Wistar rats developed hypoinsulinemia and hyperglycemia within 7 days when treated daily with 40 mg/kg body wt of cyclosporin A (CsA) and recovered from the metabolic alteration within 1 wk when CsA treatment was terminated. By light microscopy, there was no lymphocytic infiltration, but cytoplasmic vacuolization in the islets of Langerhans from the CsA-treated rats was seen. By electron microscopy, severe degranulation, cytoplasmic vacuolization, and dilation of endoplasmic reticulum were clearly seen in the pancreatic beta-cells. Islet cells isolated from the CsA-treated rats showed greater than 50% reduction in mRNA synthesis. A similar inhibitory pattern of mRNA synthesis was observed in in vitro CsA-treated (10 micrograms/ml) human pancreatic islet cells from one biopsy sample and in similarly treated rat insulinoma cells (RINm5F). The inhibitory effect of CsA on mRNA synthesis in RINm5F cells was dose dependent, with a 50%-inhibiting dose of 5 micrograms/ml. In addition to the inhibition of mRNA synthesis, CsA also inhibited protein and DNA syntheses, although the inhibitory effect on these macromolecular syntheses was significantly less than that on mRNA synthesis. However, there was only a minor effect of CsA on in vitro transcription and translation compared with that on RINm5F and islet cells. It is concluded that CsA-induced degranulation of the beta-cells in Wistar rats, accompanied by hypoinsulinemia and hyperglycemia, may be due to indirect, reversible interference of the cellular function primarily involved in mRNA synthesis.