Insulin-like growth factor-1 (IGF-1) has many insulin-like activities, including stimulation of glucose uptake in skeletal muscle. However, those with diabetes or chronic liver disease are insulin resistant but show a normal hypoglycemic response to IGF-1. We have previously shown that insulin sensitivity depends on a hepatic parasympathetic reflex release of a hormone from the liver. The hypothesis was tested that insulin action, but not IGF-1 action, is dependent on the hepatic parasympathetic reflex. Glucose disposal in response to three doses of IGF-1 (25, 100, 200 mu g/kg) was determined in rats. IGF-1 at 200 mu g/kg had similar effect on glucose disposal as did 50 mU/kg of insulin. Interruption of the hepatic parasympathetic reflex either by surgical ablation of the anterior nerve plexus or by atropine (1.0 mg/kg) resulted in insulin, but not IGF-1, resistance. Sixteen hours of fasting resulted in insulin, but not IGF-1, resistance. In conclusion, insulin, but not IGF-1, triggers the hepatic parasympathetic dependent release of a putative hepatic insulin sensitizing substance (HISS) that stimulates glucose uptake in skeletal muscle.