To elucidate the direct effect of an intestinal osmolality on insulin release, we investigated the insulin response to intra-duodenal infusion of mannitol in rats. After the anesthesia with intraperitoneal pentobarbital sodium, one milliliter of mannitol solution (10% or 20%) was infused into the duodenum. Portal and femoral blood insulin concentrations significantly increased at 30, 60, and 120 min after intra-duodenal infusion of mannitol, although the blood glucose level did not change. Subcutaneous pre-administration of propranolol (0.4mg/kg) or metoprolol (25mg/kg) completely abolished this phenomenon. These results suggest that intestinal osmolality can directly enhance insulin secretion and that beta 1-adrenergic mechanism is involved in this phenomenon.