title: Altered hepatic gluconeogenesis during L-alanine infusion in weight-losing lung cancer patients as observed by phosphorus magnetic resonance spectroscopy and turnover measurements.
abstract: Profound alterations in host metabolism in lung cancer patients with weight loss have been reported, including elevated phosphomonoesters (PMEs) as detected by 31P magnetic resonance spectroscopy (MRS). In healthy subjects, infusion of L-alanine induced significant increases in hepatic PMEs and phosphodiesters (PDEs) due to rising concentrations of 3-phosphoglycerate and phosphoenolpyruvate, respectively. The aim of the present study was to monitor these changes in the tumor-free liver of lung cancer patients during L-alanine infusion by means of simultaneous 31P MRS and turnover measurements. Twenty-one lung cancer patients without liver metastases with (CaWL) or without weight loss (CaWS), and 12 healthy control subjects were studied during 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 infusion, from 0.35-0.37 mM at baseline to 5.37 +/- 0.14 mM in the CaWL patients, 6.67 +/- 0.51 mM in the CaWS patients, and 8.47 +/- 0.88 mM in the controls (difference from baseline and between groups during alanine infusion, all P < 0.001). Glucose turnover and liver PME levels at baseline were significantly elevated in the CaWL patients. Alanine infusion increased whole-body glucose turnover by 8 +/- 3% in the CaWS patients (P = 0.03), whereas no significant change occurred in the CaWL and controls. PME levels increased 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 significant changes in PME levels were observed in the CaWL patients. Plasma insulin concentrations increased during L-alanine infusion in all groups to levels that were lower in the CaWL patients than in the CaWS patients and controls (P < 0.05). In lung cancer patients, but not in controls, changes in PME and PDE levels during alanine infusion were inversely correlated with their respective baseline levels (r = -0.82 and -0.86, respectively; P < 0.001). In addition, changes in PMEs during alanine infusion in lung cancer patients 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 gluconeogenic 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 suggest altered gluconeogenic enzyme activities and elevated alanine uptake within the livers of weight-losing/weight-stable lung cancer patients.
authors.affiliation: Institute of Internal Medicine II, Rotterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Leij-Halfwerk
authors.forename: J W
authors.initials: JW
authors.lastname: van den Berg
authors.forename: P E
authors.initials: PE
authors.lastname: Sijens
authors.forename: J H
authors.initials: JH
authors.lastname: Wilson
authors.forename: M
authors.initials: M
authors.lastname: Oudkerk
authors.forename: P C
authors.initials: PC
authors.lastname: Dagnelie
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D005260:Female; D005934:Glucagon / Q000097:blood; D005943:Gluconeogenesis; D006801:Humans; D007328:Insulin / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D015431:Weight Loss
chemical_list: D007328:Insulin; D005934:Glucagon; D000409:Alanine