The role of gluconeogenesis from protein in the pathogenesis of weight loss in lung cancer is unclear.Our aim was to study gluconeogenesis from alanine in lung cancer patients and to analyze its relation to the degree of weight loss.In this cross-sectional study, we used primed-constant infusions of [6,6-(2)H(2)]-D-glucose and [3-(13)C]-L-alanine to assess whole-body glucose and alanine turnover and gluconeogenesis from alanine in weight-losing (WL, n = 9) and weight-stable (WS, n = 10) lung cancer patients and healthy control (n = 15) subjects.Energy intake and plasma alanine concentrations did not differ significantly among the subject groups. Mean (+/-SEM) whole-body glucose production was significantly higher in WL than in WS and control subjects (0.74 +/- 0.06 compared with 0.55 +/- 0.04 and 0.51 +/- 0.04 mmol*kg(-)(1)*h(-)(1), respectively, P <0.01). Alanine turnover was significantly elevated in WL compared with WS and control subjects (0.57 +/- 0.04 compared with 0.42 +/- 0.05 and 0.40 +/- 0.03 mmol*kg(-)(1)*h(-)(1), respectively, P <0.01). Gluconeogenesis from alanine was significantly higher in WL than in WS and control subjects (0.47 +/- 0.04 compared with 0.31 +/- 0.04 and 0.29 +/- 0.04 mmol*kg(-)(1)*h(-)(1), respectively, P <0.01). The degree of weight loss was positively correlated with glucose and alanine turnover and with gluconeogenesis from alanine (r = 0.45 for all, P <0.01).Aberrant glucose and alanine metabolism occurred in WL lung cancer patients. These changes were related to the degree of weight loss and not to the presence of lung cancer per se.