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Our objective was to investigate the impact of late gestation fetal hyperglucagonaemia on <jats:italic>in vivo<\/jats:italic> insulin secretion and pancreatic islet structure. Chronically catheterized late gestation fetal sheep received an intravenous infusion of glucagon at low (5\u00a0ng\/kg\/min; GCG\u20105) or high (50\u00a0ng\/kg\/min; GCG\u201050) concentrations or a vehicle control (CON) for 8\u201310\u00a0days.\u00a0Glucose\u2010stimulated fetal insulin secretion (GSIS) was measured following 3\u00a0h (acute response) and 8\u201310\u00a0days (chronic response) of experimental infusions. Insulin, glucose and amino acid concentrations were measured longitudinally. The pancreas was collected at the study end for histology and gene expression analysis. Acute exposure (3\u00a0h) to GCG\u201050 induced a 3\u2010fold increase in basal insulin concentrations with greater GSIS. Meanwhile, chronic exposure to both GCG\u20105 and GCG\u201050 decreased basal insulin concentrations 2\u2010fold by day 8\u201310. Chronic GCG\u201050 also blunted GSIS at the study end. Fetal amino acid concentrations were decreased within 24\u00a0h of GCG\u20105 and GCG\u201050, while there were no differences in fetal glucose. Histologically, GCG\u20105 and GCG\u201050 had lower \u03b2\u2010 and \u03b1\u2010cell proliferation, as well as lower \u03b1\u2010cell mass and pancreas weight, while GCG\u201050 had lower islet area. This study demonstrates that chronic glucagon elevation in late gestation fetuses impairs \u03b2\u2010cell proliferation and insulin secretion, which has the potential to contribute to later\u2010life diabetes risk. We speculate that the action of glucagon in lower circulating fetal amino acid concentrations may have a suppressive effect on insulin secretion.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16344-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>We have previously demonstrated in a chronically catheterized fetal sheep model that experimentally elevated glucagon in the fetus impairs placental function, reduces fetal protein accretion and lowers fetal weight.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In the present study, we further characterized the effects of elevated fetal glucagon on fetal physiology with a focus on pancreatic development and \u03b2\u2010cell function.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We show that experimentally elevated fetal glucagon results in lower \u03b2\u2010 and \u03b1\u2010cell proliferation, as well as decreased insulin secretion after 8\u221210\u00a0days of glucagon infusion.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These results have important implications for \u03b2\u2010cell reserve and later\u2010life predisposition to diabetes.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp286974","type":"journal-article","created":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T17:38:22Z","timestamp":1728495502000},"page":"6329-6345","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Chronic late gestation fetal hyperglucagonaemia results in lower insulin secretion, pancreatic mass, islet area and beta\u2010 and \u03b1\u2010cell 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