Recent studies indicate an important role of the kidney in postprandial glucose homeostasis in normal humans. To determine its role in the abnormal postprandial glucose metabolism in type 2 diabetes mellitus (T2DM), we used a combination of the dual-isotope technique and net balance measurements across kidney and skeletal muscle in 10 subjects with T2DM and 10 age-, weight-, and sex-matched nondiabetic volunteers after ingestion of 75 g of glucose. Over the 4.5-h postprandial period, diabetic subjects had increased mean blood glucose levels (14.1 +/- 1.1 vs. 6.2 +/- 0.2 mM, P < 0.001) and increased systemic glucose appearance (100.0 +/- 6.3 vs. 70.0 +/- 3.3 g, P < 0.001). The latter was mainly due to approximately 23 g greater endogenous glucose release (39.8 +/- 5.9 vs. 17.0 +/- 1.8 g, P < 0.002), since systemic appearance of the ingested glucose was increased by only approximately 7 g (60.2 +/- 1.4 vs. 53.0 +/- 2.2 g, P < 0.02). Approximately 40% of the diabetic subjects' increased endogenous glucose release was due to increased renal glucose release (19.6 +/- 3.1 vs. 10.6 +/- 2.4 g, P < 0.05). Postprandial systemic tissue glucose uptake was also increased in the diabetic subjects (82.3 +/- 4.7 vs. 69.8 +/- 3.5 g, P < 0.05), and its distribution was altered; renal glucose uptake was increased (21.0 +/- 3.5 vs. 9.8 +/- 2.3 g, P < 0.03), whereas muscle glucose uptake was normal (18.5 +/- 1.8 vs. 25.9 +/- 3.3 g, P = 0.16). We conclude that, in T2DM, 1) both liver and kidney contribute to postprandial overproduction of glucose, and 2) postprandial renal glucose uptake is increased, resulting in a shift in the relative importance of muscle and kidney for glucose disposal. The latter may provide an explanation for the renal glycogen accumulation characteristic of diabetes mellitus as well as a mechanism by which hyperglycemia may lead to diabetic nephropathy.