Stable-isotope tracers were used to assess whether levels of phosphomonoesters (PME) and phosphodiesters (PDE) in the livers of lung cancer patients, as observed by P-31 magnetic resonance (MR) spectroscopy, reflect elevated whole-body glucose turnover and gluconeogenesis from alanine. Patients with advanced non-small-cell lung cancer without liver metastases (n = 24;weight loss 0-24%) and healthy control subjects (n = 13) were stud led after an overnight fast. P-31 MR spectra of the liver in vivo were obtained, and glucose turnover and gluconeogenesis from alanine were determined simultaneously using primed-constant infusions of [6,6-H-2(2)]glucose and [3-C-13]alanine. Liver PME concentrations were 6% higher in lung cancer patients compared with controls (not significant); PME levels in patients with greater than or equal to 5% weight loss were significantly higher than in patients with <5% weight loss (P <0.01). PDE levels did not differ between the groups. In lung cancer patients, whole-body glucose production was 19% higher (not significant) and gluconeogenesis from alanine was 42% higher (P <0.05) compared with healthy subjects; turnover rates in lung cancer patients with greater than or equal to 5% weight loss were significantly elevated compared with both patients with <5% weight loss and healthy subjects (P <0.05). PME levels were significantly correlated with glucose turnover and gluconeogenesis from alanine in lung cancer patients (r = 0.48 and r = 0.48 respectively; P <0.05). In conclusion, elevated PME levels in lung cancer patients appear to reflect increased glucose flux and gluconeogenesis from alanine. These results are consistent with the hypothesis that elevated PME levels are due to contributions from gluconeogenic intermediates.