Our aim was to determine whether complete hepatic denervation would affect the hormonal response to insulin-induced hypoglycemia in dogs. Two weeks before study, dogs underwent either hepatic denervation (DN) or sham denervation (CONT). In addition, all dogs had hollow steel coils placed around their vagus nerves. The CONT dogs were used for a single study in which their coils were perfused with 37 degrees C ethanol. The DN dogs were used for two studies in a random manner, one in which their coils were perfused with -20 degrees C ethanol (DN + COOL) and one in which they were perfused with 37 degrees C ethanol (DN). Insulin was infused to create hypoglycemia (51 +/- 3 mg/dl). In response to hypoglycemia in CONT, glucagon, cortisol, epinephrine, norepinephrine, pancreatic polypeptide, glycerol, and hepatic glucose production increased significantly. DN alone had no inhibitory effect on any hormonal or metabolic counterregulatory response to hypoglycemia. Likewise, DN in combination with vagal cooling also had no inhibitory effect on any counterregulatory response except to reduce the arterial plasma pancreatic polypeptide response. These data suggest that afferent signaling from the liver is not required for the normal counterregulatory response to insulin-induced hypoglycemia.