Islet cell antibodies (ICAs), thyrogastric antibodies, and HLA-DR antigens were determined in 204 patients with type II (non-insulin-dependent) diabetes controlled with diet and/or oral hypoglycemic agents (NIR) and in 108 age-matched patients who required insulin to control their hyperglycemia (IR). β-Cell function measured as C-peptide response to glucagon was evaluated in relation to the presence of ICAs and HLA-DR antigens. The IR patients differed from the NIR patients with respect to higher frequency of ICAs (P < .001), thyroid antibodies (P < .02), and the HLA antigen DR4 (P < .02). The highest frequency of ICAs and thyroid antibodies was observed in female insulin-treated subjects (51.2 and 46.4%). Patients who were heterozygous for HLA-DR3/DR4 showed significantly higher frequency of ICAs (P < .01) and complement-fixing ICAs (P < .001) than patients without the heterozygous form DR3/DR4. Neither the presence of ICA alone nor DR3/DR4 alone was associated with a significant impairment of β-cell function. However, when both ICA and DR3/DR4 were present in a diabetic individual, β-cell function was markedly impaired (P < .001), suggesting that both genetic and autoimmune factors are necessary to facilitate the process leading to β-cell destruction of the patients. Our findings suggest that type II diabetes is a heterogeneous disorder including at least two major subgroups, which can be further characterized by HLA-DR antigens and organ-specific antibodies

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