Antibodies to the Mr 64,000 (64K) protein in islet cell antibody positive non-diabetic individuals indicate high risk for impaired Beta-cell function

A prospective study of a normal childhood population identified 44 islet cell antibody positive individuals. These subjects were typed for HLA DR and DQ alleles and investigated for the presence of antibodies to the Mr 64,000 (64K) islet cell antigen, complement-fixing islet cell antibodies and radiobinding insulin autoantibodies to determine their potency in detecting subjects with impaired Beta-cell function. At initial testing 64K antibodies were found in six of 44 islet cell antibody positive subjects (13.6%). The same sera were also positive for complement-fixing islet cell antibodies and five of them had insulin autoantibodies. During the follow-up at 18 months, islet cell antibodies remained detectable in 50% of the subjects studied. In all six cases who were originally positive, 64K antibodies were persistently detectable, whereas complement-fixing islet cell antibodies became negative in two of six and insulin autoantibodies in one of five individuals. HLA DR4 (p < 0.005) and absence of asparic acid (Asp) at position 57 of the HLA DQ chain (p < 0.05) were significantly increased in subjects with 64K antibodies compared with control subjects. Of 40 individuals tested in the intravenous glucose tolerance test, three had a first phase insulin response below the first percentile of normal control subjects. Two children developed Type 1 (insulin-dependent) diabetes mellitus after 18 and 26 months, respectively. Each of these subjects was non-Asp homozygous and had persistent islet cell and 64K antibodies. We conclude that 64K antibodies, complement-fixing islet cell antibodies and insulin autoantibodies represent sensitive serological markers in assessing high risk for a progression to Type 1 diabetes in islet cell antibody positive non-diabetic individuals

Insulin autoantibodies as determined by competitive radiobinding assay are positively correlated with impaired beta-cell function — The Ulm-Frankfurt population study

Out of a random population of 4208 non-diabetic pupils without a family history of Type I diabetes 44 (1.05%) individuals had islet cell antibody (ICA) levels greater or equal to 5 Juvenile Diabetes Foundation (JDF) units. 39 of these ICA-positives could be repeatedly tested for circulating insulin autoantibodies (CIAA) using a competitive radiobinding assay. The results were compared with the insulin responses in the intravenous glucose tolerance tests (IVGTT) and with HLA types. Six pupils were positive for CIAA. All of them had complement-fixing ICA, and 5 of them were HLA-DR4 positive. Three of the 6 showed a first-phase insulin response below the first percentile of normal controls. Our data indicate that in population-based studies CIAA can be considered as a high risk marker for impaired beta-cell function in non-diabetic ICA-positive individuals

Structure of the adaptor protein p14 reveals a profilin-like fold with distinct function

The adaptor protein p14 is associated with the cytoplasmic face of late endosomes that is involved in cell-surface receptor endocytosis and it also directly interacts with MP1, a scaffolding protein that binds the MAP kinase ERK1 and its upstream kinase activator MEK1. The interaction of p14 with MP1 recruits the latter to late endosomes and the endosomal localization of p14/MP1-MEK1-ERK1 scaffolding complex is required for signaling via ERK MAP kinase in an efficient and specific manner upon receptor stimulation. Here, we report the three-dimensional solution structure of the adaptor protein p14. The structure reveals a profilin-like fold with a central five-stranded β-sheet sandwiched between α-helices. Unlike profilin, however, p14 exhibits weak interaction with selective phosphoinositides but no affinity towards proline-rich sequences. Structural comparison between profilin and p14 reveals the molecular basis for the differences in these functions. We further mapped the MP1 binding sites on p14 by NMR, and discuss the implications of these important findings on the possible function of p14. © 2005 Elsevier Ltd. All rights reserved.link_to_subscribed_fulltex