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, we used a combination of the dual isotope technique and net balance measurements across kidney and skeletal muscle in 10 subjects with type 2 diabetes and 10 age-weight-gender matched non-diabetic volunteers after ingestion of 75 gm glucose. Over the 4-1/2 hour 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 gm, p < 0.001). The latter was mainly due to the ~23 gm greater endogenous glucose release (39.8 ± 5.9 vs 17.0 ± 1.8 gm, p < 0.002) since systemic appearance of the ingested glucose was increased by only ~7 gm (60.2 ± 1.4 vs 53.0 ± 2.2 gm, 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 gm, p < 0.05). Postprandial systemic tissue glucose uptake was also increased in the diabetic subjects (82.3 ± 4.7 vs 69.8 ± 3.5 gm, p < 0.05) and its distribution was altered; renal glucose uptake was increased (21.0 ± 3.5 vs 9.8 ± 2.3 gm, p < 0.03) whereas muscle glucose uptake was normal (18.5 ± 1.8 vs 25.9 ± 3.3 gm, p = 0.16). We conclude that in type 2 diabetes 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.