Chronic late gestation fetal hyperglucagonaemia results in lower insulin secretion, pancreatic mass, islet area and beta- and α-cell proliferation

Fetal glucagon concentrations are elevated in the presence of a compromised intrauterine environment, as in cases of placental insufficiency and perinatal acidaemia. Our objective was to investigate the impact of late gestation fetal hyperglucagonaemia on in vivo insulin secretion and pancreatic islet structure. Chronically catheterized late gestation fetal sheep received an intravenous infusion of glucagon at low (5 ng/kg/min; GCG-5) or high (50 ng/kg/min; GCG-50) concentrations or a vehicle control (CON) for 8-10 days. Glucose-stimulated fetal insulin secretion (GSIS) was measured following 3 h (acute response) and 8-10 days (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 h) to GCG-50 induced a 3-fold increase in basal insulin concentrations with greater GSIS. Meanwhile, chronic exposure to both GCG-5 and GCG-50 decreased basal insulin concentrations 2-fold by day 8-10. Chronic GCG-50 also blunted GSIS at the study end. Fetal amino acid concentrations were decreased within 24 h of GCG-5 and GCG-50, while there were no differences in fetal glucose. Histologically, GCG-5 and GCG-50 had lower beta- and alpha-cell proliferation, as well as lower alpha-cell mass and pancreas weight, while GCG-50 had lower islet area. This study demonstrates that chronic glucagon elevation in late gestation fetuses impairs beta-cell proliferation and insulin secretion, which has the potential to contribute to later-life diabetes risk. We speculate that the action of glucagon in lower circulating fetal amino acid concentrations may have a suppressive effect on insulin secretion. imageKey points 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. In the present study, we further characterized the effects of elevated fetal glucagon on fetal physiology with a focus on pancreatic development and beta-cell function. We show that experimentally elevated fetal glucagon results in lower beta- and alpha-cell proliferation, as well as decreased insulin secretion after 8-10 days of glucagon infusion. These results have important implications for beta-cell reserve and later-life predisposition to diabetes. figure legend This study investigated the effects of fetal hyperglucagonaemia on insulin secretion and pancreatic development in late-gestation sheep. Fetal sheep were infused with low (GCG-5) or high (GCG-50) doses of glucagon, resulting in reduced plasma insulin and amino acid concentrations, with no changes in plasma glucose. Chronic exposure to impaired glucose-stimulated insulin secretion (GCG-50 only), decreased beta- and alpha-cell proliferation, reduced pancreatic mass and lowered islet area (GCG-50 only). These findings demonstrate that elevated fetal glucagon negatively impacts fetal pancreatic development and insulin secretion, potentially increasing the risk of metabolic diseases later in life. image