We determined whether insulin resistance in Type I diabetes is caused by a defect in glucose extraction or blood flow and whether it is the rate of glucose metabolism rather than insulin that increases blood flow in these patients. To make this determination, 9 Type I diabetic patients (age 33 +/- 3 yr, body mass index 24 +/- 1 kg/m2, HbA1c 8.3 +/- 0.1%) and 10 matched normal subjects were first studied under normoglycemic hyperinsulinemic conditions. The diabetic patients were then restudied under similar conditions, but now whole body glucose uptake was normalized by glucose mass-action (glucose 8.7 +/- 0.6 mmol/L). During normoglycemia, rates of whole body (46 +/- 2 vs. 66 +/- 3 mumol/kg.min, P < 0.001) and forearm (47 +/- 9 vs. 78 +/- 7 mumol/kg forearm.min, P < 0.05) glucose uptake were decreased in the diabetic patients, because of a 32% decrease in the glucose AV-difference (1.5 +/- 0.2 vs. 2.2 +/- 0.2 mmol/L, P < 0.05). Forearm blood flow was similar in the diabetic patients (3.6 +/- 0.7 mL/dl.min) and normal subjects (3.7 +/- 0.3 mL/dL.min). During matched rates of whole body glucose uptake (68 +/- 1 vs. 66 +/- 3 mumol/kg.min, normoglycemic study in controls vs. hyperglycemic study in the diabetic patients), the glucose AV-difference across the forearm was 64% higher than during normoglycemia (2.4 +/- 0.3 vs. 1.5 +/- 0.2 mmol/L, P < 0.05). Forearm blood flow (3.6 +/- 0.4 mL/dL.min) under conditions of matched glucose flux was similar to that during the normoglycemic study. We conclude that a defect in glucose extraction rather than blood flow characterizes insulin resistance in uncomplicated Type I diabetes. The signal for the flow increase is insulin and not the rate of glucose metabolism.