Medicago sativa (lucerne) is used as a traditional plant treatment of diabetes. In the present study, administration of lucerne in the diet (62.5 g/kg) and drinking water (2.5 g/l) reduced the hyperglycaemia of streptozotocin-diabetic mice. An aqueous extract of lucerne (1 mg/ml) stimulated 2-deoxy-glucose transport (1.8-fold), glucose oxidation (1.7-fold) and incorporation of glucose into glycogen (1.6-fold) in mouse abdominal muscle. In acute 20 min tests, 0.25-1 mg/ml aqueous extract of lucerne evoked a stepwise 2.5-6.3-fold stimulation of insulin secretion from the BRIN-BD11 pancreatic B-cell line. This effect was abolished by 0.5 mM-diazoxide, and prior exposure to extract did not affect subsequent stimulation of insulin secretion by 10 mM-L-alanine, thereby negating a detrimental effect on cell viability. The effect of extract was potentiated by 16.7 mM-glucose and by 1 mM-3-isobutyl-1-methylxanthine. L-Alanine (10 mM) and a depolarizing concentration of KCl (25 mM) did not augment the insulin-releasing activity of lucerne. Activity of the extract was found to be heat stable and largely acetone insoluble, and was enhanced by exposure to acid and alkali (0.1 M-HCl and NaOH) but decreased 25% with dialysis to remove components with molecular mass < 2000 Da. Sequential extraction with solvents revealed insulin-releasing activity in both methanol and water fractions indicating a cumulative effect of more than one extract constituent. The results demonstrate the presence of antihyperglycaemic, insulin-releasing and insulin-like activity in the traditional antidiabetic plant, Medicago sativa.