Lactate is the predominant gluconeogenic precursor in man. To determine the dose-response relationships between plasma lactate concentration and rates of lactate incorporation in plasma glucose (lactate gluconeogenesis, LGN), we infused 17 normal volunteers with sodium lactate for 180 min at rates ranging from 6 to 40 mumol kg-1 min-1 and measured [U-14C]lactate incorporation into plasma glucose, as well as rates of lactate and glucose appearance in plasma. With the highest lactate infusions, plasma lactate increased up to 7 mM (compared to 1.1 +/- 0.13 mM during control sodium bicarbonate infusions, n = 10) and LGN averaged 4.73 +/- 0.23 mumol kg-1 min-1 (compared to 1.57 +/- 0.26 mumol kg-1 min-1 in bicarbonate control experiments, P < 0.001). The data relating plasma lactate concentration to LGN best fit a sigmoidal curve which plateaued at plasma lactate concentrations of approximately 6 mM and yielded an ED50 of 2.04 +/- 0.20 (SD) mM and a Vmax (6.25 +/- 1.2) (SD) (mumol kg-1 min-1). The sum of the basal rate of lactate appearance and the rate of lactate infusion was not significantly different from the overall rates of lactate appearance during the lactate infusions (35.8 +/- 2.2 vs. 34.8 +/- 2.9 mumol kg-1 min-1, P = 0.23). Thus, our results support the view that infusion of exogenous lactate does not suppress endogenous lactate appearance in plasma.