The metabolic response to glucose ingestion was studied in 10 normal men (aged 21-23 yr) by the simultaneous application of the forearm and double isotope techniques. The latter consisted of a primed constant infusion of [3-3H]glucose, followed by the administration of an oral glucose load (mean +/- SE, 90.7 +/- 0.7 g) containing [1-14C]glucose. Most (80.6 +/- 8.1%) of the ingested glucose appeared systemically within 270 min, suggesting that initial splanchnic glucose extraction accounted for 19.4 +/- 3.1% (17.7 +/- 2.8 g) of the oral load. Basal hepatic glucose output (2.22 +/- 0.12 mg/kg X min) was reduced (P less than 0.005) within 30 min after glucose loading and remained suppressed throughout the study; its mean reduction from 0-270 min was 54.9 +/- 9.9%, thereby accounting for the conservation of 26.5 +/- 4.9 g glucose. Suprabasal glucose appearance from 0-270 min was 46.6 +/- 4.3 g. Forearm glucose uptake rose 8.5-fold to 0.664 +/- 0.083 mg/100 ml forearm X min at 45 min, but basal forearm oxygen uptake (6.1 +/- 0.4 mumol/100 ml forearm X min) did not change. The increment in glucose disappearance from 0-270 min was 46.4 +/- 3.8 g, of which increased glucose uptake by muscle, determined from the forearm glucose uptake data, accounted for 37.7 +/- 5.1 g (81%). If uptake of the remaining 8.7 g was shared equally by the liver and peripheral tissues, the splanchnic bed and periphery would account, respectively, for 47.1 g (52%) and 43.5 g (48%) of the ingested load. We conclude that splanchnic and peripheral tissues contribute almost equally to the total homeostatic response; in kinetic terms, decreased hepatic glucose output and increased glucose uptake (splanchnic plus peripheral) constitute 29% and 71% of the total response, respectively; restoration of basal glucose kinetics after glucose ingestion requires more than 270 min; and increased peripheral oxygen uptake is not the mechanism of glucose-induced thermogenesis which, instead, may reflect increased splanchnic oxygen consumption.