It is unclear whether insulin sensitivity independent of body weight regulates control of heart rate variation (HRV) by the autonomic nervous system. Insulin action on whole-body glucose uptake (M-value) and heart rate variability were measured in 21 normal men. The subjects were divided into 2 groups [normally insulin sensitive (IS, 8.0 +/- 0.4 mg/kg.min) and less insulin sensitive (IR, 5.1 +/- 0.3 mg/kg.min)] based on their median M-value (6.2 mg/kg x min). Spectral power analysis of heart rate variability was performed in the basal state and every 30 min during the insulin infusion. The IS and IR groups were comparable, with respect to age (27 +/- 2 vs. 26 +/- 2 yr), body mass index (22 +/- 1 vs. 23 +/- 1 kg/m(2)), body fat (13 +/- 1 vs. 13 +/- 1%), systolic (121 +/- 16 vs. 117 +/- 14 mm Hg) and diastolic (74 +/- 11 vs. 73 +/- 11 mm Hg) blood pressures, and fasting plasma glucose (5.4 +/- 0.1 vs. 5.5 +/- 0.1 mmol/L) concentrations. Fasting plasma insulin was significantly higher in the IR (30 +/- 4 pmol/L) than in the IS (17 +/- 3 pmol/L, P < 0.05) group. In the IS group, insulin significantly increased the normalized low-frequency (LFn) component, a measure of predominantly sympathetic nervous system activity, from 36 +/- 5 to 48 +/- 4 normalized units (nu; 0 vs. 30-120 min, P < 0.001); whereas the normalized high-frequency (HFn) component, a measure of vagal control of HRV, decreased from 66 +/- 9 to 48 +/- 5 nu (P < 0.001). No changes were observed in either the normalized LF component [35 +/- 5 vs. 36 +/- 2 nu, not significant (NS)] or the normalized HF component (52 +/- 6 vs. 51 +/- 4 nu, NS) in the IR group. The ratio LF/HF, a measure of sympathovagal balance, increased significantly in the IS group (0.92 +/- 0.04 vs. 1.01 +/- 0.04, P < 0.01) but remained unchanged in the IR group (0.91 +/- 0.04 vs. 0.92 +/- 0.03, NS). Heart rate and systolic and diastolic blood pressures remained unchanged during the insulin infusion in both groups. We conclude that insulin acutely shifts sympathovagal control of HRV toward sympathetic dominance in insulin-sensitive, but not in resistant, subjects. These data suggest that sympathetic overactivity is not a consequence of hyperinsulinemia.