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Infiltration of immunocytes into pancreatic islets precedes loss of [small beta, Greek] cells in type 1 diabetes.It is conceivable that local release of cytokines affects the function of [small beta, Greek] cells before their apoptosis. This study examines whether the elevated proinsulin levels that have been described in prediabetes can result from exposure of [small beta, Greek] cells to cytokines. Human [small beta, Greek]-cell preparations were cultured for 48 or 72 hours with or without IL-1[small beta, Greek], TNF-[small alpha, Greek], or IFN-[small gamma, Greek], alone or in combination. None of these conditions were cytotoxic, nor did they reduce insulin biosynthetic activity. Single cytokines did not alter medium or cellular content in insulin or proinsulin. Cytokine combinations, in particular IL-1[small beta, Greek] plus IFN-[small gamma, Greek], disproportionately elevated medium proinsulin levels. This effect expresses an altered functional state of the [small beta, Greek] cells characterized by preserved proinsulin synthesis, a slower hormone conversion, and an increased ratio of cellular proinsulin over insulin content. The delay in proinsulin conversion can be attributed to lower expression of PC1 and PC2 convertases. It is concluded that disproportionately elevated proinsulin levels in pre-type 1 diabetic patients might result from exposure of their [small beta, Greek] cells to cytokines released from infiltrating immunocytes. This hormonal alteration expresses an altered functional state of the [small beta, Greek] cells that can occur independently of [small beta, Greek]-cell death.J.Clin. Invest. 104:67-72 (1999).