: OBJECTIVES: The distribution of serotonin (5-HT) and its effect on insulin and glucagon secretion were investigated to examine whether there are changes in the pattern of distribution and effect of 5-HT after the onset of experimental diabetes. METHODS: The pattern of 5-HT and its effect of insulin and glucagon secretion was examined using immunohistochemical and radioimmunoassay techniques, respectively. RESULTS: 5-HT was demonstrated mainly in the neural elements of the pancreas. 5-HT-containing fine varicose nerve fibers were discerned in the wall of blood vessels and pancreatic ducts. 5-HT-containing nerves were also observed in the periacinar and periinsular regions of normal pancreas. The pattern or intensity of the distribution of serotonergic nerves did not change after the onset of diabetes. The perivascular, periductal, periacinar and periinsular regions of diabetic pancreas all contained 5-HT positive nerves. 5-HT elicited marked increases in insulin secretion from normal pancreas but had an inhibitory effect on insulin secretion from diabetic pancreatic tissues. In contrast, 5HT inhibited glucagon secretion from normal pancreatic tissue fragments but stimulated glucagon release from diabetic pancreatic tissue fragments. conclusion: 5-HT is well distributed in normal and diabetic pancreatic tissues and has stimulatory effects on insulin secretion from normal pancreas and glucagon secretion from diabetic pancreas. This result indicates that although 5-HT may help in the maintenance of the blood sugar level in normal pancreas by increasing insulin secretion and decreasing glucagon secretion, it may also aggravate the hyperglycemia observed in diabetes mellitus and hence exacerbate the symptoms of hyperglycemia in poorly controlled diabetes mellitus.