Cilvik Sarah N, Boehmer Brit, Wesolowski Stephanie R, Brown Laura D, Rozance Paul J
Perinatal Research Center, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
J Physiol. 2024 Nov;602(22):6329-6345. doi: 10.1113/JP286974. Epub 2024 Oct 9.
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 β- and α-cell proliferation, as well as lower α-cell mass and pancreas weight, while GCG-50 had lower islet area. This study demonstrates that chronic glucagon elevation in late gestation fetuses impairs β-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. KEY 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 β-cell function. We show that experimentally elevated fetal glucagon results in lower β- and α-cell proliferation, as well as decreased insulin secretion after 8-10 days of glucagon infusion. These results have important implications for β-cell reserve and later-life predisposition to diabetes.
在子宫内环境受损的情况下，如胎盘功能不全和围产期酸血症病例中，胎儿胰高血糖素浓度会升高。我们的目的是研究妊娠晚期胎儿高胰高血糖素血症对体内胰岛素分泌和胰岛结构的影响。对慢性插管的妊娠晚期胎羊进行低浓度（5纳克/千克/分钟；GCG - 5）或高浓度（50纳克/千克/分钟；GCG - 50）的胰高血糖素静脉输注或载体对照（CON），持续8 - 10天。在实验输注3小时（急性反应）和8 - 10天（慢性反应）后测量葡萄糖刺激的胎儿胰岛素分泌（GSIS）。纵向测量胰岛素、葡萄糖和氨基酸浓度。在研究结束时收集胰腺用于组织学和基因表达分析。急性暴露（3小时）于GCG - 50可使基础胰岛素浓度增加3倍，且GSIS增加。同时，在第8 - 10天，长期暴露于GCG - 5和GCG - 50均使基础胰岛素浓度降低2倍。在研究结束时，长期GCG - 50也使GSIS减弱。在GCG - 5和GCG - 50作用24小时内胎儿氨基酸浓度降低，而胎儿葡萄糖无差异。组织学上，GCG - 5和GCG - 50使β细胞和α细胞增殖减少，α细胞质量和胰腺重量降低，而GCG - 50使胰岛面积减小。本研究表明，妊娠晚期胎儿长期胰高血糖素升高会损害β细胞增殖和胰岛素分泌，这可能会增加日后患糖尿病的风险。我们推测胰高血糖素在降低胎儿循环氨基酸浓度中的作用可能对胰岛素分泌有抑制作用。要点：我们之前在慢性插管的胎羊模型中证明，实验性升高胎儿胰高血糖素会损害胎盘功能，减少胎儿蛋白质积累并降低胎儿体重。在本研究中，我们进一步研究了胎儿胰高血糖素升高对胎儿生理的影响，重点关注胰腺发育和β细胞功能。我们表明，实验性升高胎儿胰高血糖素会导致β细胞和α细胞增殖降低，以及在胰高血糖素输注8 - 10天后胰岛素分泌减少。这些结果对β细胞储备和日后患糖尿病的易感性具有重要意义。
