The effect of two doses (3 mg and 10 mg) of the inhibitor of pancreatic alpha-amylase trestatin on the metabolism of an oral load of 75 g of starch was observed in healthy human subjects. The mean elevation of plasma glucose over the 4 h following the load was markedly reduced both with 10 mg (mean +/- s.e.m.: 1.4 +/- 1.2 mg/dl) and with 3 mg of trestatin (7.2 +/- 2.0 mg/dl) when compared to placebo (19.5 +/- 5.1 mg/dl) (P less than 0.01 in both cases). The mean elevation of plasma insulin was decreased with both 10 mg (mean +/- s.e.m.: 1 +/- 1 microU/ml) and 3 mg of trestatin (6 +/- 2 microU/ml) when compared to placebo (20 +/- 4 microU/ml) (P less than 0.01 in both cases). Suprabasal glucose oxidation, measured by indirect calorimetry, was markedly decreased by trestatin (mean +/- s.e.m.: 2.5 +/- 1.1 g/4 h with 10 mg of trestatin versus 12.0 +/- 2.0 g/4 h with placebo, P less than 0.001). To examine whether trestatin had any action on alpha-1-4 glycosidase activity, an oral load of 100 g sucrose together with either 50 mg trestatin or with a placebo was administered to four healthy human subjects. Trestatin was observed to have only few effects on plasma glucose and insulin levels following sucrose ingestion. This suggests that its main site of action is at the alpha-amylase level. Breath hydrogen was shown to increase after ingestion of starch plus trestatin at the two doses studied. It is concluded that trestatin is a powerful inhibitor of pancreatic alpha-amylase which could be of great help in the dietary management of diabetic patients.