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Altered Hepatic Gluconeogenesis during L-Alanine Infusion in Weight-losing Lung Cancer Patients as Observed by Phosphorus Magnetic Resonance Spectroscopy and Turnover Measurements¹

Institute of Internal Medicine II, 3015 GD Rotterdam [S. L-H., J. W. O. v. d. B., J. H. P. W., P. C. D.]; Department of Diagnostic Radiology, 3008 AE Rotterdam [S. L-H., P. E. S., M. O., P. C. D.]; Department of Epidemiology, Maastricht University, 6200 MB Maastricht [P. C. D.], The Netherlands

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.

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