Alternate day fasting combined with exercise for the treatment of NAFLD

项目摘要/摘要 背景：大约65%的肥胖者患有非酒精性脂肪肝(NAFLD)，而这 病情与胰岛素抵抗和糖尿病的发展密切相关。创新的生活方式 迫切需要治疗非酒精性脂肪肝的策略。隔日禁食(ADF)已经在动物身上显示出来 减少肝脏脂肪变性和改善肝脏胰岛素敏感性，但这些发现尚未得到证实 人类受试者。ADF由个人被允许随意食用食物的“节日”组成， 与“禁食日”交替进行，即个人摄入平时摄入量的25%(约500千卡)。我们最近 进行了一项初步研究，以评估ADF与运动相结合的效果，以及ADF或单独运动的效果 糖尿病前期非酒精性脂肪肝患者肝脏参数的变化我们的结果表明，ADF PLUS的组合 运动使丙氨酸氨基转移酶(ALT)显著降低；ALT是肝脏的间接标志 脂肪变性)，与12周后单独使用ADF或单独锻炼相比。胰岛素抵抗的下降幅度更大， 糖化血红蛋白、低密度脂蛋白胆固醇，以及更显著的高密度脂蛋白胆固醇增加，在 联合组与单独干预。我们试点试验的数据也表明，这些减少在 胰岛素抵抗可能部分是通过肝细胞衍生激素(肝细胞因子)的变化来调节的 随着肝脏脂肪减少而发生。尽管这些试点发现非常有希望，但这些数据仍然需要 通过一项强大的长期(24周)临床试验证实。假设：目前的提案将检验 以下假设：(1)联合组(ADF加运动)将经历更大的减少 与ADF或运动相比，肝脏脂肪变性(通过磁共振波谱测量；MRS) (2)联合治疗组肝细胞因子谱有较大改善(胎球蛋白-A、胎球蛋白B、 成纤维细胞生长因子-21、RBP4、硒蛋白P、SHBG、肾上腺素)与ADF或单独运动比较； 联合组在肝脏胰岛素敏感性、胰岛素抵抗和 糖化血红蛋白和其他代谢性疾病风险变量(空腹血糖、空腹胰岛素、甘油三酯、低密度脂蛋白 胆固醇、低密度脂蛋白颗粒大小、血压、炎症参数)与ADF或运动进行比较 独自一人。方法：为了测试这些目标，将进行为期24周的随机、对照、平行手臂喂养试验 实施。患有NAFLD的肥胖糖尿病前期患者(n=180)将随机分为4组： (1)ADF(禁食日：能量摄入量的25%，饲喂日：自由采食，不运动)，(2)运动(自由采食， 有监督的5天/周训练)，(3)组合(ADF加运动)，和(4)对照(随意喂养，不 锻炼)。意义：如果这项应用的目标实现，这项研究将第一次表明 隔日禁食和有氧运动相结合是一种有效的非药物疗法 减少肝脏脂肪变性，改善肝脏胰岛素敏感性，防止糖尿病前期进展为 2非酒精性脂肪肝患者合并糖尿病。

Project Summary/ Abstract Background: Approximately 65% of obese individuals have non-alcoholic fatty liver disease (NAFLD), and this condition is strongly related to the development of insulin resistance and diabetes. Innovative lifestyle strategies to treat NAFLD are critically needed. Alternate day fasting (ADF) has been shown in animals to reduce hepatic steatosis and improve hepatic insulin sensitivity, but these findings have yet to be confirmed in human subjects. ADF consists of a “feast day” where individuals are permitted to consume food ad libitum, alternated with a “fast day” where individuals consume 25% of their usual intake (~500 kcal). We recently performed a pilot study to evaluate the effects of ADF combined with exercise, versus ADF or exercise alone, on hepatic parameters in prediabetic NAFLD patients. Our results show that the combination of ADF plus exercise produced greater reductions in alanine aminotransferase (ALT; an indirect marker of hepatic steatosis), compared to ADF alone, or exercise alone, after 12 weeks. Greater decreases in insulin resistance, HbA1c, LDL cholesterol, and more pronounced increases in HDL cholesterol, were observed in the combination group versus individual interventions. Data from our pilot trial also suggest that these decreases in insulin resistance may be mediated in part by changes in hepatocyte-derived hormones (hepatokines) that occur with liver fat reduction. Although these pilot findings are very promising, these data still require confirmation by a well powered longer-term (24 week) clinical trial. Hypotheses: The present proposal will test the following hypotheses: (1) The combination group (ADF plus exercise) will experience greater reductions in hepatic steatosis (measured by magnetic resonance spectroscopy; MRS) when compared to ADF or exercise alone; (2) The combination group will experience greater improvements in hepatokine profile (fetuin-A, fetuin B, FGF-21, RBP4, selenoprotein P, SHBG, adropin) when compared to ADF or exercise alone; (3) The combination group will experience greater improvements in hepatic insulin sensitivity, insulin resistance and HbA1c and other metabolic disease risk variables (fasting glucose, fasting insulin, triglycerides, LDL cholesterol, LDL particle size, blood pressure, inflammatory parameters) when compared to ADF or exercise alone. Methods: To test these objectives, a 24-week randomized, controlled, parallel-arm feeding trial will be implemented. Obese prediabetic individuals with NAFLD (n = 180) will be randomized to 1 of 4 groups: (1) ADF (fast day: 25% energy intake, feed day: ad libitum fed, no exercise), (2) exercise (ad libitum fed, training 5 days/week supervised), (3) combination (ADF plus exercise), and (4) control (ad libitum fed, no exercise). Significance: If the aims of this application are achieved, this study will be the first to show that the combination of alternate day fasting plus aerobic exercise is an effective non-pharmacological therapy to reduce hepatic steatosis, improve hepatic insulin sensitivity and prevent the progression of prediabetes to type 2 diabetes in NAFLD patients.