Dietary fiber intake is associated with several beneficial effects on carbohydrate metabolism. Some authors have speculated that this improvement may be due to short-chain fatty acids (SCFA) produced by the colonic fermentation of dietary fibers. To test this hypothesis, six healthy men aged 26 +/- 2 (SE) yr with a body mass index of 20.9 +/- 0.7 received on three occasions an 18-h ileal perfusion infused at a flow rate of 3.3 ml/min, containing either 90 mmol/l of SCFA (60% acetate, 25% propionate, and 15% butyrate) (A), SCFA during the first 12 h and then a saline solution (A/S), or a saline solution (S). Basal hepatic glucose production (BHGP), insulin sensitivity (3-step euglycemic-hyperinsulinic clamp), and erythrocyte insulin binding (EIB) were studied 12 h after the beginning of the ileal perfusion. There was no change in BHGP or insulin sensitivity. However, maximal EIB was significantly different: 7.1 +/- 0.1 (A), 6.8 +/- 0.1 (A/S), vs. 6.5 +/- 0.1% (S) (P = 0.03). We conclude that acute administration of SCFA does not significantly alter glucose metabolism in healthy subjects.