Patients with type 2 diabetes (DM) demonstrate inadequate insulin release, elevated gluconeogenesis, and diminished nonoxidative glucose disposal. Similar metabolic changes occur during systemic injury caused by infection, trauma, or cancer. Described here are metabolic changes occurring in 16 DM and 11 lung cancer patients (CA) and 13 normal volunteers (NV). After a 10-h overnight fast, all subjects had fasting hormone and substrate concentrations determined, along with rates of glucose production, leucine appearance (LA), and leucine oxidation (LO). Fasting insulin (data not shown) and C-peptide concentrations were elevated in DM and CA compared with weight-matched NV (0.72 ± 0.09 and 0.64 ± 0.08 vs. 0.51 ± 0.03 mg/l, P < 0.05). C-reactive protein concentration was elevated in CA compared with DM and NV (23.3 ± 6.0 vs. 4.2 ± 1.4 and 2.1 ± 0.5 mg/l, P < 0.01). All counterregulatory hormones were normal except for serum cortisol (11.4 ± 1.0 and 12.1 ± 1.0 vs. 8.9 ± 0.7 µg/dl, DM and CA vs. NL, respectively, P < 0.05). Glucose production was increased in DM and CA compared with NV (4.22 ± 0.6 and 3.53 ± 0.3 vs. 2.76 ± 0.2 mg · kg lean body wt¹ · min¹, P < 0.01). LO and LA were increased in DM and CA compared with NV (LO: 27.3 ± 1.5 and 19.7 ± 1.5 vs. 12.5 ± 1.1 mmol · kg lean body wt¹ · min¹, P < 0.05; LA: 91.9 ± 6.6 and 90.7 ± 7.0 vs. 79.1 ± 6.0 mmol · kg lean body wt¹ · min¹, P < 0.01). DM share similar metabolic derangements with CA. The increase in LA may be secondary to an increased glucose production where amino acids are mobilized to provide the liver with adequate substrate to make glucose. The increase in glucose production may also be part of the injury response, or it may represent a form of insulin resistance that exists in both the DM and (non-DM) CA patients.