Irisin在运动降低妊娠期糖尿病发病中的作用及其分子机制

Gestational diabetes mellitus (GDM) is a major medical complication in pregnancy, which brings short and longterm health issues for both mothers and offspring. Our previous study has confirmed that exercise during pregnancy could significantly lower the risk of GDM in overweight and obese pregnant women. However, the mechanism behind this effect is not clear. Irisin is a recently identified myokine suggested to induce browning of white adipocytes, promote energy expenditure and reduce insulin resistance level. Therefore, irisin is an attractive target for the treatment of obesity and diabetes, and a point cut selected in our study to explore the mechanism of exercise in reducing the risk of GDM. Thus, the hypothesis of our project is exercise during pregnancy can increase the secretion of irisin, then prevent the development of GDM by inducing browning of white adipocytes, promoting energy expenditure and reducing insulin resistance. And this project will base on the clinical cohort established in our previous study “A randomized clinical trial of exercise during pregnancy to prevent GDM”, and through establishing animal model ( irisin injection group, exercise group, exercise + anti-FNDC5 antibodies group, control group) and vitro cell model (adipocyte and myocyte treated with different concentrations of irisin). Consequently, providing experimental basis for the effect of exercise during pregnancy on preventing the development of GDM. Furthermore, providing strong evidence to explain the physiology of irisin in exercise and the prevention and treatment of metabolic diseases.

妊娠期糖尿病（GDM）是产科常见并发症之一，可造成母儿近远期一系列不良影响。申请者前期研究结果证实孕期运动可显著降低孕妇GDM的发生风险，下降幅度达45.8%，并有效控制孕妇孕期的体重增长及胰岛素抵抗水平。鸢尾素（Irisin）是新发现的一类肌肉因子，具有促进白色脂肪米色化及减轻胰岛素抵抗的功能，被认为是治疗肥胖和糖尿病的靶点。本课题将以Irisin为切入点，基于前期建立的运动预防GDM随机对照临床队列，并构建食源性肥胖孕鼠胰岛素抵抗模型（Irisin注射治疗组、运动组、运动+抗FNDC5抗体组及对照组）和体外细胞模型（不同浓度Irisin刺激脂肪或肌肉细胞），探讨运动预防GDM的可能机制：引起骨骼肌Irisin分泌增加，进而促使白色脂肪米色化、增加机体能量消耗及胰岛素敏感性。从而为临床运动预防GDM发生提供实验依据，也为阐述Irisin在运动功能的改善及代谢性疾病的防治作用增添有力证据。

妊娠期糖尿病（gestational diabetes mellitus，GDM）是妊娠期最常见的合并症之一，该疾病由于胰岛素抵抗引起的妊娠期高血糖水平可导致母儿一系列近、远期并发症的发生，增加社会的医疗经济负担。因此，加强对 GDM 高危人群的预防至关重要。运动已被证实可有效降低孕妇妊娠期罹患 GDM 的风险，但具体机制尚不明确。骨骼肌作为人体最主要的运动器官，其合成和分泌的活性物质具有调节机体代谢的作用。研究显示，鸢尾素（Irisin）是新近发现的一种过氧化物酶体增殖物激活受体γ辅激活因子（peroxisome proliferators-activated receptor γ coactivator-1α，PGC-1α）依赖性肌肉因子，PGC-1α可促进跨膜蛋白III型纤连蛋白结构域5（Fibronectin Type III Domain Containing 5，FNDC5）表达，FNDC5被蛋白酶切成Irisin，并分泌进入血液循环。.运动能显著上调骨骼肌FNDC5 mRNA和外周Irisin水平，从而促进线粒体解偶联蛋白1（uncoupling protein 1，UCP1）和棕色脂肪特异性基因表达（如：跨膜蛋白26（transmembrane protein 26，TMEM26），肿瘤坏死因子受体超家族成员9（tumer necrosis factor receptor superfamily member 9，CD137），T-box转录调控因子1（T-box transcription factor 1，TBX1）），增加能量消耗以及减少肥胖和胰岛素抵抗的作用，进而发挥对GDM的预防作用。