慢性胎儿亮氨酸输注增强胎儿胰岛素分泌并增加妊娠晚期绵羊胰岛的大小、血管生成和β细胞。
A Chronic Fetal Leucine Infusion Potentiates Fetal Insulin Secretion and Increases Pancreatic Islet Size, Vascularity, and β Cells in Late-Gestation Sheep.
机构信息
Perinatal Research Center, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
出版信息
J Nutr. 2020 Aug 1;150(8):2061-2069. doi: 10.1093/jn/nxaa138.
BACKGROUND
Infusion of a complete amino acid mixture into normal late-gestation fetal sheep potentiates glucose-stimulated insulin secretion (GSIS). Leucine acutely stimulates insulin secretion in late-gestation fetal sheep and isolated fetal sheep islets in vitro.
OBJECTIVES
We hypothesized that a 9-d leucine infusion would potentiate GSIS in fetal sheep.
METHODS
Columbia-Rambouillet fetal sheep at 126 days of gestation received a 9-d leucine infusion to achieve a 50%-100% increase in leucine concentrations or a control infusion. At the end of the infusion we measured GSIS, pancreatic morphology, and expression of pancreatic mRNAs. Pancreatic islet endothelial cells (ECs) were isolated from fetal sheep and incubated with supplemental leucine or vascular endothelial growth factor A (VEGFA) followed by collection of mRNA. Data measured at multiple time points were compared with a repeated-measures 2-factor ANOVA. Data measured at 1 time point were compared using Student's t test or the Mann-Whitney test.
RESULTS
Glucose-stimulated insulin concentrations were 80% higher in leucine-infused (LEU) fetuses than in controls (P < 0.05). In the pancreas, LEU fetuses had a higher proportion of islets >5000 μm2 than controls (75% more islets >5000 μm2; P < 0.05) and a larger proportion of the pancreas that stained for β cells (12% greater; P < 0.05). Pancreatic and pancreatic islet vascularity were both 25% greater in LEU fetuses (P < 0.05). Pancreatic VEGFA and hepatocyte growth factor (HGF) mRNA expressions were 38% and 200% greater in LEU fetuses than in controls (P < 0.05), respectively. In isolated islet ECs, HGF mRNA was 20% and 50% higher after incubation in supplemental leucine (P < 0.05) or VEGFA (P < 0.01), respectively.
CONCLUSIONS
A 9-d leucine infusion potentiates fetal GSIS, demonstrating that glucose and leucine act synergistically to stimulate insulin secretion in fetal sheep. A greater proportion of the pancreas being comprised of β cells and higher pancreatic vascularity contributed to the higher GSIS.
背景
在正常妊娠晚期胎儿羊中输注完整的氨基酸混合物可增强葡萄糖刺激的胰岛素分泌（GSIS）。亮氨酸可在妊娠晚期胎儿羊和离体胎儿胰岛中急性刺激胰岛素分泌。
目的
我们假设 9 天的亮氨酸输注会增强胎儿羊的 GSIS。
方法
哥伦比亚-兰布赖特胎儿羊在妊娠 126 天时接受 9 天的亮氨酸输注，以达到亮氨酸浓度增加 50％-100％或对照输注。输注结束时，我们测量了 GSIS、胰腺形态和胰腺 mRNA 的表达。从胎儿羊中分离胰岛内皮细胞（EC），并在补充亮氨酸或血管内皮生长因子 A（VEGFA）孵育后收集 mRNA。在多个时间点测量的数据与重复测量的 2 因素方差分析进行比较。在 1 个时间点测量的数据使用学生 t 检验或曼-惠特尼检验进行比较。
结果
与对照组相比，亮氨酸输注（LEU）胎儿的葡萄糖刺激胰岛素浓度高 80％（P <0.05）。在胰腺中，LEU 胎儿的胰岛> 5000μm2 的比例高于对照组（胰岛> 5000μm2 的比例高 75％；P <0.05），β细胞染色的胰腺比例也更高（高 12％；P <0.05）。LEU 胎儿的胰腺和胰岛血管均增加 25％（P <0.05）。LEU 胎儿的胰腺 VEGFA 和肝细胞生长因子（HGF）mRNA 表达分别比对照组高 38％和 200％（P <0.05）。在分离的胰岛 EC 中，补充亮氨酸（P <0.05）或 VEGFA（P <0.01）孵育后，HGF mRNA 分别高 20％和 50％。
结论
9 天的亮氨酸输注增强了胎儿的 GSIS，表明葡萄糖和亮氨酸协同作用刺激胎儿羊的胰岛素分泌。更多的胰腺由β细胞组成，更高的胰腺血管密度有助于更高的 GSIS。
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