W e hypothesized that sera from type 2 diabetic patients with neuropathy contains an autoimmune immunoglobulin that promotes complement-independent, calcium-dependent apoptosis in neuronal cell lines. Neuronal cells were cultured in the presence of complement-inactivated sera obtained from patients with type 2 diabetes with and without neuropathy and healthy adult control patients. Serum from diabetic patients with neuropathy was associated with a significantly greater induction of apoptosis, compared to serum from diabetic patients without neuropathy and controls. In the presence of calcium channel antagonists, induction of apoptosis was reduced by approximately 50%. Pretreatment of neuronal cells with serum from diabetic patients with neuropathy was associated with a significant increase in elevated K+-evoked cytosolic calcium concentration. Serum-induced enhancement in cytosolic calcium and calcium current density was blocked by treatment with trypsin and filtration of the serum using a 100,000-kd molecular weight filter. Treatment with an anti-human IgG antibody was associated with intense fluorescence on the surface of neuronal cells exposed to sera from patients with type 2 diabetes mellitus with neuropathy. We conclude that sera from type 2 diabetic patients with neuropathy contains an autoimmune immunoglobulin that induces complement-independent, calcium-dependent apoptosis in neuronal cells.