The importance of impaired glucose utilization in the pathogenesis of postprandial hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM) is controversial. Three methods were used to assess glucose utilization following ingestion of a mixed meal in 18 NIDDM and 12 nondiabetic subjects. Dual glucose isotopes were used to determine first-pass splanchnic glucose uptake, suppression of endogenous glucose production, and systemic glucose utilization. Leg balance was used to evaluate skeletal muscle glucose metabolism, and systemic and limb indirect calorimetry were used to assess glucose and lipid oxidation. NIDDM subjects had marked postprandial hyperglycemia as compared with nondiabetics (15.35 +/- 0.72 v 5.83 +/- 0.28 mmol, P < .001), accompanied by lower postprandial insulin (179 +/- 25 v 253 +/- 46 pmol, P < .01) and elevated plasma free fatty acids ([FFA] 569 +/- 34 v 314 +/- 20 mumol/L, P < .001). Cumulative postprandial glucose appearance was nearly twofold greater in NIDDM (82.2 +/- 4.7 v 48.7 +/- 4.9 g.5h, P < .001) due to increased endogenous glucose production (56.4 +/- 4.8 v 24.5 +/- 1.9 g, P < .001), whereas first-pass splanchnic uptake of ingested glucose was normal in NIDDM. Cumulative postprandial glucose utilization in NIDDM, after correction for urinary glucose, was unchanged from postabsorptive rates, a pattern also found for postprandial glucose oxidation. Cumulative leg glucose uptake was somewhat less in NIDDM subjects (123 +/- 18 v 173 +/- 14 mumol/100 mL leg tissue.5 h, P = .06), whereas lactate and alanine net release across the leg were nevertheless twofold greater in NIDDM (P = .04) and accounted for nearly half of the leg glucose metabolism in NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)