The effect of 48-hour starvation on glucose metabolism was studied in six non-diabetic, normal weight men using a hyperinsulinemic (100 mU/min/m2) glucose clamp (3.5 mmol/L). The rate of glucose oxidation was calculated from measurements of respiratory gas exchange, after allowing for the oxidation of ketones and of protein. During the glucose clamp, the whole body glucose disposal rate decreased from 39.8 (SEM 4.6) mumol/kg/min in the fed state to 24.1 (2.1) mumol/kg/min in the starved state (P less than .01), consistent with insulin "resistance." The glucose oxidation rate decreased from 21.8 (1.3) to 3.9 (1.4) mumol/kg/min with starvation (P less than .001), but the nonoxidative glucose disposal rate was unchanged (18.0 [3.9] mumol/kg/min normally fed, and 20.2 [1.2] mumol/kg/min starved). With starvation, the rate of glucose uptake in the forearm during the glucose clamp was reduced from 59.4 to 15.4 mumol/min/L forearm (SE 5.6, P less than .01, ANOVA). There was a significant net increase in thermogenesis during the glucose clamp in the normally fed state (0.27 [0.08] kJ/min, P less than .01, ANOVA), but not following starvation (0.11 [0.09] kJ/min, NS, ANOVA). Therefore, starvation caused decreases in oxidative glucose disposal and in forearm glucose uptake; despite the whole body nonoxidative disposal rate of glucose being unchanged, the associated net thermogenic response was diminished.