V ery little is known about the regulation of protein metabolism in adipose tissue. In this study systemic, adipose tissue, and forearm phenylalanine kinetics were determined in healthy postabsorptive volunteers before and during a 2-h glucose infusion (7 mg.kg-1.min-1). [3H]Phenylalanine was infused and blood was sampled from a radial artery, a subcutaneous abdominal vein, and a deep forearm vein. Adipose tissue and forearm blood flow were measured with 133Xe and plethysmography, respectively, and body fat mass was determined by dual energy x-ray absorptiometry. During glucose infusion, glucose concentration increased from 86 +/- 2 to 228 +/- 13 mg/dl and insulin concentration increased from 6.6 +/- 0.6 to 35.0 +/- 3.9 mU/liter, both P < 0.001. Systemic phenylalanine appearance decreased from 40.3 +/- 1.9 to 37.0 +/- 1.6 mumol/min during glucose infusion (P < 0.05). Baseline whole body adipose tissue phenylalanine release (5.2 +/- 1.4 mumol/min) was approximately 12% of systemic phenylalanine appearance and decreased (P < 0.05) to 2.3 +/- 0.9 mumol/min during glucose infusion. In contrast, phenylalanine release from the forearm did not change during glucose infusion. These results indicate that adipose tissue is a small but significant contributor to systemic phenylalanine appearance. Phenylalanine release from adipose tissue like lipolysis, is relatively sensitive to hyperinsulinemia.