These studies examined the hypothesis that GRP stimulates insulin release from the endocrine pancreas of ovine fetuses. This could occur due to the action of GRP directly within the fetal compartment or due to indirect effects of GRP on glucose and insulin concentrations in the maternal compartment which in turn influences the availability of glucose for transplacental transfer to the fetus and hence produce alterations in fetal insulin release.;The studies performed provided the following results: (1) IR-GRP was detectable in nerves of the GI tract and in the systemic circulation but not in the pancreas of fetal and adult sheep; (2) Intravenous administration of GRP stimulates insulin and glucagon release and potentiates glucose stimulated insulin release in adult non-pregnant sheep; (3) Preliminary studies suggest that plasma IR-GRP concentrations rise in non-pregnant sheep following feeding. These results are consistent with a proposed incretin action of GRP which acts systemically to alter insulin release. However, further experiments are necessary to confirm this suggestion. The ability of GRP to stimulate insulin release and potentiate glucose stimulated insulin release, is attenuated in pregnant compared to non-pregnant sheep. Furthermore, the diminished insulin response to GRP and/or glucose observed in pregnant sheep was reproduced in non-pregnant ovariectomized sheep treated with progesterone and estradiol but not estradiol alone. This suggests that elevated circulating progesterone concentrations which occur during pregnancy mediate, at least in part, the reduced ability for GRP to influence insulin release observed in pregnant sheep. Similar doses of GRP and/or glucose administered to fetal sheep over the last one-third of gestation did not alter fetal plasma insulin concentrations significantly. IR-GRP is present in very high concentrations in fetal plasma which probably explains why exogenous GRP administration into fetal sheep did not alter circulating GRP or insulin concentrations. Further experiments are necessary to determine the site of production and function of GRP within the fetus
