PURPOSE: After a glucose load, futile glucose/glucose-6-phosphate (G6P) cycling (FGC) generates [2-(2) H]glucose from (2) H2 O thereby mimicking a paradoxical glycogenolytic contribution to plasma glucose levels. Contributions of load and G6P derived from gluconeogenesis, FGC, and glycogenolysis to plasma glucose levels need resolution. A simple methodology is proposed integrating the administration of (2) H2 O with a glucose load containing [1-(2) H, 1-(13) C]glucose and [2-(2) H, 2-(13) C]glucose. METHODS: Mice fasted for 6 (n = 7) or 24 h (n = 5) were intraperitoneally injected with 2 mg/g 10\% enriched glucose in 35 µL/g (2) H2 O. Plasma glucose enrichment was analyzed by (2) H NMR after 30 min. RESULTS: For 6-h fasted mice, 12.3 ± 1.5\% of plasma glucose was pre-existing, 44.3 ± 2.7\% was load derived, and 43.4 ± 1.8\% G6P derived. G6P origins were 26.0 ± 2.0\% gluconeogenesis, 10.9 ± 2.6\% FGC, and 6.5 ± 3.4\% glycogenolysis. For 24-h fasted mice, 18.2 ± 8.5\% was pre-existing, 41.1 ± 5.0 \% was load derived, and 40.8 ± 4.3\% G6P derived. G6P origins were 27.1 ± 3.3\% gluconeogenesis, 13.1 ± 2.8\% FGC, and 0.6 ± 2.4\% glycogenolysis. CONCLUSION: After a glucose load, glycogenolytic contribution to plasma glucose was negligible, whereas FGC was significant for both 6- and 24-h fasted mice. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.