To investigate the possible role of insulin per se in the thermic response to glucose/insulin infusions, respiratory exchange measurements were performed on eight healthy young men for 45 min before and 210 min after somatostatin infusion. Two tests were performed on separate days and each had two consecutive phases of 90 min each. Test 1. Two different rates of glucose uptake were imposed, one at euglycemia (phase 1) and the other at hyperglycemia (phase 2) while insulinemia was maintained constant throughout. Test 2. Glucose uptake was maintained constant throughout while insulin was infused at two different rates: 1 mU/kg per min with hyperglycemia (phase 1) and 6.45 mU/kg per min with "euglycemia" (phase 2). The thermic effect of glucose and insulin, obtained from phase 1 in both tests, was 5.9 +/- 1.2 and 5.8 +/- 0.5% (NS) of the energy infused, respectively. A step increase in glucose uptake alone, test 1, phase 2, (0.469 +/- 0.039 to 1.069 +/- 0.094 g/min) caused an increase in energy expenditure of 0.14 +/- 0.03 kcal/min (thermic effect 5.9 +/- 1.1%). When insulin was increased by 752 +/- 115 microU/ml, with no change in glucose uptake, energy expenditure rose by 0.05 +/- 0.02 kcal/min, which correlated with the increase in plasma catecholamines. It is concluded that a large proportion of the thermic response to glucose/insulin infusions is due to glucose metabolism alone. The thermic effect of insulin is small and appears to be mediated by the sympathetic nervous system; thus at physiological insulin concentrations, the thermic effect of insulin per se is negligible.