Altered hepatic gluconeogenesis during L-alanine infusion in weight-losinglung cancer patients as observed by phosphorus magnetic resonance spectroscopy and turnover measurements

Profound alterations in host metabolism in lung cancer patients with weight loss have been reported, including elevated phosphomonoesters (PMEs) as de tected by P-31 magnetic resonance spectroscopy (MRS). In healthy subjects, infusion of L-alanine induced significant increases in hepatic PMEs and pho sphodiesters (PDEs) due to rising concentrations of 3-phosphoglycerate and phosphoenolpyruvate, respectively, The aim of the present study was to moni tor these changes in the tumor-free liver of lung cancer patients during L- alanine infusion by means of simultaneous P-31 MRS and turnover measurement s, Twenty-one lung cancer patients without liver metastases with (CaWL) or without weight loss (CaWS), and 12 healthy control subjects were studied du ring an i.v. L-alanine challenge of 1.4-2.8 mmol/kg followed by 2.8 mmol/kg /h for 90 min. Plasma L-alanine concentrations increased during alanine inf usion, from 0.35-0.37 mM at baseline to 5.37 +/- 0.14 mM in the CaWL patien ts, 6.67 +/- 0.51 mM in the CaWS patients, and 8.47 +/- 0.88 mM in the cont rols (difference from baseline and between groups during alanine infusion, all P < 0.001). Glucose turnover and liver PME levels at baseline were sign ificantly elevated in the CaWL patients. Alanine infusion increased whole-b ody glucose turnover by 8 +/- 3% in the CaWS patients (P = 0.03), whereas n o significant change occurred in the CaWL and controls. PME levels increase d by 50 +/- 16% in controls (area under the curve, P < 0.01) and by 87 +/- 31% in the CaWS patients (P < 0.05) after 45-90 min, In contrast, no signif icant changes in PME levels were observed in the CaWL patients. Plasma insu lin concentrations increased during L-alanine infusion in all groups to lev els that were lower in the CaWL patients than in the CaWS patients and cont rols (P < 0.05), In lung cancer patients, but not in controls, changes in P ME and PDE levels during alanine infusion mere inversely correlated with th eir respective baseline levels (r = -0.82 and -0.86, respectively; P < 0.00 1). In addition, changes in PMEs during alanine infusion in lung cancer pat ients were inversely correlated with the degree of weight loss (r = -0.54; P < 0.05), This study demonstrates the presence of major alterations in the pathway of hepatic gluconeogenesis in weight-losing lung cancer patients, as shown by elevated glucose flux before and during L-alanine infusion, and by the increased PME and PDE levels, which reflect accumulation of glucone ogenic intermediates in these patients, Weight-stable lung cancer patients show accelerated increases in PME and PDE levels during L-alanine infusion, suggesting enhanced induction of the gluconeogenic pathway. Our results su ggest altered gluconeogenic enzyme activities and elevated alanine uptake w ithin the livers of weight-losing/weight-stable lung cancer patients.