The hepatic parasympathetic system is one of the major contributors for preserving insulin sensitivity in the postprandial state. Postprandial hepatic vagal control of whole-body glucose clearance and its effect on specific organs remains unknown. Our hypothesis is that, in the postprandial state, the hepatic parasympathetic nerves (HPN) are responsible for a considerable part of extra-hepatic tissue glucose clearance. Two groups of 9-week-old Sprague-Dawley rats were studied, comparing sham-operated versus hepatic parasympathetic denervated animals. Insulin sensitivity was evaluated in the postprandial state by the rapid insulin sensitivity test (RIST). [(3) H]2-deoxy-d-glucose was administered during the RIST. Plasma glucose rate of the disappearance and clearance by skeletal muscle, adipose tissue, liver, pancreas, heart and kidney of this radioisotope was measured. The postprandial denervated group showed a decrease insulin sensitivity of 41.4 ± 5.2%. This group of animals showed a decrease in the rate of plasma [(3) H]2-deoxy-d-glucose disappearance and skeletal muscle, heart and kidney glucose clearance by 45%, 35% and 67%, respectively. These studies show that the major contributor of postprandial whole-body glucose clearance was skeletal muscle; in the range 69-38%, depending on HPN integrity. The results obtained in the present study indicate that HPN are crucial for postprandial action of insulin through a mechanism that is essential for maintenance of skeletal muscle, heart and kidney glucose clearance. These results suggest that hepatic parasympathetic dysfunction could lie at the genesis of type 2 diabetes complications, namely insulin resistance, nephropathy and cardiomyopathy.