Hepatic sugar phosphate levels reflect gluconeogenesis in lung cancer: simultaneous turnover measurements and 31P magnetic resonance spectroscopy in vivo

Abstract

A B S T R A C TStable-isotope tracers were used to assess whether levels of phosphomonoesters (PME) and phosphodiesters (PDE) in the livers of lung cancer patients, as observed by 31 P 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 l 24 ; weight loss 0-24 %) and healthy control subjects (n l 13) were studied after an overnight fast. 31 P MR spectra of the liver in vivo were obtained, and glucose turnover and gluconeogenesis from alanine were determined simultaneously using primed-constant infusions of [6,6-2 H 2 ]glucose and [3-13 C]alanine. Liver PME concentrations were 6 % higher in lung cancer patients compared with controls (not significant) ; PME levels in patients with 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 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 l 0.48 and r l 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.

Evidence for altered hepatic gluconeogenesis in patients with cirrhosis using in vivo 31-phosphorus magnetic resonance spectroscopy

“…As with previously published studies,9 12 13 25 26 the most obvious change in the current study was a rise in PME resonance with a reciprocal decrease in P i resonance. Baseline PME values in patients with decompensated cirrhosis were the most elevated and our previous cross sectional in vivo and in vitro 31 P MRS studies of the cirrhotic liver have shown that this elevated baseline PME resonance correlated with worsening functional severity of liver disease 24.…”

“…These observations have been demonstrated previously in the rat12 and in patients with lung cancer 1325 26 Unlike our study where it was not possible to use isotope tracer studies to confirm the MRS findings, the series of studies on patients with cancer cachexia have confirmed using tracer methodologies that the PME changes represent altered hepatic gluconeogenesis following l -alanine infusion 1326 The negligible PME response in patients with decompensated cirrhosis suggests that the gluconeogenic capacity of the cirrhotic liver was already at maximal capacity.…”

“…The elevation in PME resonance following intravenous l -alanine infusion has been demonstrated to be related to increased gluconeogenesis rather than glycolysis 1325 26 …”

Liver Metabolomic Changes Identify Biochemical Pathways in Hemorrhagic Shock

“…Our data demonstrated a significant reduction in PDEs at 8 h PR in shock survivors but our PME data were inconclusive. However, an increase in PMEs during hemorrhagic shock as been demonstrated in the current literature by Leij-Halfwerk et al who found significantly elevated PMEs using NMR spectroscopy on liver in vivo during hemorrhagic shock and after liver surgery [26,27]. The coordinated decrease in PDEs and increase in PMEs support the idea that gluconeogenesis increases during shock, specifically gluconeogenesis from lipids.…”

“…GPC and GPE baseline levels within the cell can provide the choline and ethanolamine required for new phospholipid synthesis and cell membrane repair following shock without the energy cost of synthesizing these two precursors de novo via alternate routes. Furthermore, the production of glycerol-3-phosphate provides an alternate source for gluconeogenesis, which as been suggested to increase in the liver during hemorrhagic shock [26,27]. Our data demonstrated a significant reduction in PDEs at 8 h PR in shock survivors but our PME data were inconclusive.…”