Alternate day fasting combined with exercise for the treatment of NAFLD

项目概要/摘要 背景：大约65%的肥胖个体患有非酒精性脂肪性肝病（NAFLD）， 这种情况与胰岛素抵抗和糖尿病的发展密切相关。创新的生活方式 治疗NAFLD的策略是迫切需要的。隔日禁食（ADF）已在动物中显示， 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， 人类实验对象ADF包括一个“节日”，允许个人随意食用食物， 与“禁食日”交替进行，其中个人消耗其通常摄入量的25%（约500千卡）。我们最近 进行了一项试点研究，以评估ADF与运动相结合的效果，与ADF或运动单独相比， 糖尿病前期NAFLD患者的肝脏参数。我们的研究结果表明，ADF + 运动使丙氨酸氨基转移酶（ALT，一种肝损害的间接标志物） 脂肪变性），与单独ADF或单独运动相比，12周后。胰岛素抵抗的下降幅度更大， HbA 1c、LDL胆固醇和HDL胆固醇更明显的增加，在 组合组与单独干预。我们的试点试验数据也表明， 胰岛素抵抗可能部分由肝细胞衍生激素（肝细胞因子）的变化介导， 发生在肝脏脂肪减少。尽管这些试点发现非常有希望，但这些数据仍然需要 通过一项有效的长期（24周）临床试验证实。假设：本提案将测试 以下假设：（1）组合组（ADF加运动）将经历更大的减少， 与ADF或运动相比，肝脂肪变性（通过磁共振波谱法测量; MRS） （2）联合组将经历肝细胞因子谱（胎球蛋白-A，胎球蛋白B， FGF-21、RBP 4、硒蛋白P、SHBG、adropin）;（3） 联合治疗组的肝脏胰岛素敏感性、胰岛素抵抗和 HbA 1c和其他代谢疾病风险变量（空腹血糖、空腹胰岛素、甘油三酯、LDL 胆固醇、LDL颗粒大小、血压、炎症参数）与ADF或运动相比 一个人方法：为了检验这些目标，将进行一项为期24周的随机、对照、平行臂喂养试验， 切实贯彻患有NAFLD的肥胖前驱糖尿病个体（n = 180）将被随机分配至4组之一： (1)ADF（禁食日：25%能量摄入，进食日：随意进食，不运动），（2）运动（随意进食， 训练5天/周监督），（3）组合（ADF加运动），和（4）对照（自由进食，不 锻炼）。意义：如果本申请的目的得以实现，这项研究将首次表明， 隔日禁食加有氧运动的组合是一种有效的非药物治疗， 减少肝脏脂肪变性，改善肝脏胰岛素敏感性，防止前驱糖尿病进展为2型糖尿病 NAFLD患者的2型糖尿病。

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.