Skeletal muscle biopsy studies have consistently shown a decreased oxidative phenotype in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Limited information is available regarding potential adaptations or abnormalities in anaerobic metabolism and glucose homeostasis. Whole-body glucose production was assessed at rest and during exercise in COPD patients with moderate disease severity (forced expiratory volume in 1 second, 52% +/- 3%), prestratified into normal-weight (n = 7; body mass index [BMI], 27.5 +/- 0.9 kg.m(-2)) and underweight subjects (n = 6; BMI, 20.6 +/- 0.7 kg.m(-2)), and in 8 healthy controls matched for age and BMI with the normal-weight COPD group. Glucose tolerance was normal in all subjects. Rate of appearance (R(a)) of glucose at rest and during submaximal cycling exercise was measured in postabsorptive state by infusion of stable isotope tracer [6,6-(2)H(2)]glucose. Resting glucose R(a) was significantly enhanced in underweight COPD patients compared with controls (16.7 +/- 0.3 vs 15.1 +/- 0.4 mumol.kg fat-free mass(-1).min(-1), P < .05) and was inversely related to fat-free mass (r = -0.75, P < .01). Furthermore, the exercise-induced increase in glucose R(a) was enhanced in COPD patients (81.9% +/- 3.4% vs 72.1% +/- 2.0%, P = .05), resulting in elevated end-of-exercise glucose output. Differences were most pronounced in underweight patients, who were also characterized by enhanced plasma catecholamine levels and decreased insulin concentrations (all, P < .05). In normal-weight patients, there was evidence for decreased insulin sensitivity assessed by homeostatic modeling technique. Whole-body glucose production is increased in underweight COPD patients with normal glucose tolerance. It is hypothesized that lowered body weight in COPD has unique effects on glucose uptake despite reduced skeletal muscle oxidative capacity, relative hypoxemia, and sympathetic activation.