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Recent studies indicate a link between carbohydrate intake and the functional state of the sympathetic nervous system. Fasting or carbohydrate restriction decreases sympathetic activity, while glucose ingestion or dietary supplementation with sucrose increases sympathetic nerve activity. To examine the potential contributions of hyperglycemia and hyperinsulinemia to sympathetic stimulation, sympathetic activity was assessed by measurement of plasma norepinephrine (NE) levels and concomitant cardiovascular indices in nonobese young men during glucose and insulin infusions using glucose clamp techniques. In the insulin infusion studies (euglycemic glucose clamp), insulin was administered at 2 mU/kg/min and 5 mU/kg/min for 2 h while blood glucose was maintained at basal levels by a variable rate of glucose infusion. In the hyperglycemic studies, blood glucose was raised 125 mg/dl above basal and maintained at that level for 2h. In response to both insulin infusions, plasma NE rose progressively over the course of the study, increasing 50% with the 2-mU infusion (from mean basal value of 240 ± 34 pg/ml to 360 ± 41 at 150 min, P < 0.001 for changes over time by analysis of variance) and 117% with the 5-mil infusion (from 254 ± 20 pg/ml to 551 ± 88 at 150 min, P < 0.001). The plasma NE response was greater with the 5-mll than with the 2-mU insulin infusion (P < 0.001), and similarly, was greater during the 2-mU insulin infusion than during a control test in which neither insulin nor glucose was infused (P < 0.001). Associated with the elevations in plasma NE In the 2-mU insulin infusion were increases in pulse rate (P < 0.05), pulse pressure (P < 0.005), and pulse rate - systolic blood pressure product (P < 0.01), and during the 5-mU insulin infusions there were increases in pulse pressure (P < 0.001), mean arterial blood pressure (P < 0.001), and pulse rate - systolic blood pressure product (P < 0.001). Plasma NE did not change during the hyperglycemic glucose clamp nor during control tests, and pulse pressure in the hyperglycemic studies (P < 0.005) was the only cardiovascular measurement increased by these two infusion protocols. The clearance of NE in three subjects was unaffected by the 2-mU insulin infusion. Thus, insulin infusion increases sympathetic nervous system activity in the absence of changes in blood glucose.