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

Abstract

Summary.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 13 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 i (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.

Immunological heterogeneity in Type I diabetes: presence of distinct autoantibody patterns in patients with acute onset and slowly progressive disease

“…Our observations suggest that autoimmunity to PTPs reflect a severe beta-cell destruction leading to manifestation of the disease early in life or to acute onset of diabetes and insulin dependency when present in older individuals. This is consistent with studies in prediabetic subjects where rapid progression to overt diabetes was described in subjects at risk for Type I diabetes positive for IA-2A as compared with subjects positive only for ICA or GADA [16,24,26]. As described for the 37 kD/40 kD antibodies and IA-2A, both the prevalence and levels of IA-2Ab were closely associated with IA-2A and both were positively correlated with ICA but not with GADA [26±28].…”

Recombinant human preproinsulin expression, purification and reaction with insulin autoantibodies in sera from patients with insulin-dependent diabetes mellitus

“…All sera were positively assayed for autoantibodies directed against GAD65 (Seissler et al, 1992). Such autoantibodies are commonly believed to be one of the major predictive serum markers for IDDM (Baekkeskov et al, 1982(Baekkeskov et al, , 1990Kaufman et al, 1992).…”

“…All sera from autoimmune patients with recent-onset IDDM tested in this study were positively assayed for anti-GAD65 autoantibodies by immunoprecipitation as described previously (Seissler et al, 1992). The antigen sample for screening the sera of patients was metabolically labeled recombinant full-length human GAD65 which was expressed in infected Spodoptera frugiperda (Sf9) insect cells mediated by recombinant baculovirus Autographa californica (L.…”

Cytoplasmic Islet Cell Antibodies Recognize Distinct Islet Antigens in IDDM But Not in Stiff Man Syndrome

“…Serial serum samples were analyzed from 6 ICA + individuals (mean age 15.7 ± 2.4 yr; range 10-17 yr) over a period of 32 mo. The individuals were characterized previously elsewhere (14), and 3 of them developed IDDM during this time of follow-up. Antibody analyses.…”