The present study was designed to examine the effects of excess T3 on total body glucose production and forearm exchange of glucose, amino acids, and other metabolites. Five healthy male volunteers were studied after an overnight fast, before and 7 days after the administration of 150 µg/day T3. Glucose production (milligrams per kg/min) was measured using a primed continuous infusion of [3-3H]glucose and gluconeogenic index (micromoles per kg/min) was measured by following the conversion of infused [14C]alanine to [14C]glucose. Blood flow across the forearm was measured using capacitance plethysmography and forearm release of substrates was determined by the Fick principle. After T3 administration, there was a 3.7-fold rise in T3 from 150 ± 15 to 530 ± 12 ng/dl (P < 0.001), with no change in insulin (12 ± 1 µ/ml pre-T3vs. 13 µ 2 /U/ml post-T3) and glucagon (79 ± 5 pre-T3vs. 84 ± 7 pg/ml post-T3). T3 administration resulted in an increase in plasma glucose (from 83 ± 5 to 98 ± 5 mg/dl; P < 0.05), net glucose uptake by the forearm (from 250 ± 90 to 712 ± 60 ±mol/100 ml forearm tissue-min; P < 0.005) and glucose production (1.7 ± 0.09 to 2.2 ± 0.08 mg/kg-min; P < 0.005), without a change in glucose clearance (2.1 ± 0.02 vs. 2.0 ± 0.02 ml/kg-min); the rate of conversion of [14C]alanine to [14CJglucose increased by 30÷ (0.56 ± 0.03 to 0.74 ± 0.03 3, to levels comparable to those seen in hyperthyroidism, results in enhanced glucose production, with an increse in glucose uptake by the forearm. The former can be partially accounted for by an increase in hepatic gluconeogenesis, glycogenolysis, or possibly increased renal glucose production. The increased peripheral glucose utilization could be directly or indirectly due to an effect of T3 on skeletal muscle. Furthermore, excess T3 resulted in both enhanced proteolysis and lipolysis. These resemble in many ways the in vitro metabolic effects of T3. (J Clin Endocrinol Metab56: 479, 1983)