The rate of insulin-stimulated glucose disposal is reduced in individuals with insulin resistance, and is associated with a blunted or absent increase in energy expenditure in response to a glucose load. The magnitude of the effect of glucose on energy expenditure (EGEE) may be a function of opposing changes in the rate of glucose disposal (Rd) and hepatic glucose production (HGP). In this study, six women with non-insulin-dependent diabetes mellitus (NIDDM) were studied on a metabolic ward in each of three conditions. On days 1 and 2, they did no exercise (NX) or else performed low-intensity exercise ([LO]3,118 kJ [745 kcal]) at 50% maximal oxygen consumption [Vo 2 max]) or high-intensity exercise ([HI]3,114 kJ [744 kcal] at 75% Vo 2 max). On day 3, infusion of 6,6 2 H-glucose in the basal state was immediately followed by infusion of glucose, 6,6 2 H-glucose, and insulin at fixed rates. Indirect calorimetry was performed during the last 30 minutes of each infusion. EGEE was not different among the three conditions (mean +/- SEM: NX -0.18 +/- 0.11, LO -0.08 +/- 0.05, and HI -0.08 +/- 0.07 kJ/min) and was inversely related to steady-state plasma glucose concentration, a direct measure of insulin resistance (r = -.89, P < .05). EGEE was positively correlated with glucose Rd (r = .94, P < .001) and negatively correlated with HGP (r = -.91, P < .05). The data indicate that the glucose effect on energy expenditure was slightly positive in the more insulin-sensitive individuals, but negative in the more insulin-resistant subjects. The EGEE appears to be determined by the relative balance between energy required to store glucose and energy saved by suppression of glucose production.