age 15 years, 5-year progression (95% CI) was 57% (30-84%) and sensitivity 62%. In the absence of IA-2A, the combination of antibody persistence, HLA DQ risk and elevated PI/C ratio or later development of IA-2A and young age defines a subgroup of relatives with a high risk of type I diabetes (>/= 35% in 5 years). Together with initially IA-2A-positive relatives these individuals qualify for standardized beta cell function tests in view of prevention trials.