内分泌型FGF19/FGF21及其信号通路对妊娠期糖尿病胰岛素抵抗的作用研究

Gestational diabetes mellitus (GDM) is the most common complication in pregnancy. Both mother and offspring have a significantly increased future risk for metabolic and cardiovascular disease as a consequence of GDM. Pathological insulin resistance and the pancreatic β-cell dysfunction may contribute to the development and adverse outcomes of GDM..Recently, fibroblast growth factor 19 (FGF19) and FGF21 have emerged as key endocrine regulators of glucose, lipid and energy metabolism. Both factors activate FGFRs in the context of co-receptor βKlotho(KLB) expression. After that, both proteins alter ERK phosphorylation and stimulate glucose uptake. Furthermore, these two factors ameliorate insulin resistance through various ways including up-regulating insulin mRNA, IRS-1 expressions, down-regulating GH-IGF-1 levels in different tissues and blood circulation and also improving dyslipidemia..Our previous studies showed that FGF19 and FGF21 serum concentrations were significantly different in subjects with GDM as compared with healthy pregnant controls. The levels of FGF19/FGF21 were correlated with markers of insulin resistance and an adverse lipid profile. Furthermore, several factors which involved in insulin resistance and FGF19/FGF21 signaling pathway had differential expression in placenta from GDM and normal glucose tolerance pregnancy. In addition, FGF19 up-regulated the IRS-1 expression and down-regulated the GLUT-1 expression in human villus trophoblast cells. Those led us to hypothesize that FGF19/FGF21 signaling pathway could play an important role in the pathogenesis and development of insulin resistance state in GDM..In the present study, we therefore verify the hypothesis by two steps. Firstly, we will further investigate whether maternal and neonatal FGF19/FGF21 signaling pathway are altered and associated with insulin resistance, glucose intolerance, dyslipidemia and adverse pregnancy outcomes. Secondly, we will use the FGF19/FGF21 transgenic and knockout mice to establish a diet-induced gestational insulin resistance animal model. Thus we will evaluate the regulating action of FGF19/FGF21 on gestational insulin resistance. .The aim of this study is to elucidate the role of FGF19/FGF21 in insulin resistance and metabolic disorder in GDM.

胰岛素抵抗是GDM发生发展的关键环节。最新研究发现成纤维细胞生长因子FGF19和FGF21通过KLB/FGFR受体复合物激活FRS2-Ras-ERK通路促进细胞摄取葡萄糖，并经IRS等途径改善胰岛素抵抗。我们的前期研究证实：GDM母血及胎盘等组织中FGF19表达下降而FGF21升高，二者均与胰岛素抵抗相关；而FGF19可上调高糖培养的滋养细胞IRS-1表达并下调GLUT-1表达。据此，我们推测FGF19/FGF21信号通路参与并调控GDM胰岛素抵抗的发生发展。本项目拟：1、通过临床队列研究证实FGF19/FGF21通路的表达差异与GDM胰岛素抵抗、糖脂代谢异常相关；2、采用FGF19/FGF21转基因及基因敲除小鼠，模拟GDM构建饮食诱导的胰岛素抵抗妊娠模型，初步揭示FGF19/FGF21改善胰岛素抵抗的作用机制。

胰岛素抵抗是GDM发生发展的关键环节。最新研究发现成纤维细胞生长因子FGF19和FGF21通过KLB/FGFR受体复合物激活FRS2-Ras-ERK通路促进细胞摄取葡萄糖，并经IRS等途径改善胰岛素抵抗。我们的前期研究证实：GDM母血及胎盘等组织中FGF19表达下降而FGF21升高，二者与胰岛素抵抗相关；而FGF19可上调高糖培养的滋养细胞IRS-1表达并下调GLUT-1表达。据此，我们推测FGF19/FGF21信号通路参与并调控GDM胰岛素抵抗的发生发展。本项目研究结果：.1）通过临床试验证实，FGF19/FGF21及其信号通路的表达差异与GDM胰岛素抵抗、糖脂代谢及子代出生结局的相关；.2）通过组织学试验证实，高糖培养基培养原代滋养细胞后，IRS-1和GLUT-1的mRNA和蛋白表达均明显降低，给予外源性FGF19后，IRS-1和GLUT-1表达升高；.3）通过动物学实验证实，给予外源性FGF19或内源性FGF15表达可改善妊娠D18天高脂饮食小鼠的血脂水平，有望为临床开发FGF19/FGF21作为改善GDM母婴不良结局的新型药物提供实验依据。