Antibodies against islet cell antigens are used as predictive markers of type 1 diabetes, but it is unknown whether they reflect an ongoing autoimmune process in islet tissue. We investigated whether organs from adult donors that are positive for autoantibodies (aAbs) against islet cell antigens exhibit insulitis and/or a reduced ␤-cell mass. Serum from 1,507 organ donors (age 25-60 years) was analyzed for islet cell antibodies (ICAs), glutamate decarboxylase aAbs (GADAs), insulinoma-associated protein 2 aAbs (IA2As), and insulin aAbs. T ype 1 diabetes results from a specific and major loss of insulin-producing ␤-cells presumably through a T-cell-mediated process (1-5). At clinical onset, patients present circulating autoantibodies (aAbs) against islet cell antigens, which can appear many years before hyperglycemia is established and which are therefore used for prediction of the disease. In firstdegree relatives of type 1 diabetic patients, the risk for developing the disease is higher when multiple positivity is present for aAbs against the islet cell cytoplasm (islet cell antibodies [ICA]), insulin (insulin aAbs [IAA]), the 65,000 M r isoform of glutamate decarboxylase (glutamate decarboxylase aAbs [GADA]), or the insulinoma-associated protein 2 tyrosine phosphatase (insulinoma-associated protein 2 aAbs [IA-2A]) (6 -12). Antibody positivity is therefore used for patient recruitment in prevention trials, but it is still unknown whether it corresponds to an insulitis process in the pancreas and, if so, for which combination. There are only few studies available on the histopathology of the pancreas in antibody ϩ nondiabetic individuals (13,14). In the four reported cases, no leukocytic islet infiltrate or signs of ␤-cell damage were noticed; three of them were GADA ϩ patients with polyendocrinopathy, and one was an IA-2A ϩ organ donor. In the present study we investigated the pancreas in 62 aAb ϩ organ donors. This larger series allowed us to identify two cases with insulitis, one of whom presenting signs of ␤-cell proliferation, and to correlate these histopathological findings to the small subgroup of patients with three or four aAbs and a high-risk genotype. RESEARCH DESIGN AND METHODSCollection of pancreatic tissue. Pancreas biopsies were obtained from the Beta Cell Bank, which operates for a clinical trial on islet cell transplantation in Belgium (15,16). They were taken as part of a quality control procedure that was approved by the ethics committees of the Belgian Diabetes Registry and participating hospitals. Tissue (ϳ0.5 cm 3 ) was excised from the body region of cold-preserved (UW flushed) donor organs that were provided by Eurotransplant Foundation (Leiden, The Netherlands). It was fixed in 4% (vol/vol) phosphate-buffered formaldehyde, pH 7.4, or Bouin's fixative; embedded in paraffin; and then histologically analyzed. Between 1989 and 2004, a total of 1,507 biopsies were collected from patients aged 25-60 years for whom serum or plasma was also available for islet cell antibody assays. For none of t...

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.

SummaryPrevention 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%)

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.