Recent studies indicate a role for the kidney in postabsorptive glucose homeostasis. The present studies were undertaken to evaluate the role of the kidney in postprandial glucose homeostasis and to compare its contribution to that of liver and skeletal muscle. Accordingly, we used the double isotope technique along with forearm and renal balance measurements to assess systemic, renal, and hepatic glucose release as well as glucose uptake by kidney, skeletal muscle, and splanchnic tissues in 10 normal volunteers after ingestion of 75 g of glucose. We found that, during the 4.5-h postprandial period, 22 +/- 2 g (30 +/- 3% of the ingested glucose) were initially extracted by splanchnic tissues. Of the remaining 53 +/- 2 g that entered the systemic circulation, 19 +/- 3 g were calculated to have been taken up by skeletal muscle and 7.5 +/- 1.7 g by the kidney (26 +/- 3 and 10 +/- 2%, respectively, of the ingested glucose). Endogenous glucose release during the postprandial period (16 +/- 2 g), calculated as the difference between overall systemic glucose appearance and the appearance of ingested glucose in the systemic circulation, was suppressed 61 +/- 3%. Surprisingly, renal glucose release increased twofold (10.6 +/- 2.5 g) and accounted for ~60% of postprandial endogenous glucose release. Hepatic glucose release (6.7 +/- 2.2 g), the difference between endogenous and renal glucose release, was suppressed 82 +/- 6%. These results demonstrate a hitherto unappreciated contribution of the kidney to postprandial glucose homeostasis and indicate that postprandial suppression of hepatic glucose release is nearly twofold greater than had been calculated in previous studies (42 +/- 4%), which had assumed that there was no renal glucose release. We postulate that increases in postprandial renal glucose release may play a role in facilitating efficient liver glycogen repletion by permitting substantial suppression of hepatic glucose release.