BACKGROUND Ingested protein increases circulating insulin concentrations. Several years ago it was also determined that an intravenously administered mixture of 10 essential amino acids stimulated insulin secretion. Of these, arginine was the most potent. The effect was synergistic with administered glucose. OBJECTIVE Because the amounts of amino acid administered intravenously were very large and because ingested arginine is partially metabolized in the intestinal mucosa, we were interested in determining whether orally administered arginine stimulates a rise in circulating insulin concentration and whether arginine affects the glucose-induced rise in insulin concentration. METHODS Nine healthy subjects (4 women and 5 men aged 21-52 y) ingested 1 mmol arginine/kg lean body mass, 1 mmol arginine/kg lean body mass + 25 g glucose, 25 g glucose alone, and water only, in random order on separate occasions, at 0800. Blood samples were obtained at baseline and at 10-min intervals over the next 2 h and were assayed for glucose, insulin, glucagon, and amino acid concentrations. The half-time for gastric emptying was determined by scintigraphy. RESULTS Unlike with intravenous administration, ingested arginine did not stimulate a rise in insulin concentration. The glucagon concentration was increased. Arginine attenuated and prolonged the glucose rise when it was ingested with glucose. Gastric emptying time was similar after ingestion of glucose alone or arginine plus glucose. CONCLUSIONS Arginine, in an amount likely to be ingested in a high-protein meal, does not stimulate insulin secretion but attenuates the increase in glucose when given with glucose.