Isolated rat islets of Langerhans permeabilised by high-voltage discharge secreted insulin in response to elevations in Ca2+ over the range 100 nM to 10 microM Ca2+. The phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA), had no effects on insulin secretion in the absence of Ca2+. In the presence of Ca2+ concentrations of greater than 10 nM, TPA produced dose-related shifts in the Ca2+-activation curve to lower Ca2+ concentrations, together with marked increases in the maximum secretory response to Ca2+. These results suggest that, in islets, the activation of protein kinase C is important in modulating both the sensitivity of the exocytotic mechanism to intracellular Ca2+, and the magnitude of the insulin secretory response.