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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 μM 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 > 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.