Previous studies have indicated that individuals with type 2 diabetes have an increased resting metabolic rate (RMR) but decreased insulin-induced thermogenesis (IIT) compared with those with normal glucose tolerance (NGT). When and by which mechanisms these abnormalities occur during the development of diabetes remain unknown. In 560 Pima Indians, sleeping metabolic rate (respiratory chamber) was higher not only in subjects with diabetes (+4.9%, P < 0.001) but also in those with impaired glucose tolerance (IGT) (+2.7%, P < 0.01) compared with subjects with NGT. Longitudinally, RMR (ventilated hood) increased progressively in 17 subjects in whom glucose tolerance deteriorated from NGT to IGT (+4.2%) to diabetes (+2.6%) over 5.1 +/- 1.4 years (P < 0.05 for trend). In parallel, IIT (% increase in metabolic rate during an insulin/glucose infusion) decreased during the transition from NGT (11.7%) to IGT (7.3%) to diabetes (6.5%) (P < 0.05 for trend). In 151 subjects, basal endogenous glucose output (3-3H-glucose), fasting insulin and free fatty acid concentrations, and glucose disposal (hyperinsulinemic clamp) were significant determinants of RMR, independent of body composition, age, and sex. Nonoxidative and oxidative glucose disposal, RMR, and fasting insulin and glucose concentrations were determinants of IIT. Differences in RMR and IIT between glucose tolerance groups decreased after adjusting for these factors. These findings indicate that increases in RMR and decreases in IIT occur early in the development of type 2 diabetes, and that both changes are related to the progressive metabolic abnormalities that occur during the development of the disease.