To determine the effects of hyperglycemia and hyperinsulinemia on lactate production by adipocytes, healthy volunteers were studied during three experimental protocols. In protocol 1, the changes in interstitial lactate concentrations were measured by microdialysis (sc tissue) after oral glucose administration. The plasma lactate concentration increased by 39.4 +/- 6.0%, and the dialysate lactate concentration increased by 117.9 +/- 16.3%. In protocol 2, a 2.5-h hyperinsulinemic euglycemic clamp and somatostatin infusion were performed. The plasma and dialysate lactate concentrations increased by 27.1 +/- 5.5% and 146.8 +/- 44.5%, respectively. In addition, [U-13C]glucose was infused through the probe, and dialysate lactate was enriched in 13C at 2.5 +/- 0.3 molar percent excess basally and at 3.4 +/- 0.3 molar percent excess during the clamp (P < 0.05 vs. basal). [13C]Urea was also infused through the probe, and the outflow to inflow ratio of [13C]urea was used as an index of local blood flow. It decreased by 10.2 +/- 3.6% (P < 0.001) at the end of the hyperinsulinemic euglycemic clamp, indicating an increase in blood flow. In protocol 3, a hyperglycemic clamp (10.0 mmol/L) at the basal insulin concentration was performed. It increased the dialysate lactate concentration by 43.5 +/- 15.9% and did not alter the plasma lactate concentration or local blood flow. It is concluded that hyperinsulinemia and, to a lesser extent, hyperglycemia stimulate glucose conversion into lactate in adipocytes. Hyperinsulinemia, but not hyperglycemia, also increases adipose tissue blood flow.