Antibodies in sera from newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients are directed to a human islet cell protein of relative molecular mass (Mr) 64,000. Since Il)DM seems to develop after a prodromal period of,8-cell autoimmunity, this study has examined whether 64,000 Mr antibodies could be detected in 14 individuals who subsequently developed IDDM and five first degree relatives who have indications of altered (3-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 Mr 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 IDIM, whereas 1 patient progressed to a high 64,000 M, immunoreactivity, at a time where a commencement of a decline in (3-cell function was detected. 64,000 M, 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 Mr antibodies were detected in only one individual, who was a healthy sibling to an IDDM patient. These results suggest that antibodies against the Mr 64,000 human islet protein are an early marker of (-cell autoimmunity and may be useful to predict a later development of IDDM.

Twenty-one intravenous (i.v.) glucose tolerance tests were performed on nine subjects before the onset of overt type I diabetes mellitus. Islet cell antibodies (6 of 9 subjects) and elevated levels of Ia-positive T-lymphocytes (3 of 3 subjects studied) were detected during the prediabetic period. Elevations of fasting blood glucose and peak glucose during oral glucose tolerance tests were not observed until the year before onset of clinically overt diabetes. During the prediabetic period, there was a progressive loss of early-phase insulin release to i.v. glucose (rate of decline, 20-40 microU/ml insulin release/yr; correlation coefficient, 0.9).

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