During conditions of increased glucose disposal, plasma lactate concentrations increase due to an increase in plasma lactate appearance. The tissue sites of the elevated lactate production are controversial. Although skeletal muscle would be a logical source of this lactate, studies using the limb net balance technique have failed to demonstrate a major change in net lactate output when plasma glucose disposal is increased. Because the limb balance technique underestimates production of a substrate when the limb not only produces but also consumes that substrate, we infused 3-14C-lactate basally and during a hyperinsulinemic euglycemic clamp in seven normal volunteers to determine plasma lactate appearance, forearm lactate fractional extraction, and forearm lactate uptake and release. After 3 hours of hyperinsulinemia, glucose and lactate turnovers increased from basal values of 11.8 +/- 0.13 and 12.2 +/- 0.59 to 32.6 +/- 3.4 and 16.5 +/- 1.07 mumol/(min.kg), accompanied by an increase in plasma lactate from 0.88 +/- 0.07 to 1.16 +/- 0.09 mmol/L (P less than .05). Forearm lactate extraction increased from 27% +/- 2% to 38% +/- 2% (P less than .001), resulting in an increase in forearm lactate uptake from 0.65 +/- 0.09 to 1.18 +/- 0.08 mumol/(min.100 mL tissue) (P less than .001). Although forearm lactate net output decreased during hyperinsulinemia, forearm lactate production increased from 1.04 +/- 0.12 basally to 1.69 +/- 0.13 mumol/(min.100 mL). When forearm data was extrapolated to whole body, muscle could account for 41% +/- 4% of systemic lactate appearance basally and 45% +/- 4% during hyperinsulinemia.(ABSTRACT TRUNCATED AT 250 WORDS)