Antibodies to a 64,000 M(r) human islet cell antigen precede the clinical onset of insulin-dependent diabetes

Antibodies in sera from newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients are directed to a human islet cell protein of relative molecular mass (M(r)) 64,000. Since IDDM seems to develop after a prodromal period of β-cell autoimmunity,, this study has examined whether 64,000 M(r) antibodies could be detected in 14 individuals who subsequently developed IDDM and five first degree relatives who have indications of altered β-cell function. Sera were screened by immunoprecipitation on total detergent lysates of human islets and positive sera retested on membrane protein preparations. Antibodies to the 64,000 M(r) membrane protein were consistently detected in 11/14 IDDM patients, and in all 5 first degree relatives. 10 IDDM patients were already positive in the first samples, obtained 4-91 mo before the clinical onset of IDDM, whereas 1 patient progressed to a high 64,000 M(r) immunoreactivity, at a time where a commencement of a decline in β-cell function was detected. 64,000 M(r) antibodies were detected before islet cell cytoplasmic antibodies (ICCA) in two patients. In the control groups of 21 healthy individuals, 36 patients with diseases of the thyroid and 5 SLE patients, the 64,000 M(r) antibodies were detected in only one individual, who was a healthy sibling to an IDDM patient. These results suggest that antibodies against the M(r) 64,000 human islet protein are an early marker of β-cell autoimmunity and may be useful to predict a later development of IDDM.