Post-absorptive glucose metabolism was studied in non-insulin-dependent diabetes mellitus (NIDDM) patients and normal subjects using dideuterated glucose as tracer. From the progressive fall in blood glucose levels and the increase in isotopic enrichment, the post-absorptive situation could not be regarded as a steady state for glucose metabolism, and non-steady-state approximations had therefore to be applied. However, this did not alter significantly the results in the 10 NIDDM patients studied. Significantly higher values of endogenous glucose production (EGP) were obtained (178 center dot 1 +/- 24 center dot 0 mg m-2 min-1 vs. 80 center dot 2 +/- 14 center dot 4; P < 0 center dot 01) if the tracer priming dose was not adapted to the degree of hyperglycaemia. Valid measurements could be made after only 1 h isotopic equilibration time if an appropriately matched priming dose was employed. Methodologically acceptable values for EGP in the 10 NIDDM patients did not differ significantly from those of 10 normal control subjects (80 center dot 2 +/- 14 center dot 4 mg m-2 min-1 vs. 85 center dot 6 +/- 3 center dot 9; not significant). The post-absorptive hyperglycaemia in these patients was assumed to stem essentially from a defect in peripheral glucose uptake.