Isolated rat islets of Langerhans permeabilised by high-voltage discharge secreted insulin in response to elevations in Ca 2 + over the range 100 nM to 10 μM Ca 2 + . The phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA), had no effects on insulin secretion in the absence of Ca 2 + . In the presence of Ca 2 + concentrations of > 10 nM, TPA produced dose-related shifts in the Ca 2 + -activation curve to lower Ca 2 + concentrations, together with marked increases in the maximum secretory response to Ca 2 + . 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 Ca 2 + , and the magnitude of the insulin secretory response.