Glucose and arginine are both known to be potent insulin secretagogues and to potentiate each others insulin secretion. We investigated if repetitive infusion of arginine leads to comparable insulin secretion during fasting and if the additional infusion of glucose leads to a change in the pattern of the insulin secretion during repeated infusion of arginine. Repeated continuous infusions of arginine (0.3 g/kg in 30 min) in six normals led to a lower second phase insulin secretion during the third infusion (p less than 0.05). Pre-stimulus blood glucose levels were lower before the third infusion than before the first infusion (p less than 0.05). Repeated hyperglycaemic clamps (17.5 mmol/l during 30 min) led to comparable insulin secretion during three infusion. Combined infusion of arginine and glucose (hyperglycaemic clamps) did not lead to a decrease during the third infusion. We conclude first, that concomitant hyperglycemia potentiates second phase insulin secretion and second, that prolonged fasting leads to an adaptation of the pancreas B-cell leading to diminished arginine-induced insulin secretion, which can be overcome by additional infusion of glucose. This potentially confounding factor will have to be taken into account in planning future investigations of arginine-induced insulin secretion.