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Previous studies indicate that insulin secretion from the fetuses of dams fed a low protein (LP) diet is reduced in response to leucine or arginine. The aim of this study was to locate the defect in the insulin secretion pathway induced by a LP diet during gestation. The effects of various secretagogues acting at different levels of the insulin secretion cascade were investigated in vitro in fetal islets from dams fed either a normal or a LP diet during pregnancy. Insulin content, insulin secretion and the cAMP content were then measured. Although insulin content of LP islets did not differ from that of control islets, insulin secretion from LP fetal islets was reduced when challenged by amino acids or cAMP enhancers. This reduction did not appear to be related solely to an altered islet cAMP content. An impairment of insulin secretion remained after stimulation of fetal LP islets with either metabolic or nonmetabolic secretagogues. The insulin secretion by LP islets was restored to normal, however, with barium or cytochalasin-B. These findings demonstrate that an in utero isocaloric LP diet impairs insulin secretion of the fetus. This alteration is located at the exocytosis step in the insulin secretion cascade and not in the insulin pool of the beta cell. [ABSTRACT FROM AUTHOR]