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The purpose of this investigation was to determine whether insulin-stimulated phosphatidylinositol 3-kinase (PI3-kinase) activity is detectable in needle biopsies of human skeletal muscle. Sixteen healthy nonobese males matched for age, percent fat, fasting insulin, and fasting glucose participated in one of two experimental protocols. During an intravenous glucose tolerance test (IVGTT) protocol, insulin-stimulated PI3-kinase activity was determined from percutaneous needle biopsies at 2, 5, and 15 min post-insulin administration (0.025 U/kg). In the second group, a 2-h, 100 mU . m-2 . min-1 euglycemic hyperinsulinemic clamp was performed, and biopsies were obtained at 15, 60, and 120 min after insulin infusion was begun. Insulin stimulated PI3-kinase activity by 1.6 +/- 0.2-, 2. 2 +/- 0.3-, and 2.2 +/- 0.4-fold at 2, 5, and 15 min, respectively, during the IVGTT. During the clamp protocol, PI3-kinase was elevated by 5.3 +/- 1.3-, 8.0 +/- 2.6-, and 2.7 +/- 1.4-fold above basal at 15, 60, and 120 min, respectively. Insulin-stimulated PI3-kinase activity at 15 min post-insulin administration was significantly greater during the clamp protocol vs. the IVGTT (P < 0.05). These observations suggest that insulin-stimulated PI3-kinase activity is detectable in needle biopsies of human skeletal muscle, and furthermore, that the euglycemic, hyperinsulinemic clamp protocol may be a useful tool to assess insulin signaling in vivo.