Xiao Di, Kou Hao, Gui Shuxia, Ji Zhenyu, Guo Yu, Wu Yin, Wang Hui
Department of Pharmacology, School of Basic Medical Sciences of Wuhan University, Wuhan, China.
Department of Pharmacy, Zhongnan Hospital, Wuhan University, Wuhan, China.
Front Endocrinol (Lausanne). 2019 Feb 4;10:34. doi: 10.3389/fendo.2019.00034. eCollection 2019.
Intrauterine growth restricted offspring suffer from abnormal glucose homeostasis and β cell dysfunction. In this study, we observed the dynamic changes of glucose metabolic phenotype, pancreatic morphology, and insulin synthesis in prenatal ethanol exposure (PEE) male offspring rats, and to explore the potential intrauterine programming mechanism of the glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis. Ethanol (4 g/kg·d) was administered through oral gavage during gestational day (GD) 9-20. Serum glucose and insulin levels, pancreatic β cell mass, and expression of glucocorticoid receptor (GR), IGF1 and insulin were determined on GD20, postnatal week (PW) 6, PW12 with/without chronic stress (CS), and PW24, respectively. Both intraperitoneal glucose and insulin tolerance tests were conducted at PW12 and PW24. Results showed that the serum glucose and insulin levels as well as pancreatic β cell mass were reduced on GD20 in PEE males compared with the controls, while pancreatic GR expression was enhanced but IGF1 and INS1/2 expression were suppressed. After birth, compared with the controls, β cell mass in the PEE males was initially decreased at PW6 and gradually recovered from PW12 to PW24, which was accompanied by increased serum glucose/insulin levels and insulin resistance index (IRI) at PW6 and decreased serum glucose contents at PW12, as well as unchanged serum glucose/insulin concentrations at PW24. In addition, both improved glucose tolerance and impaired insulin sensitivity of the PEE males at PW12 were inversed at PW24. Moreover, at PW6 and PW12, pancreatic GR expression in the PEE group was decreased, while IGF1 expression was reversely increased, resulting in a compensatory increase of insulin expression. Moreover, CS induced pancreatic GR activation and inhibited IGF1 expression, resulting in impaired insulin biosynthesis. Conclusively, the above changes were associated with age and the intrauterine programming alteration of GC-IGF1 axis may be involved in prenatal and postnatal pancreatic dysplasia and impaired insulin biosynthesis in PEE male offspring.
宫内生长受限的后代存在葡萄糖稳态异常和β细胞功能障碍。在本研究中，我们观察了产前乙醇暴露（PEE）雄性后代大鼠葡萄糖代谢表型、胰腺形态和胰岛素合成的动态变化，并探讨糖皮质激素 - 胰岛素样生长因子1（GC - IGF1）轴潜在的宫内编程机制。在妊娠第9 - 20天通过灌胃给予乙醇（4 g/kg·d）。分别在妊娠第20天、出生后第6周、第12周（有无慢性应激）和第24周测定血清葡萄糖和胰岛素水平、胰腺β细胞质量以及糖皮质激素受体（GR）、IGF1和胰岛素的表达。在出生后第12周和第24周进行腹腔内葡萄糖和胰岛素耐量试验。结果显示，与对照组相比，PEE雄性大鼠在妊娠第20天时血清葡萄糖和胰岛素水平以及胰腺β细胞质量降低，而胰腺GR表达增强，但IGF1和INS1/2表达受到抑制。出生后，与对照组相比，PEE雄性大鼠的β细胞质量在出生后第6周最初下降，并从出生后第12周逐渐恢复至第24周，这伴随着出生后第6周血清葡萄糖/胰岛素水平和胰岛素抵抗指数（IRI）升高以及出生后第12周血清葡萄糖含量降低，而出生后第24周血清葡萄糖/胰岛素浓度无变化。此外，PEE雄性大鼠在出生后第12周时改善的葡萄糖耐量和受损的胰岛素敏感性在出生后第24周时发生逆转。此外，在出生后第6周和第12周，PEE组胰腺GR表达降低，而IGF1表达反向增加，导致胰岛素表达代偿性增加。此外，慢性应激诱导胰腺GR激活并抑制IGF1表达，导致胰岛素生物合成受损。总之，上述变化与年龄相关，GC - IGF1轴的宫内编程改变可能参与了PEE雄性后代产前和产后胰腺发育异常及胰岛素生物合成受损。
