Alternate day fasting combined with exercise for the treatment of NAFLD

隔日禁食联合运动治疗 NAFLD

• 批准号: 10208879
• 负责人: Krista Amy Varady
• 金额: $ 35.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208879
• 关键词: Aerobic Exercise; Alanine Transaminase; Animals; Blood Pressure; Caloric Restriction; Clinical Trials; Consumption; Data; Development; Diabetes Mellitus; Diet therapy; Energy Intake; Exercise; Fasting; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Food; Glycosylated hemoglobin A; Heavy Drinking; Hepatic; Hepatocyte; High Density Lipoprotein Cholesterol; Hormones; Individual; Inflammatory; Insulin; Insulin Resistance; Intake; Interleukin-6; Intermittent fasting; Intervention; LDL Cholesterol Lipoproteins; Life Style; Lifestyle Therapy; Light; Lipids; Liver; Low-Density Lipoproteins; Magnetic Resonance Spectroscopy; Measures; Mediating; Metabolic; Metabolic Diseases; Methods; Mus; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Nonpharmacologic Therapy; OGTT; Obesity; Particle Size; Patients; Pharmacology; Pilot Projects; Plasma; Prediabetes syndrome; RBP4 gene; Randomized; Research; SHBG gene; Safety; Supervision; TNF gene; Testing; Thiazolidinediones; Training; Triglycerides; Weight Gain; adult obesity; alpha-Fetoproteins; arm; disorder risk; experience; fasting glucose; feeding; fibroblast growth factor 21; food consumption; human data; human subject; improved; indexing; innovation; insulin sensitivity; intrahepatic; non-alcoholic fatty liver disease; obese person; pilot trial; prevent; selenoprotein

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.

项目概要/摘要 背景：大约 65% 的肥胖者患有非酒精性脂肪肝 (NAFLD)，这 病情与胰岛素抵抗和糖尿病的发展密切相关。创新生活方式 迫切需要治疗 NAFLD 的策略。隔日禁食 (ADF) 在动物身上已被证明可以 减少肝脏脂肪变性并提高肝脏胰岛素敏感性，但这些发现尚未得到证实 人类受试者。 ADF 包括一个“节日”，允许个人随意食用食物， 与“禁食日”交替，个人消耗平时摄入量的 25%（约 500 kcal）。我们最近 进行了一项试点研究，以评估 ADF 结合运动与单独 ADF 或运动的效果， 糖尿病前期 NAFLD 患者肝脏参数的影响。我们的结果表明，ADF 加上 运动使丙氨酸氨基转移酶（ALT；肝脏疾病的间接标志物）降低更多。 12 周后，与单独 ADF 或单独锻炼相比。胰岛素抵抗更大程度降低， 在以下人群中观察到 HbA1c、LDL 胆固醇和 HDL 胆固醇更明显的增加 联合组与个体干预的比较。我们的试点试验数据还表明，这些下降 胰岛素抵抗可能部分是由肝细胞源性激素（肝因子）的变化介导的。 伴随肝脏脂肪减少而发生。尽管这些试点结果非常有希望，但这些数据仍然需要 通过强有力的长期（24 周）临床试验确认。假设：本提案将测试 以下假设： (1) 联合组（ADF 加运动）将经历更大程度的减少 与 ADF 或运动相比，肝脂肪变性（通过磁共振波谱法测量；MRS） 独自的; (2) 联合治疗组的肝因子谱（胎球蛋白-A、胎球蛋白 B、 FGF-21、RBP4、硒蛋白 P、SHBG、adropin）与 ADF 或单独运动相比； (3) 的 联合治疗组将在肝脏胰岛素敏感性、胰岛素抵抗和 HbA1c 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 与 ADF 或运动相比（胆固醇、LDL 粒径、血压、炎症参数） 独自的。方法：为了测试这些目标，将进行为期 24 周的随机、对照、平行臂喂养试验 实施的。患有 NAFLD 的肥胖糖尿病前期个体 (n = 180) 将被随机分为 4 组中的一组： （1）ADF（禁食日：25%能量摄入，喂食日：随意喂食，不运动），（2）运动（随意喂食， 训练 5 天/周，有监督），(3) 组合（ADF 加运动），以及 (4) 对照（随意进食，无 锻炼）。意义：如果本申请的目的得以实现，本研究将首次表明 隔日禁食加有氧运动的结合是一种有效的非药物疗法 减少肝脏脂肪变性，提高肝脏胰岛素敏感性，预防糖尿病前期进展为Ⅰ型 2 NAFLD 患者患有糖尿病。