Hyperinsulinemia related to obesity may result in activation of the sympathetic nervous system (SNS). Acute autonomic responsiveness to insulin is influenced by body composition, particularly obesity. However, it is unclear whether skeletal muscle mass or function determines autonomic responsiveness to insulin. While muscle function is associated with insulin sensitivity, there are no studies that have assessed if skeletal muscle function modulates autonomic responses to hyperinsulinemia. Fifty healthy men (aged 18-35years) were evaluated for skeletal muscle function (hand grip strength and static and dynamic endurance) and then divided into low and high endurance (LE and HE) groups. Heart rate variability (HRV) in the frequency domain was measured during a hyperinsulinemic euglycemic clamp (HEC). With hyperinsulinemia, the HE group had a higher increment in total power of HRV (1615+/-2536 vs. 97+/-1943, P=0.08) and normalized low frequency (LF) HRV (16.2+/-17.9 vs. -1.3+/-14.8, P=0.008) as compared to the LE group. A significant reduction in the normalized high frequency (HF) HRV was seen in the HE group but not in the LE group (-12.3+/-12.9 vs. 1.7+/-13.9, P=0.009); this translated into an increase in LF/HF ratio for the HE group and but not the LE group (1.21+/-1.8 vs. -0.08+/-0.65, P=0.016). The present study indicates that there are differential cardiac autonomic responses to hyperinsulinemia in healthy human subjects with variable skeletal muscle function.