Effect of alternate day fasting combined with aerobic exercise on non-alcoholic fatty liver disease: A randomized controlled trial
隔日禁食联合有氧运动对非酒精性脂肪肝病的影响： 一项随机对照试验
Graphical abstract 图形摘要
Keywords 关键字
Introduction 介绍
The prevalence of non-alcoholic fatty liver disease (NAFLD) has reached epidemic proportions worldwide.1 NAFLD is characterized by an accumulation of fat in the liver not resulting from excessive alcohol consumption. Approximately 65% of adults with obesity have NAFLD,2 and this condition is strongly related to the development of insulin resistance and type 2 diabetes.3,4 While certain pharmacological agents have been shown to reduce hepatic steatosis, i.e., thiazolidinediones, there is mounting concern regarding the safety and weight-gaining effects of these compounds.5,6 In light of this, recent research has focused on non-pharmacological interventions to reduce hepatic steatosis.
非酒精性脂肪性肝病 （NAFLD） 的患病率已达到全球流行病的程度。 1 NAFLD 的特征是脂肪在肝脏中堆积，而不是由过量饮酒引起的。大约 65% 的肥胖成人患有 NAFLD， 2 这种情况与胰岛素抵抗和 2 型糖尿病的发展密切相关。 3 4 虽然某些药物已被证明可以减少肝脂肪变性，即噻唑烷二酮类，但人们对这些化合物的安全性和增重作用越来越担忧。 5 6 有鉴于此，最近的研究集中在减少肝脂肪变性的非药物干预上。
非酒精性脂肪性肝病 （NAFLD） 的患病率已达到全球流行病的程度。 1 NAFLD 的特征是脂肪在肝脏中堆积，而不是由过量饮酒引起的。大约 65% 的肥胖成人患有 NAFLD， 2 这种情况与胰岛素抵抗和 2 型糖尿病的发展密切相关。 3 4 虽然某些药物已被证明可以减少肝脂肪变性，即噻唑烷二酮类，但人们对这些化合物的安全性和增重作用越来越担忧。 5 6 有鉴于此，最近的研究集中在减少肝脂肪变性的非药物干预上。
Physical activity is a powerful lifestyle therapy that can improve several parameters of NAFLD.7 Data from a recent systematic review of 24 exercise-only trials in patients with NAFLD show that structured exercise (moderate to vigorous intensity, 3–5 days per week) produces a 20%–30% relative reduction in hepatic steatosis.8 Physical activity also decreases pro-inflammatory and oxidative stress markers, which in turn, improves liver enzyme profile.9 In addition, exercise enhances hepatic and peripheral insulin sensitivity,10 which can slow NAFLD progression and reduce cardiovascular disease risk. Physical activity can also improve quality of life, mood, and mental health in individuals with obesity and NAFLD.11 Although exercise alone has several benefits, current NAFLD treatment guidelines12,13 suggest that physical activity combined with a weight-reducing diet is the most effective non-pharmacological therapy to treat this condition.
体育锻炼是一种强大的生活方式疗法，可以改善 NAFLD 的几个参数。 7 最近对 NAFLD 患者 24 项仅运动试验的系统评价数据表明，结构化运动（中等强度至剧烈强度，每周 3-5 天）可相对减少 20%-30% 的肝脂肪变性。 8 体育锻炼还可以减少促炎和氧化应激标志物，从而改善肝酶谱。 9 此外，运动可增强肝脏和外周胰岛素敏感性， 10 从而减缓 NAFLD 进展并降低心血管疾病风险。体育活动还可以改善肥胖和 NAFLD 患者的生活质量、情绪和心理健康。 11 尽管单独运动有几个好处，但目前的 NAFLD 治疗指南 12 13 表明，体育锻炼与减肥饮食相结合是治疗这种情况最有效的非药物治疗。
体育锻炼是一种强大的生活方式疗法，可以改善 NAFLD 的几个参数。 7 最近对 NAFLD 患者 24 项仅运动试验的系统评价数据表明，结构化运动（中等强度至剧烈强度，每周 3-5 天）可相对减少 20%-30% 的肝脂肪变性。 8 体育锻炼还可以减少促炎和氧化应激标志物，从而改善肝酶谱。 9 此外，运动可增强肝脏和外周胰岛素敏感性， 10 从而减缓 NAFLD 进展并降低心血管疾病风险。体育活动还可以改善肥胖和 NAFLD 患者的生活质量、情绪和心理健康。 11 尽管单独运动有几个好处，但目前的 NAFLD 治疗指南 12 13 表明，体育锻炼与减肥饮食相结合是治疗这种情况最有效的非药物治疗。
Recently, it has been shown that alternate day fasting (ADF) may be an effective dietary weight loss therapy for patients with NAFLD.14,15 ADF has greatly increased in popularity over the past decade and is currently one of the most researched diets on the internet.16 This diet involves a fast day, where individuals consume approximately 600 kcal (2,500 kJ), alternated with a feast day where individuals are permitted to consume food ad libitum.17 Evidence from two randomized controlled trials show that ADF is effective for reducing liver steatosis score, circulating levels of alanine transaminase (ALT), and body weight in patients with NAFLD.14,15 While these studies show promise for the use of ADF in treating this condition, they are limited in that changes in intrahepatic triglyceride (IHTG) content were not quantified. Moreover, these studies did not include an exercise intervention in their design. Thus, they were not able to assess whether exercise combined with ADF would yield superior improvements in NAFLD activity markers, versus diet or exercise alone.
最近，研究表明隔日禁食 （ADF） 可能是 NAFLD 患者的一种有效的饮食减肥疗法。 14 15 ADF 在过去十年中越来越受欢迎，目前是互联网上研究最多的饮食法之一。 16 这种饮食包括禁食日，个人消耗大约 600 大卡（2,500 千焦），与允许个人随意进食的节日交替。 17 来自两项随机对照试验的证据表明，ADF 可有效降低 NAFLD 患者的肝脂肪变性评分、丙氨酸转氨酶 （ALT） 的循环水平和体重。 14 15 虽然这些研究表明使用 ADF 治疗这种情况的前景，但它们的局限性在于肝内甘油三酯 （IHTG） 含量的变化没有被量化。此外，这些研究的设计中没有包括运动干预。因此，他们无法评估与单独饮食或运动相比，运动联合 ADF 是否会产生 NAFLD 活动标志物的更好改善。
最近，研究表明隔日禁食 （ADF） 可能是 NAFLD 患者的一种有效的饮食减肥疗法。 14 15 ADF 在过去十年中越来越受欢迎，目前是互联网上研究最多的饮食法之一。 16 这种饮食包括禁食日，个人消耗大约 600 大卡（2,500 千焦），与允许个人随意进食的节日交替。 17 来自两项随机对照试验的证据表明，ADF 可有效降低 NAFLD 患者的肝脂肪变性评分、丙氨酸转氨酶 （ALT） 的循环水平和体重。 14 15 虽然这些研究表明使用 ADF 治疗这种情况的前景，但它们的局限性在于肝内甘油三酯 （IHTG） 含量的变化没有被量化。此外，这些研究的设计中没有包括运动干预。因此，他们无法评估与单独饮食或运动相比，运动联合 ADF 是否会产生 NAFLD 活动标志物的更好改善。
Accordingly, this study aimed to compare the effects of ADF combined with aerobic exercise, with ADF alone, or exercise alone, on IHTG content and metabolic risk factors in patients with NAFLD. We hypothesized that the combination intervention would produce superior reductions in IHTG content when compared with each intervention alone and compared with control.
因此，本研究旨在比较 ADF 联合有氧运动、单独 ADF 或单独运动对 NAFLD 患者 IHTG 含量和代谢危险因素的影响。我们假设，与单独使用每种干预和对照相比，联合干预将产生更好的 IHTG 含量降低。
因此，本研究旨在比较 ADF 联合有氧运动、单独 ADF 或单独运动对 NAFLD 患者 IHTG 含量和代谢危险因素的影响。我们假设，与单独使用每种干预和对照相比，联合干预将产生更好的 IHTG 含量降低。
Results 结果
We conducted a 3-month randomized parallel-arm trial to compare the effects of ADF combined with aerobic exercise, with ADF alone, exercise alone, and a control group on IHTG content in adults with obesity and NAFLD. Participants were randomized by a stratified random sample (based on age, sex, body mass index [BMI], and IHTG content) into 1 of 4 groups: combination, ADF, exercise, or a no-intervention control group. Participants randomized to the combination group and ADF group were instructed to consume 600 kcal (2,500 kJ) as a dinner (between 5:00 and 8:00 p.m.) on fast days and eat food as desired on alternating feast days. Subjects randomized to the combination group and exercise group participated in a moderate-intensity aerobic exercise program 5 times per week for 3 months. Control participants were instructed to maintain their body weight throughout the trial and not to change their eating or physical activity habits. Controls did not receive any dietary advice, but they visited the research center at the same frequency as the intervention groups for clinical measurements. The primary outcome measure was change in IHTG content from baseline to month 3 (measured by magnetic resonance imaging proton density fat fraction [MRI-PDFF]). Secondary outcome measures were body weight, body composition, liver enzymes, glucoregulatory factors, blood pressure (BP), plasma lipids, hepatokines, adherence, dietary intake, and habitual activity.
我们进行了一项为期 3 个月的随机平行组试验，以比较 ADF 联合有氧运动、单独 ADF、单独运动和对照组对肥胖和 NAFLD 成人 IHTG 含量的影响。参与者通过分层随机样本 （基于年龄、性别、体重指数 [BMI] 和 IHTG 含量）随机分为 4 组中的 1 组：组合组、ADF组、运动组或无干预对照组。随机分配到组合组和 ADF 组的参与者被指示在斋戒日（下午 5：00 至 8：00 之间）作为晚餐消耗 600 kcal （2,500 kJ），并在交替的节日里根据需要吃食物。随机分配到联合组和运动组的受试者每周参加 5 次中等强度的有氧运动计划，持续 3 个月。对照组参与者被指示在整个试验过程中保持体重，不要改变他们的饮食或身体活动习惯。对照组没有收到任何饮食建议，但他们以与干预组相同的频率访问研究中心进行临床测量。主要结局指标是 IHTG 含量从基线到第 3 个月的变化（通过磁共振成像质子密度脂肪分数 [MRI-PDFF] 测量）。次要结局指标是体重、身体成分、肝酶、葡萄糖调节因子、血压 （BP）、血脂、肝因子、依从性、饮食摄入和习惯性活动。
我们进行了一项为期 3 个月的随机平行组试验，以比较 ADF 联合有氧运动、单独 ADF、单独运动和对照组对肥胖和 NAFLD 成人 IHTG 含量的影响。参与者通过分层随机样本 （基于年龄、性别、体重指数 [BMI] 和 IHTG 含量）随机分为 4 组中的 1 组：组合组、ADF组、运动组或无干预对照组。随机分配到组合组和 ADF 组的参与者被指示在斋戒日（下午 5：00 至 8：00 之间）作为晚餐消耗 600 kcal （2,500 kJ），并在交替的节日里根据需要吃食物。随机分配到联合组和运动组的受试者每周参加 5 次中等强度的有氧运动计划，持续 3 个月。对照组参与者被指示在整个试验过程中保持体重，不要改变他们的饮食或身体活动习惯。对照组没有收到任何饮食建议，但他们以与干预组相同的频率访问研究中心进行临床测量。主要结局指标是 IHTG 含量从基线到第 3 个月的变化（通过磁共振成像质子密度脂肪分数 [MRI-PDFF] 测量）。次要结局指标是体重、身体成分、肝酶、葡萄糖调节因子、血压 （BP）、血脂、肝因子、依从性、饮食摄入和习惯性活动。
Participants 参与者
As shown in Figure 1, 132 individuals expressed interest in the study. Of these participants, 52 were excluded as they did not meet one or more inclusion criteria. Inclusion and exclusion criteria are listed in the STAR Methods section. A total of 80 participants were randomized to the combination group (n = 20), ADF group (n = 20), exercise group (n = 20), or the control group (n = 20). At the conclusion of the 3-month trial, there were 20 completers in the combination group, 19 completers in the ADF group, 15 completers in the exercise group, and 20 completers in the control group. On average, 93% of participants randomized to the interventions completed the trial. Participants withdrew from the study due to schedule conflicts, inability to contact, personal reasons, or a car accident. Notably, no one dropped out of the study due to a dislike of the ADF diet or the exercise intervention. Table 1 displays the baseline characteristics of the completers, dropouts, and a pooled analysis of all participants. At baseline, there were no significant differences between groups for the primary outcome measure (IHTG content) or any secondary outcome measure. Participants were primarily middle aged, Hispanic and Black females with obesity and NAFLD.
如图 1 所示 ，132 人表示对这项研究感兴趣。在这些参与者中，有 52 名被排除在外，因为他们不符合一项或多项纳入标准。纳入和排除标准列在 STAR 方法部分。共有 80 名参与者被随机分配到组合组 （n = 20）、ADF 组 （n = 20）、运动组 （n = 20） 或对照组 （n = 20）。在 3 个月的试验结束时，联合组有 20 名完成者，ADF 组有 19 名完成者，运动组有 15 名完成者，对照组有 20 名完成者。平均而言，随机分配到干预措施的参与者中有 93% 完成了试验。参与者因日程冲突、无法联系、个人原因或车祸而退出研究。值得注意的是，没有人因为不喜欢 ADF 饮食或运动干预而退出研究。表 1 显示了完成者、退出者的基线特征和所有参与者的汇总分析。在基线时，组间主要结局指标（IHTG 含量）或任何次要结局指标均无显著差异。参与者主要是患有肥胖和 NAFLD 的中年、西班牙裔和黑人女性。
如图 1 所示 ，132 人表示对这项研究感兴趣。在这些参与者中，有 52 名被排除在外，因为他们不符合一项或多项纳入标准。纳入和排除标准列在 STAR 方法部分。共有 80 名参与者被随机分配到组合组 （n = 20）、ADF 组 （n = 20）、运动组 （n = 20） 或对照组 （n = 20）。在 3 个月的试验结束时，联合组有 20 名完成者，ADF 组有 19 名完成者，运动组有 15 名完成者，对照组有 20 名完成者。平均而言，随机分配到干预措施的参与者中有 93% 完成了试验。参与者因日程冲突、无法联系、个人原因或车祸而退出研究。值得注意的是，没有人因为不喜欢 ADF 饮食或运动干预而退出研究。表 1 显示了完成者、退出者的基线特征和所有参与者的汇总分析。在基线时，组间主要结局指标（IHTG 含量）或任何次要结局指标均无显著差异。参与者主要是患有肥胖和 NAFLD 的中年、西班牙裔和黑人女性。
Figure 1 Subject flow chart
图 1主题流程图
图 1主题流程图
| Combination 组合 | Alternate day fasting 隔日禁食 | Exercise 锻炼 | Control 控制 | All participants 所有参与者 | Completers 完成者 | Dropouts 辍学 | |
|---|---|---|---|---|---|---|---|
| n | 20 | 20 | 20 | 20 | 80 | 74 | 6 |
| Age (years) 年龄 （岁） | 44 ± 13 | 44 ± 16 | 44 ± 13 | 44 ± 12 | 44 ± 13 | 44 ± 13 | 39 ± 15 |
| Sex 性 | |||||||
| Female 女性 | 17 (85%) | 16 (80%) | 16 (80%) | 16 (80%) | 65 (81%) | 61 (82%) | 4 (67%) |
| Male 雄 | 3 (15%) | 4 (20%) | 4 (20%) | 4 (20%) | 15 (19%) | 13 (18%) | 2 (33%) |
| Race or ethnic group 种族或民族 | |||||||
| Black 黑 | 7 (35%) | 7 (35%) | 6 (30%) | 4 (20%) | 24 (30%) | 23 (31%) | 1 (17%) |
| Hispanic 西班牙的 | 10 (50%) | 8 (40%) | 10 (50%) | 12 (60%) | 40 (50%) | 35 (47%) | 5 (83%) |
| White 白 | 2 (10%) | 2 (10%) | 4 (20%) | 1 (5%) | 9 (11%) | 9 (12%) | 0 (0%) |
| Asian 亚裔 | 1 (5%) | 3 (15%) | 0 (0%) | 3 (15%) | 7 (9%) | 7 (9%) | 0 (0%) |
| Liver parameters 肝脏参数 | |||||||
| IHTG (%) | 18 ± 8 | 16 ± 6 | 17 ± 6 | 17 ± 9 | 17 ± 8 | 17 ± 8 | 15 ± 6 |
| ALT (U/L) | 28 ± 15 | 31 ± 33 | 24 ± 18 | 22 ± 8 | 26 ± 20 | 26 ± 20 | 32 ± 32 |
| AST (U/L) | 23 ± 8 | 23 ± 15 | 21 ± 12 | 18 ± 5 | 21 ± 11 | 21 ± 10 | 25 ± 21 |
| Fibrosis (FIB-4) | 0.91 ± 0.36 | 0.93 ± 0.57 | 0.86 ± 0.35 | 0.76 ± 0.22 | 0.87 ± 0.39 | 0.87 ± 0.40 | 0.78 ± 0.32 |
| Body composition 身体成分 | |||||||
| Body weight (kg) | 101 ± 20 | 96 ± 21 | 100 ± 21 | 100 ± 17 | 99 ± 19 | 98 ± 19 | 111 ± 26 |
| Fat mass (kg) 脂肪量 （kg） | 46 ± 12 | 40 ± 8 | 45 ± 13 | 45 ± 11 | 44 ± 11 | 44 ± 11 | 49 ± 13 |
| Lean mass (kg) 瘦体重 （kg） | 51 ± 12 | 51 ± 9 | 52 ± 9 | 51 ± 10 | 51 ± 10 | 51 ± 10 | 57 ± 13 |
| Visceral fat mass (kg) 内脏脂肪量 （kg） | 1.6 ± 0.8 | 1.6 ± 0.8 | 1.7 ± 0.8 | 1.7 ± 0.8 | 1.6 ± 0.8 | 1.6 ± 0.8 | 1.7 ± 1.2 |
| Waist circumference (cm) 腰围 （cm） | 111 ± 13 | 107 ± 17 | 111 ± 14 | 109 ± 12 | 109 ± 14 | 109 ± 14 | 114 ± 18 |
| Height (cm) 高度 （cm） | 166 ± 9 | 164 ± 9 | 165 ± 8 | 165 ± 8 | 165 ± 8 | 165 ± 8 | 165 ± 10 |
| BMI (kg/m2) 体重指数 （kg/m2） | 37 ± 5 | 36 ± 8 | 37 ± 6 | 37 ± 5 | 36 ± 6 | 36 ± 6 | 41 ± 7 |
| Glucoregulatory factors 糖调节因素 | |||||||
| Fasting insulin (μIU/mL) 空腹胰岛素 （μIU/mL） | 31 ± 35 | 17 ± 10 | 26 ± 25 | 19 ± 15 | 23 ± 24 | 23 ± 25 | 21 ± 11 |
| Insulin resistance (HOMA-IR) 胰岛素抵抗 （HOMA-IR） | 7.1 ± 7.3 | 3.8 ± 2.3 | 5.8 ± 5.3 | 4.5 ± 3.8 | 5.3 ± 5.1 | 5.3 ± 5.2 | 5.0 ± 3.3 |
| Insulin sensitivity (QUICKI) 胰岛素敏感性 （QUICKI） | 0.29 ± 0.03 | 0.31 ± 0.03 | 0.30 ± 0.04 | 0.31 ± 0.03 | 0.30 ± 0.03 | 0.30 ± 0.03 | 0.31 ± 0.03 |
| Fasting glucose (mg/dL) 空腹血糖 （mg/dL） | 94 ± 12 | 90 ± 15 | 91 ± 14 | 98 ± 38 | 93 ± 22 | 93 ± 23 | 97 ± 14 |
| HbA1c (%) 糖化血红蛋白 （%） | 5.7 ± 0.5 | 5.8 ± 0.5 | 5.6 ± 1.0 | 5.9 ± 0.4 | 5.8 ± 0.9 | 5.7 ± 0.8 | 6.1 ± 1.7 |
| Blood pressure and heart rate 血压和心率 | |||||||
| Systolic BP (mm Hg) 收缩压 （mm Hg） | 127 ± 18 | 126 ± 16 | 130 ± 17 | 126 ± 22 | 127 ± 18 | 127 ± 18 | 131 ± 20 |
| Diastolic BP (mm Hg) 舒张压 （mm Hg） | 87 ± 9 | 87 ± 10 | 85 ± 10 | 84 ± 9 | 86 ± 9 | 86 ± 9 | 86 ± 9 |
| Heart rate (bpm) 心率 （bpm） | 75 ± 13 | 78 ± 18 | 74 ± 14 | 75 ± 8 | 76 ± 13 | 76 ± 13 | 74 ± 18 |
| Plasma lipids 血脂 | |||||||
| Total cholesterol (mg/dL) 总胆固醇 （mg/dL） | 192 ± 29 | 175 ± 34 | 168 ± 47 | 186 ± 37 | 180 ± 38 | 182 ± 37 | 159 ± 45 |
| LDL cholesterol (mg/dL) 低密度脂蛋白胆固醇 （mg/dL） | 116 ± 24 | 97 ± 29 | 87 ± 40 | 108 ± 35 | 102 ± 34 | 103 ± 33 | 90 ± 43 |
| HDL cholesterol (mg/dL) HDL 胆固醇 （mg/dL） | 53 ± 13 | 50 ± 13 | 55 ± 18 | 51 ± 13 | 52 ± 14 | 53 ± 15 | 45 ± 7 |
| Triglycerides (mg/dL) 甘油三酯 （mg/dL） | 116 ± 37 | 141 ± 72 | 129 ± 63 | 109 ± 40 | 124 ± 55 | 124 ± 56 | 117 ± 41 |
| Hepatokines 肝因子 | |||||||
| Fetuin-A (ng/mL) 胎球蛋白-A （ng/mL） | 285 ± 602 | 310 ± 323 | 279 ± 362 | 370 ± 624 | 309 ± 480 | 316 ± 499 | 233 ± 93 |
| FGF-21 (ng/mL) FGF-21 （纳克/毫升） | 0.55 ± 0.74 | 0.82 ± 1.23 | 1.36 ± 1.59 | 0.58 ± 1.04 | 0.83 ± 1.21 | 0.83 ± 1.17 | 0.88 ± 1.79 |
| Selenoprotein P (ng/mL) 硒蛋白 P （ng/mL） | 1,175 ± 129 | 1,168 ± 124 | 1,203 ± 123 | 1,191 ± 384 | 1,184 ± 211 | 1,184 ± 219 | 1,177 ± 44 |
Table 1 表 1
Baseline characteristics 基线特征
Data are expressed as mean (SD) unless otherwise indicated. Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; BP, blood pressure; FGF-21, fibroblast growth factor-21, FIB-4, fibrosis-4, IHTG, intrahepatic triglyceride content; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; HOMA, homeostasis model assessment of insulin resistance; LDL, low-density lipoprotein; QUICKI, quantitative insulin sensitivity check index.
除非另有说明，否则数据以平均值 （SD） 表示。缩写：ALT，丙氨酸转氨酶;AST，天冬氨酸转氨酶;BP，血压;FGF-21、成纤维细胞生长因子 21、FIB-4、纤维化 4、IHTG、肝内甘油三酯含量;HbA1c，糖化血红蛋白;HDL，高密度脂蛋白;HOMA，胰岛素抵抗的稳态模型评估;LDL，低密度脂蛋白;QUICKI，定量胰岛素敏感性检查指数。
除非另有说明，否则数据以平均值 （SD） 表示。缩写：ALT，丙氨酸转氨酶;AST，天冬氨酸转氨酶;BP，血压;FGF-21、成纤维细胞生长因子 21、FIB-4、纤维化 4、IHTG、肝内甘油三酯含量;HbA1c，糖化血红蛋白;HDL，高密度脂蛋白;HOMA，胰岛素抵抗的稳态模型评估;LDL，低密度脂蛋白;QUICKI，定量胰岛素敏感性检查指数。
The combination intervention produces superior reductions in IHTG content versus exercise alone, but not fasting alone
与单独运动相比，联合干预可以更好地降低 IHTG 含量，但不能单独禁食
By month 3, IHTG content (expressed as absolute percent change) was significantly reduced in the combination group (−5.48%; 95% CI, −7.77% to −3.18%), compared with the exercise group (−1.30%; 95% CI, −3.80% to 1.20%; p = 0.02) and the control group (−0.17%; 95% CI, −2.17% to 1.83%; p < 0.01) (Figure 2A; Table 2). However, the reduction in IHTG content in the combination group was not significantly different compared with the ADF group (−2.25%; 95% CI, −4.46% to −0.04%; p = 0.05). Change in serum ALT by month 3 in the combination group (−5.97 U/L; 95% CI, −10.66 to −1.28 U/L) was significantly different compared with the control group (0.65 U/L; 95% CI, −1.90 to 3.20 U/L; p = 0.01), but not significantly different compared with the ADF group (−11.24 U/L; 95% CI, −26.12 to 3.64 U/L; p = 0.48) or exercise group (−0.70 U/L; 95% CI, −5.03 to 3.64 U/L; p = 0.09) (Figure 2B; Table 2). Change in serum aspartate transaminase (AST) by month 3 did not significantly differ among the four groups (Figure 2B; Table 2). Changes in hepatic fibrosis score (estimated using the fibrosis-4 [FIB-4] index) did not significantly differ between groups by month 3 (Table 2).
到第 3 个月，与运动组（-1.30%;95% CI，-3.80% 至 1.20%;p = 0.02）和对照组（-0.17%;95% CI，-2.17% 至 1.83%;p < 0.01）相比，组合组（-5.48%;95% CI，-7.77% 至 -3.18%）的 IHTG 含量（表示为绝对百分比变化）显著降低（图 2A;表 2）。然而，与 ADF 组相比，联合组 IHTG 含量的降低没有显著差异 （-2.25%;95% CI，-4.46% 至 -0.04%;p = 0.05）。联合组（-5.97 U/L;95% CI，-10.66 至 -1.28 U/L）与对照组（0.65 U/L;95% CI，-1.90 至 3.20 U/L;p = 0.01）相比，第 3 个月血清 ALT 的变化有显著差异，但与 ADF 组（-11.24 U/L;95% CI，-26.12 至 3.64 U/L;p = 0.48）或运动组（-0.70 U/L;95% CI、 −5.03 至 3.64 U/L;p = 0.09）（图 2B;表 2）。到 3 个月时血清天冬氨酸转氨酶 （AST） 的变化在四组之间没有显着差异（图 2B;表 2）。到第 3 个月，肝纤维化评分的变化 （使用纤维化-4 [FIB-4] 指数估计）在各组之间没有显著差异（表 2）。
到第 3 个月，与运动组（-1.30%;95% CI，-3.80% 至 1.20%;p = 0.02）和对照组（-0.17%;95% CI，-2.17% 至 1.83%;p < 0.01）相比，组合组（-5.48%;95% CI，-7.77% 至 -3.18%）的 IHTG 含量（表示为绝对百分比变化）显著降低（图 2A;表 2）。然而，与 ADF 组相比，联合组 IHTG 含量的降低没有显著差异 （-2.25%;95% CI，-4.46% 至 -0.04%;p = 0.05）。联合组（-5.97 U/L;95% CI，-10.66 至 -1.28 U/L）与对照组（0.65 U/L;95% CI，-1.90 至 3.20 U/L;p = 0.01）相比，第 3 个月血清 ALT 的变化有显著差异，但与 ADF 组（-11.24 U/L;95% CI，-26.12 至 3.64 U/L;p = 0.48）或运动组（-0.70 U/L;95% CI、 −5.03 至 3.64 U/L;p = 0.09）（图 2B;表 2）。到 3 个月时血清天冬氨酸转氨酶 （AST） 的变化在四组之间没有显着差异（图 2B;表 2）。到第 3 个月，肝纤维化评分的变化 （使用纤维化-4 [FIB-4] 指数估计）在各组之间没有显著差异（表 2）。
Figure 2 Intrahepatic triglyceride content, liver enzymes, and body weight
图 2肝内甘油三酯含量、肝酶和体重
图 2肝内甘油三酯含量、肝酶和体重
| Outcomes 结果 | Change by month 3 (95% CI) 第 3 个月的变化 （95% CI） | p values p 值 | |||||
|---|---|---|---|---|---|---|---|
| Combination 组合 | Alternate day fasting 隔日禁食 | Exercise 锻炼 | Control 控制 | Combination versus ADF 联合治疗与 ADF 治疗 | Combination versus exercise 联合用药 vs 运动 | Combination versus control 联合治疗 vs 对照 | |
| IHTG (%) | −5.48 (−7.77, −3.18) | −2.25 (−4.46, −0.04) | −1.30 (−3.80, 1.20) | −0.17 (−2.17, 1.83) | 0.05 | 0.02 | <0.01 |
| ALT (U/L) | −5.97 (−10.66, −1.28) | −11.24 (−26.12, 3.64) | −0.70 (−5.03, 3.64) | 0.65 (−1.90, 3.20) | 0.48 | 0.09 | 0.01 |
| AST (U/L) | −1.59 (−5.98, 2.79) | −5.39 (−9.8, −0.98) | 0.34 (−4.71, 5.39) | −0.33 (−4.51, 3.85) | 0.23 | 0.56 | 0.68 |
| Fibrosis (FIB-4) | 0.16 (−0.22, 0.55) | −0.08 (−0.31, 0.15) | 0.06 (−0.02, 0.13) | −0.01 (−0.06, 0.05) | 0.26 | 0.58 | 0.36 |
| Body weight (%) 体重 （%） | −4.58 (−5.62, −3.55) −4.58 （−5.62， −3.55） | −5.06 (−6.81, −3.32) −5.06（−6.81、−3.32） | −2.11 (−3.41, −0.80) −2.11 （−3.41， −0.80） | −0.60 (−2.04, 0.83) −0.60 （−2.04， 0.83） | 0.62 | <0.01 | <0.01 |
| Body weight (kg) 体重 （kg） | −4.18 (−4.65, −3.71) −4.18（−4.65、−3.71） | −4.45 (−4.93, −3.97) −4.45 （−4.93， −3.97） | −1.79 (−2.33, −1.26) −1.79 （−2.33， −1.26） | −0.52 (−1.00, −0.05) −0.52 （−1.00， −0.05） | 0.43 | <0.01 | <0.01 |
| Fat mass (kg) 脂肪量 （kg） | −3.24 (−4.31, −2.16) −3.24（−4.31、−2.16） | −3.32 (−4.39, −2.24) −3.32（−4.39、−2.24） | −1.34 (−2.52, −0.16) −1.34（−2.52、−0.16） | −0.62 (−1.69, 0.46) −0.62 （−1.69， 0.46） | 0.92 | 0.02 | <0.01 |
| Lean mass (kg) 瘦体重 （kg） | −0.83 (−1.57, −0.09) −0.83 （−1.57， −0.09） | −1.20 (−1.95, −0.46) −1.20 （−1.95， −0.46） | −0.90 (−1.71, −0.08) −0.90 （−1.71， −0.08） | 0.05 (−0.69, 0.79) 0.05 （-0.69， 0.79） | 0.48 | 0.91 | 0.10 |
| Visceral fat mass (kg) 内脏脂肪量 （kg） | −0.20 (−0.33, −0.07) −0.20 （−0.33， −0.07） | −0.21 (−0.34, −0.09) −0.21 （−0.34， −0.09） | −0.08 (−0.23, 0.06) −0.08 （−0.23， 0.06） | −0.02 (−0.15, 0.10) −0.02 （−0.15， 0.10） | 0.86 | 0.25 | 0.06 |
| Waist circumference (cm) 腰围 （cm） | −5.02 (−6.85, −3.19) −5.02（−6.85、−3.19） | −4.59 (−6.37, −2.80) −4.59（−6.37、−2.80） | −3.24 (−5.25, −1.24) −3.24 （−5.25， −1.24） | −0.52 (−2.30, 1.26) −0.52 （−2.30， 1.26） | 0.73 | 0.20 | <0.01 |
| BMI (kg/m2) 体重指数 （kg/m2） | −1.63 (−2.35, −0.92) −1.63 （−2.35， −0.92） | −1.88 (−2.62, −1.15) −1.88（−2.62、−1.15） | −0.86 (−1.69, −0.04) −0.86 （−1.69， −0.04） | −0.67 (−1.39, 0.04) −0.67 （−1.39， 0.04） | 0.63 | 0.16 | 0.06 |
| Fasting insulin (μIU/mL) 空腹胰岛素 （μIU/mL） | −9.59 (−15.16, −4.02) −9.59（−15.16、−4.02） | −7.41 (−13.58, −1.24) −7.41 （−13.58， −1.24） | −3.93 (−8.87, 1.01) −3.93 （−8.87， 1.01） | 1.22 (−2.48, 4.92) 1.22（−2.48、4.92） | 0.58 | 0.11 | <0.01 |
| Insulin resistance (HOMA-IR) 胰岛素抵抗 （HOMA-IR） | −2.55 (−4.03, −1.08) −2.55 （−4.03， −1.08） | −1.80 (−3.07, −0.54) −1.80（−3.07、−0.54） | −1.25 (−2.76, 0.27) −1.25 （−2.76， 0.27） | 0.49 (−0.83, 1.80) 0.49 （−0.83， 1.80） | 0.41 | 0.19 | <0.01 |
| Insulin sensitivity (QUICKI) 胰岛素敏感性 （QUICKI） | 0.04 (0.02, 0.05) | 0.02 (0.00, 0.03) | 0.02 (0.00, 0.03) | 0.00 (−0.02, 0.01) 0.00 （−0.02， 0.01） | 0.05 | 0.07 | <0.01 |
| Fasting glucose (mg/dL) 空腹血糖 （mg/dL） | −5.28 (−11.76, 1.21) −5.28 （−11.76， 1.21） | −5.14 (−11.64, 1.35) −5.14 （−11.64， 1.35） | −2.12 (−9.75, 5.50) −2.12 （−9.75， 5.50） | 0.62 (−5.67, 6.90) 0.62（−5.67、6.90） | 0.98 | 0.53 | 0.20 |
| HbA1c (%) 糖化血红蛋白 （%） | −0.08 (−0.20, 0.05) −0.08 （−0.20， 0.05） | −0.12 (−0.24, 0.01) −0.12 （−0.24， 0.01） | 0.02 (−0.13, 0.16) 0.02 （−0.13， 0.16） | 0.04 (−0.08, 0.16) 0.04 （−0.08， 0.16） | 0.66 | 0.33 | 0.17 |
| Systolic BP (mm Hg) 收缩压 （mm Hg） | −3.78 (−8.67, 1.12) −3.78 （−8.67， 1.12） | −3.85 (−8.86, 1.17) −3.85 （−8.86， 1.17） | −3.19 (−8.77, 2.39) −3.19 （−8.77， 2.39） | 1.95 (−2.95, 6.85) 1.95 （−2.95， 6.85） | 0.98 | 0.88 | 0.10 |
| Diastolic BP (mm Hg) 舒张压 （mm Hg） | −4.25 (−7.48, −1.02) −4.25 （−7.48， −1.02） | −1.82 (−5.13, 1.49) −1.82 （−5.13， 1.49） | −1.03 (−4.70, 2.63) −1.03 （−4.70， 2.63） | 0.10 (−3.13, 3.33) 0.10 （−3.13， 3.33） | 0.30 | 0.19 | 0.06 |
| Heart rate (bpm) 心率 （bpm） | −3.78 (−8.2, 0.65) −3.78（−8.2、0.65） | −0.87 (−5.38, 3.65) −0.87 （−5.38， 3.65） | 1.16 (−3.84, 6.17) 1.16 （−3.84， 6.17） | 0.25 (−4.17, 4.67) 0.25（−4.17、4.67） | 0.36 | 0.14 | 0.20 |
| Total cholesterol (mg/dL) 总胆固醇 （mg/dL） | −6.32 (−15.72, 3.07) −6.32 （−15.72， 3.07） | −2.24 (−11.65, 7.17) −2.24 （−11.65， 7.17） | 0.01 (−11.61, 11.64) 0.01 （−11.61， 11.64） | −7.81 (−16.63, 1.00) −7.81 （−16.63， 1.00） | 0.54 | 0.40 | 0.82 |
| LDL cholesterol (mg/dL) 低密度脂蛋白胆固醇 （mg/dL） | −3.88 (−12.33, 4.57) −3.88 （−12.33， 4.57） | 2.54 (−5.92, 11.00) 2.54 （-5.92， 11.00） | 8.89 (−1.57, 19.35) 8.89 （-1.57， 19.35） | −2.52 (−10.45, 5.41) −2.52 （−10.45， 5.41） | 0.29 | 0.06 | 0.82 |
| HDL cholesterol (mg/dL) HDL 胆固醇 （mg/dL） | 0.24 (−3.62, 4.10) 0.24 （−3.62， 4.10） | 3.74 (−0.12, 7.61) 3.74 （−0.12， 7.61） | −4.64 (−9.41, 0.13) −4.64 （−9.41， 0.13） | −1.54 (−5.16, 2.09) −1.54 （−5.16， 2.09） | 0.20 | 0.12 | 0.50 |
| Triglycerides (mg/dL) 甘油三酯 （mg/dL） | −13.28 (−36.53, 9.96) −13.28 （−36.53， 9.96） | −41.29 −63.75, −18.83) −41.29 −63.75， −18.83） | −18.75 (−46.92, 9.43) −18.75 （−46.92， 9.43） | 3.07 (−10.37, 16.51) 3.07 （-10.37， 16.51） | 0.07 | 0.74 | 0.20 |
Table 2 表 2
Liver parameters, body composition, and metabolic risk factors
肝脏参数、身体成分和代谢危险因素
肝脏参数、身体成分和代谢危险因素
Data were included for 80 participants; means were estimated using an intention-to-treat analysis using a linear mixed model. Error bars indicate 95% confidence intervals for each parameter from baseline by diet group. Abbreviations: ALT, Alanine transaminase; AST, aspartate transaminase; BP, blood pressure; FIB-4, Fibrosis-4, HDL, high-density lipoprotein; HOMA, homeostasis model assessment of insulin resistance; IHTG, Intrahepatic triglyceride content; LDL, low-density lipoprotein; and QUICKI, Quantitative insulin sensitivity check index.
纳入了 80 名参与者的数据;使用线性混合模型的意向治疗分析来估计平均值。误差线表示饮食组每个参数相对于基线的 95% 置信区间。缩写：ALT，丙氨酸转氨酶;AST，天冬氨酸转氨酶;BP，血压;FIB-4、纤维化-4、HDL、高密度脂蛋白;HOMA，胰岛素抵抗的稳态模型评估;IHTG，肝内甘油三酯含量;LDL，低密度脂蛋白;和 QUICKI，定量胰岛素敏感性检查指数。
纳入了 80 名参与者的数据;使用线性混合模型的意向治疗分析来估计平均值。误差线表示饮食组每个参数相对于基线的 95% 置信区间。缩写：ALT，丙氨酸转氨酶;AST，天冬氨酸转氨酶;BP，血压;FIB-4、纤维化-4、HDL、高密度脂蛋白;HOMA，胰岛素抵抗的稳态模型评估;IHTG，肝内甘油三酯含量;LDL，低密度脂蛋白;和 QUICKI，定量胰岛素敏感性检查指数。
The combination intervention produces superior reductions in body weight and fat mass versus exercise alone, but not fasting alone
与单独运动相比，联合干预可以更好地减轻体重和脂肪量，但不能单独禁食
During the 3-month intervention, weight loss was significantly greater in the combination group (−4.58%; 95% CI, −5.62% to −3.55%) compared with the exercise group (−2.11%; 95% CI, −3.41% to −0.80%; p < 0.01) and the control group (−0.60%; 95% CI, −2.04% to 0.83%; p < 0.01) (Figure 2C; Table 2). However, weight loss did not significantly differ in the combination group compared with the ADF group (−5.06%; 95% CI, −6.81% to −3.32%; p = 0.62). Likewise, fat mass loss was significantly greater in the combination group (−3.24 kg; 95% CI, −4.31 to −2.16 kg), compared with the exercise group (−1.34 kg; 95% CI, −2.52 to −0.16 kg; p = 0.02) and the control group (−0.62 kg; 95% CI, −1.69 to 0.46 kg; p < 0.01) but not the ADF group (−3.32 kg; 95% CI, −4.39 to −2.24 kg; p = 0.92) (Figure 3A; Table 2). Change in waist circumference by month 3 in the combination group (−5.02 cm; 95% CI, −6.85 to −3.19 cm) was significantly different compared with the control group (−0.52 cm; 95% CI, −2.30 to −1.26 cm; p < 0.01), but not significantly different compared with the ADF group (−4.59 cm; 95% CI, −6.37 to −2.80 cm; p = 0.73) or exercise group (−3.24 cm; 95% CI, −5.25 to −1.24 cm; p = 0.20) (Figure 3D; Table 2). Change in lean mass, visceral fat mass, and BMI did not significantly differ among the four groups (Figure 3; Table 2).
在为期 3 个月的干预期间，与运动组（-2.11%;95% CI，-3.41% 至 -0.80%;p < 0.01）和对照组（-0.60%;95% CI，-2.04% 至 0.83%;p < 0.01）相比，联合组（-4.58%;95% CI，-5.62% 至 -3.55%）的体重减轻显著更大（图 2C;表 2）。然而，与 ADF 组相比，联合组的体重减轻没有显著差异 （-5.06%;95% CI，-6.81% 至 -3.32%;p = 0.62）。同样，与运动组（-1.34 kg;95% CI，-2.52 至 -0.16 kg;p = 0.02）和对照组（-0.62 kg;95% CI，-1.69 至 0.46 kg;p < 0.01）相比，联合组（-3.24 kg;95% CI，-4.39 至 -2.24 kg;p = 0.92）的脂肪量损失显著更大，但 ADF 组（-3.32 kg;95% CI，-4.39 至 -2.24 kg;p = 0.92）（图 3一个;表 2）。联合组第 3 个月腰围的变化（-5.02 cm;95% CI，-6.85 至 -3.19 cm）与对照组（-0.52 cm;95% CI，-2.30 至 -1.26 cm;p < 0.01）相比差异显著，但与 ADF 组（-4.59 cm;95% CI，-6.37 至 -2.80 cm;p = 0.73）或运动组（-3.24 cm;95% CI、 -5.25 至 -1.24 厘米;p = 0.20）（图 3D;表 2）。四组之间的瘦体重、内脏脂肪量和 BMI 的变化没有显著差异（图 3;表 2）。
在为期 3 个月的干预期间，与运动组（-2.11%;95% CI，-3.41% 至 -0.80%;p < 0.01）和对照组（-0.60%;95% CI，-2.04% 至 0.83%;p < 0.01）相比，联合组（-4.58%;95% CI，-5.62% 至 -3.55%）的体重减轻显著更大（图 2C;表 2）。然而，与 ADF 组相比，联合组的体重减轻没有显著差异 （-5.06%;95% CI，-6.81% 至 -3.32%;p = 0.62）。同样，与运动组（-1.34 kg;95% CI，-2.52 至 -0.16 kg;p = 0.02）和对照组（-0.62 kg;95% CI，-1.69 至 0.46 kg;p < 0.01）相比，联合组（-3.24 kg;95% CI，-4.39 至 -2.24 kg;p = 0.92）的脂肪量损失显著更大，但 ADF 组（-3.32 kg;95% CI，-4.39 至 -2.24 kg;p = 0.92）（图 3一个;表 2）。联合组第 3 个月腰围的变化（-5.02 cm;95% CI，-6.85 至 -3.19 cm）与对照组（-0.52 cm;95% CI，-2.30 至 -1.26 cm;p < 0.01）相比差异显著，但与 ADF 组（-4.59 cm;95% CI，-6.37 至 -2.80 cm;p = 0.73）或运动组（-3.24 cm;95% CI、 -5.25 至 -1.24 厘米;p = 0.20）（图 3D;表 2）。四组之间的瘦体重、内脏脂肪量和 BMI 的变化没有显著差异（图 3;表 2）。
Figure 3 Body composition and glucoregulatory factors
图 3身体成分和血糖调节因素
图 3身体成分和血糖调节因素
The combination intervention improved insulin resistance and insulin sensitivity versus controls, but not versus exercise alone or fasting alone
与对照组相比，联合干预改善了胰岛素抵抗和胰岛素敏感性，但与单独运动或单独禁食相比没有改善
By month 3, fasting insulin was significantly reduced in the combination group (−9.59 μIU/mL; 95% CI, −15.16 to −4.02 μIU/mL) compared with the control group (1.22 μIU/mL; 95% CI, −2.48 to 4.92 μIU/mL; p < 0.01) but was not significantly different compared with the ADF group (−7.41 μIU/mL; 95% CI, −13.58 to −1.24 μIU/mL; p = 0.58) or the exercise group (−3.93 μIU/mL; 95% CI, −8.87 to 1.01 μIU/mL; p = 0.11) (Figure 3F; Table 2). Likewise, insulin resistance (absolute change in homeostasis model assessment of insulin resistance [HOMA-IR]) was significantly reduced in the combination group (−2.55; 95% CI, −4.03 to −1.08) compared with the control group (0.49; 95% CI, −0.83 to 1.80; p < 0.01) but was not significantly different compared with the ADF group (−1.80; 95% CI, −3.07 to −0.54; p = 0.41) or the exercise group (−1.25; 95% CI, −2.76 to 0.27; p = 0.19) (Figure 3G; Table 2). Insulin sensitivity (absolute change in quantitative insulin sensitivity check index [QUICKI]) was significantly increased in the combination group (0.04; 95% CI, 0.02 to 0.05) compared with the control group (0.00; 95% CI, −0.02 to 0.01; p < 0.01) but was not significantly different compared with the ADF group (0.02; 95% CI, 0.00 to 0.03; p = 0.05) or the exercise group (0.02; 95% CI, 0.00 to 0.03; p = 0.07) (Figure 3H; Table 2). Change in fasting glucose and glycated hemoglobin (HbA1c) did not significantly differ among the four groups by the end of the trial (Figure 3; Table 2).
到第 3 个月时，与对照组（1.22 μIU/mL;95% CI，-2.48 至 4.92 μIU/mL;p < 0.01）相比，联合治疗组（-9.59 μIU/mL;95% CI，-15.16 至 -4.02 μIU/mL）的空腹胰岛素显著降低，但与 ADF 组（-7.41 μIU/mL;95% CI，-13.58 至 -1.24 μIU/mL;p = 0.58）或运动组（-3.93 μIU/mL;95% CI，）相比没有显著差异 −8.87 至 1.01 μIU/mL;p = 0.11）（图 3F;表 2）。同样，与对照组（0.49;95% CI，-0.83 至 1.80;p < 0.01）相比，联合组（-2.55;95% CI，-4.03 至 -1.08）的胰岛素抵抗（胰岛素抵抗稳态模型评估的绝对变化 [HOMA-IR]）显著降低，但与 ADF 组（-1.80;95% CI，-3.07 至 -0.54;p = 0.41）或运动组（-1.25;95% CI， -2.76 到 0.27;p = 0.19）（图 3G;表 2）。与对照组（0.00;95% CI，-0.02 至 0.01;p < 0.01）相比，联合组（0.04;95% CI，0.02 至 0.05）的胰岛素敏感性（胰岛素定量敏感性检查指数 [QUICKI] 的绝对变化）显著增加，但与 ADF 组（0.02;95% CI，0.00 至 0.03;p = 0.05）或运动组（0.02;95% CI、 0.00 至 0.03;p = 0.07）（图 3H;表 2）。到试验结束时，四组空腹血糖和糖化血红蛋白 （HbA1c） 的变化没有显着差异（图 3;表 2）。
到第 3 个月时，与对照组（1.22 μIU/mL;95% CI，-2.48 至 4.92 μIU/mL;p < 0.01）相比，联合治疗组（-9.59 μIU/mL;95% CI，-15.16 至 -4.02 μIU/mL）的空腹胰岛素显著降低，但与 ADF 组（-7.41 μIU/mL;95% CI，-13.58 至 -1.24 μIU/mL;p = 0.58）或运动组（-3.93 μIU/mL;95% CI，）相比没有显著差异 −8.87 至 1.01 μIU/mL;p = 0.11）（图 3F;表 2）。同样，与对照组（0.49;95% CI，-0.83 至 1.80;p < 0.01）相比，联合组（-2.55;95% CI，-4.03 至 -1.08）的胰岛素抵抗（胰岛素抵抗稳态模型评估的绝对变化 [HOMA-IR]）显著降低，但与 ADF 组（-1.80;95% CI，-3.07 至 -0.54;p = 0.41）或运动组（-1.25;95% CI， -2.76 到 0.27;p = 0.19）（图 3G;表 2）。与对照组（0.00;95% CI，-0.02 至 0.01;p < 0.01）相比，联合组（0.04;95% CI，0.02 至 0.05）的胰岛素敏感性（胰岛素定量敏感性检查指数 [QUICKI] 的绝对变化）显著增加，但与 ADF 组（0.02;95% CI，0.00 至 0.03;p = 0.05）或运动组（0.02;95% CI、 0.00 至 0.03;p = 0.07）（图 3H;表 2）。到试验结束时，四组空腹血糖和糖化血红蛋白 （HbA1c） 的变化没有显着差异（图 3;表 2）。
The combination intervention does not affect BP, heart rate, LDL cholesterol, HDL cholesterol, or triglycerides
联合干预不会影响血压、心率、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇或甘油三酯
As shown in Table 2, changes in BP and heart rate did not significantly differ when the combination group was compared with the ADF group, exercise group, or control group. Likewise, change in total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride concentrations did not significantly differ among the four groups by the end of the study.
如表 2 所示，当将组合组与 ADF 组、运动组或对照组进行比较时，血压和心率的变化没有显着差异。同样，到研究结束时，四组的总胆固醇、低密度脂蛋白 （LDL） 胆固醇、高密度脂蛋白 （HDL） 胆固醇和甘油三酯浓度的变化没有显着差异。
如表 2 所示，当将组合组与 ADF 组、运动组或对照组进行比较时，血压和心率的变化没有显着差异。同样，到研究结束时，四组的总胆固醇、低密度脂蛋白 （LDL） 胆固醇、高密度脂蛋白 （HDL） 胆固醇和甘油三酯浓度的变化没有显着差异。
Adherence to the interventions was high
对干预措施的依从性很高
Actual energy intake on the fast day in the combination group (673 ± 234 kcal; 2,815 ± 979 kJ) and ADF group (581 ± 168 kcal; 2,430 ± 702 kJ) was not significantly different from that of the prescribed fast day energy goal (600 kcal; 2,500 kJ) (Figure 4A). Thus, participants were adherent with the intermittent fasting protocol during the 3-month trial. Adherence to the exercise program, defined as participating in 80% or more of the supervised exercise sessions, was very good. Participants in the combination group attended 80% ± 18% of the exercise sessions (Figure 4B). Likewise, participants in the exercise group attended 81% ± 18% of the exercise sessions. Willingness to continue with the diet intervention was assessed via survey on the last day of the trial. Results reveal that 95% of combination subjects (19/20) and 85% of ADF subjects (17/20) were interested in continuing the ADF diet on their own at home. Unfortunately, we did not collect data on whether the exercise group was willing to continue with their intervention after the study was over.
联合组（673 ± 234 kcal;2,815 ± 979 kJ）和 ADF 组（581 ± 168 kcal;2,430 ± 702 kJ）在禁食日的实际能量摄入与规定的禁食日能量目标（600 kcal;2,500 kJ）没有显著差异（图 4A）。因此，参与者在 3 个月的试验期间遵守间歇性禁食方案。对锻炼计划的依从性非常好，定义为参加 80% 或更多的监督锻炼课程。组合组的参与者参加了 80% ± 18% 的锻炼课程（图 4B）。同样，运动组的参与者参加了 81% ± 18% 的锻炼课程。在试验的最后一天通过调查评估了继续饮食干预的意愿。结果显示，95% 的组合受试者 （19/20） 和 85% 的 ADF 受试者 （17/20） 有兴趣在家中自行继续 ADF 饮食。不幸的是，我们没有收集关于运动组是否愿意在研究结束后继续干预的数据。
联合组（673 ± 234 kcal;2,815 ± 979 kJ）和 ADF 组（581 ± 168 kcal;2,430 ± 702 kJ）在禁食日的实际能量摄入与规定的禁食日能量目标（600 kcal;2,500 kJ）没有显著差异（图 4A）。因此，参与者在 3 个月的试验期间遵守间歇性禁食方案。对锻炼计划的依从性非常好，定义为参加 80% 或更多的监督锻炼课程。组合组的参与者参加了 80% ± 18% 的锻炼课程（图 4B）。同样，运动组的参与者参加了 81% ± 18% 的锻炼课程。在试验的最后一天通过调查评估了继续饮食干预的意愿。结果显示，95% 的组合受试者 （19/20） 和 85% 的 ADF 受试者 （17/20） 有兴趣在家中自行继续 ADF 饮食。不幸的是，我们没有收集关于运动组是否愿意在研究结束后继续干预的数据。
Figure 4 Adherence to the alternate fasting diet and exercise program
图 4坚持交替禁食饮食和锻炼计划
图 4坚持交替禁食饮食和锻炼计划
The combination intervention produces similar reductions in energy intake compared with fasting alone
与单独禁食相比，联合干预产生的能量摄入减少相似
As shown in Table 3, energy, fiber, cholesterol, and macronutrient intake at baseline was similar when the combination group was compared with the ADF group, exercise group, and control group. Energy and fiber intake significantly decreased (p < 0.05) in the combination group and ADF group by month 3, on the fast day and feast day, versus baseline. In addition, cholesterol intake significantly decreased (p < 0.05) in the combination and ADF groups at month 3, on the fast day, versus baseline. In contrast, energy, fiber, and cholesterol intake did not change from baseline to month 3 in the exercise group or control group. Percent intake of macronutrients was not significantly different by month 3 in any of the groups versus baseline. At baseline, regular physical activity measured as steps/day was not significantly different between the four groups. By month 3, regular physical activity (excluding the exercise intervention program) did not change in any of the groups, when compared with baseline.
如表 3 所示，当将组合组与 ADF 组、运动组和对照组进行比较时，基线时的能量、纤维、胆固醇和常量营养素摄入量相似。与基线相比，到第 3 个月，联合组和 ADF 组的能量和纤维摄入量显着降低 （p < 0.05）。此外，与基线相比，联合组和 ADF 组在第 3 个月禁食日的胆固醇摄入量显着降低 （p < 0.05）。相比之下，运动组或对照组的能量、纤维和胆固醇摄入量从基线到第 3 个月没有变化。到第 3 个月时，任何一组的宏量营养素摄入量百分比与基线均无显著差异。在基线时，以步数/天测量的定期身体活动在四组之间没有显著差异。到第 3 个月，与基线相比，任何组的定期身体活动（不包括运动干预计划）都没有变化。
如表 3 所示，当将组合组与 ADF 组、运动组和对照组进行比较时，基线时的能量、纤维、胆固醇和常量营养素摄入量相似。与基线相比，到第 3 个月，联合组和 ADF 组的能量和纤维摄入量显着降低 （p < 0.05）。此外，与基线相比，联合组和 ADF 组在第 3 个月禁食日的胆固醇摄入量显着降低 （p < 0.05）。相比之下，运动组或对照组的能量、纤维和胆固醇摄入量从基线到第 3 个月没有变化。到第 3 个月时，任何一组的宏量营养素摄入量百分比与基线均无显著差异。在基线时，以步数/天测量的定期身体活动在四组之间没有显著差异。到第 3 个月，与基线相比，任何组的定期身体活动（不包括运动干预计划）都没有变化。
| Variable 变量 | Combination 组合 | Alternate day fasting 隔日禁食 | Exercise 锻炼 | Control 控制 | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Time 时间 | Feast day baseline 节日基线 | Feast day month 3 节日 第 3 个月 | Fast day month 3 禁食日 第 3 个月 | Feast day baseline 节日基线 | Feast day month 3 节日 第 3 个月 | Fast day month 3 禁食日 第 3 个月 | Baseline 基线 | Month 3 第 3 个月 | Baseline 基线 | Month 3 第 3 个月 |
| Energy (kcal) 能量 （kcal） | 2,062 ± 1,111 | 1,356 ± 628a | 673 ± 234a | 1,940 ± 478 | 1,285 ± 469a | 581 ± 168a | 1,808 ± 637 | 1,779 ± 656 | 1,810 ± 438 | 1,833 ± 497 |
| Protein (% kcal) 蛋白质 （% kcal） | 18 ± 5 | 18 ± 6 | 21 ± 6 | 17 ± 4 | 20 ± 3 | 21 ± 7 | 19 ± 4 | 18 ± 4 | 18 ± 5 | 18 ± 5 |
| Carbohydrates (% kcal) 碳水化合物 （% kcal） | 44 ± 8 | 43 ± 12 | 44 ± 12 | 44 ± 9 | 38 ± 11 | 46 ± 8 | 39 ± 9 | 43 ± 13 | 43 ± 9 | 41 ± 9 |
| Fat (% kcal) 脂肪 （% kcal） | 38 ± 7 | 39 ± 10 | 35 ± 10 | 39 ± 8 | 42 ± 7 | 33 ± 11 | 42 ± 7 | 39 ± 11 | 39 ± 6 | 41 ± 9 |
| Cholesterol (mg) 胆固醇 （mg） | 324 ± 178 | 246 ± 182 | 174 ± 111a | 336 ± 132 | 323 ± 160 | 112 ± 97a | 294 ± 156 | 308 ± 97 | 280 ± 131 | 255 ± 121 |
| Fiber (g) 纤维 （g） | 19 ± 12 | 15 ± 10a | 10 ± 5a | 18 ± 7 | 11 ± 8a | 9 ± 3a | 15 ± 8 | 17 ± 12 | 14 ± 4 | 12 ± 4 |
| Steps/day 步数/天 | 7,434 ± 3,889 | 7,455 ± 3,847 | – | 7,528 ± 4,340 | 7,041 ± 3,740 | – | 6,754 ± 2,446 | 6,936 ± 2,476 | 6,497 ± 2,688 | 6,004 ± 2,377 |
Table 3 表 3
Dietary intake and physical activity
饮食摄入和身体活动
饮食摄入和身体活动
Data are expressed as mean (SD); only observed values included. At baseline, there were no differences in nutrient intake or steps/day between the combination group, alternate day fasting group, exercise group, or control group.
数据表示为平均值 （SD）;仅包括观测值。基线时，联合组、隔日空腹组、运动组或对照组之间的营养摄入量或步数/天没有差异。
数据表示为平均值 （SD）;仅包括观测值。基线时，联合组、隔日空腹组、运动组或对照组之间的营养摄入量或步数/天没有差异。
a
Significant changes (p < 0.05) from baseline to month 3.
从基线到第 3 个月的显着变化 （p < 0.05）。
从基线到第 3 个月的显着变化 （p < 0.05）。
The combination intervention does not affect hepatokine concentrations
联合干预不影响肝托因浓度
Changes in hepatokines from baseline to month 3 are reported in Figure S2. Change in fetuin-A, fibroblast growth factor-21 (FGF-21), and selenoprotein P did not significantly differ among the four groups by the end of the study. Correlations between hepatokines and metabolic disease risk factors are displayed in Table S1. A positive correlation was observed between change in fetuin-A and fasting glucose concentrations (r = 0.465, p = 0.006). Similarly, a positive correlation was noted between change in fetuin-A and HbA1c (r = 0.432, p = 0.012). No correlations were observed for FGF-21 or selenoprotein P and any metabolic outcome.
肝因子从基线到第 3 个月的变化报告在图 S2 中。截至研究结束时，四组胎儿球蛋白-A 、成纤维细胞生长因子-21 （FGF-21） 和硒蛋白 P 的变化无显著差异。肝因子与代谢疾病危险因素之间的相关性显示在表 S1 中。观察到胎球蛋白-A 的变化与空腹血糖浓度呈正相关 （r = 0.465，p = 0.006）。同样，胎球蛋白-A 和 HbA1c 的变化呈正相关 （r = 0.432，p = 0.012）。未观察到 FGF-21 或硒蛋白 P 与任何代谢结局的相关性。
肝因子从基线到第 3 个月的变化报告在图 S2 中。截至研究结束时，四组胎儿球蛋白-A 、成纤维细胞生长因子-21 （FGF-21） 和硒蛋白 P 的变化无显著差异。肝因子与代谢疾病危险因素之间的相关性显示在表 S1 中。观察到胎球蛋白-A 的变化与空腹血糖浓度呈正相关 （r = 0.465，p = 0.006）。同样，胎球蛋白-A 和 HbA1c 的变化呈正相关 （r = 0.432，p = 0.012）。未观察到 FGF-21 或硒蛋白 P 与任何代谢结局的相关性。
Discussion 讨论
The results of this randomized clinical trial demonstrate that 3 months of ADF combined with aerobic exercise is an effective lifestyle therapy to reduce IHTG content versus exercise alone or a no-intervention control group. However, further research will be required to elucidate whether the combination intervention produces greater reductions in IHTG content versus fasting alone. Our findings also indicate that the combination intervention was effective for reducing body weight, fat mass, waist circumference, ALT, fasting insulin, insulin resistance, and increasing insulin sensitivity, among patients with obesity and NAFLD, versus controls.
这项随机临床试验的结果表明，与单独运动或无干预对照组相比，3 个月的 ADF 联合有氧运动是一种有效的生活方式疗法，可以减少 IHTG 含量。然而，需要进一步的研究来阐明与单独禁食相比，联合干预是否能使 IHTG 含量降低得更大。我们的研究结果还表明，与对照组相比，联合干预可有效降低肥胖和 NAFLD 患者的体重、脂肪量、腰围、ALT、空腹胰岛素、胰岛素抵抗和增加胰岛素敏感性。
这项随机临床试验的结果表明，与单独运动或无干预对照组相比，3 个月的 ADF 联合有氧运动是一种有效的生活方式疗法，可以减少 IHTG 含量。然而，需要进一步的研究来阐明与单独禁食相比，联合干预是否能使 IHTG 含量降低得更大。我们的研究结果还表明，与对照组相比，联合干预可有效降低肥胖和 NAFLD 患者的体重、脂肪量、腰围、ALT、空腹胰岛素、胰岛素抵抗和增加胰岛素敏感性。
This is the first study to examine the effect of intermittent fasting combined with exercise on NAFLD outcomes. After 3 months, significant reductions in hepatic steatosis (5.5%) were observed in the combination group. These beneficial changes in IHTG content were significantly different compared with the exercise group (1.3%, p = 0.02) but not compared with the ADF group (2.3%, p = 0.05). Since the latter comparison was marginally significant (p = 0.05), more research will be needed to inform whether the combination intervention produces greater reductions in IHTG content versus fasting alone. The changes noted for IHTG content are on par with what has been observed in previous lifestyle intervention trials.18,19,20 For instance, Cheng and colleagues18 observed a 5.5% absolute reduction from baseline in IHTG content after 8 months of calorie restriction combined with aerobic exercise (150 min per week) in adults with NAFLD and prediabetes. Likewise, Kantartzis et al.20 demonstrated a 4.6% absolute decrease from baseline in IHTG content when patients with NAFLD followed a low-calorie diet combined with exercise (180 min per week) for 9 months. Improvements in liver fat content and fibrosis scores have also been observed with intermittent fasting alone.14,15,21 Moreover, Holmer et al.21 showed that fasting 2 days per week produced comparable reductions from baseline in absolute IHTG content (6.1%) when compared with daily calorie restriction (7.2%) after 3 months. In view of these findings, it is possible that intermittent fasting may be a suitable alternative to daily energy restriction for patients with NAFLD who struggle with calorie counting. More studies that directly compare the effects of intermittent fasting versus daily calorie restriction on NAFLD outcomes are well warranted.
这是第一项检查间歇性禁食联合运动对 NAFLD 结果影响的研究。3 个月后，在联合治疗组中观察到肝脂肪变性显着减少 （5.5%）。与运动组 （1.3%，p = 0.02） 相比，IHTG 含量的这些有益变化显著不同，但与 ADF 组 （2.3%，p = 0.05） 相比没有差异。由于后一种比较略有显著性 （p = 0.05），因此需要更多的研究来了解与单独禁食相比，联合干预是否能更大程度地降低 IHTG 含量。IHTG 含量的变化与之前生活方式干预试验中观察到的变化相当。 18 19 20 例如，Cheng 及其同事 18 观察到，在患有 NAFLD 和糖尿病前期的成年人中，在卡路里限制 8 个月并结合有氧运动（每周 150 分钟）后，IHTG 含量绝对比基线减少了 5.5%。同样，Kantartzis 等人 20 证明，当 NAFLD 患者遵循低热量饮食结合运动（每周 180 分钟）9 个月时，IHTG 含量绝对比基线下降 4.6%。单独间歇性禁食也观察到肝脏脂肪含量和纤维化评分的改善。 14 15 21 此外，Holmer 等人 21 表明，与 3 个月后每日卡路里限制 （7.2%） 相比，每周禁食 2 天的 IHTG 绝对含量 （6.1%） 比基线降低相当。鉴于这些发现，对于难以计算卡路里的 NAFLD 患者来说，间歇性禁食可能是日常能量限制的合适替代方案。 有更多研究直接比较间歇性禁食与每日卡路里限制对 NAFLD 结局的影响。
这是第一项检查间歇性禁食联合运动对 NAFLD 结果影响的研究。3 个月后，在联合治疗组中观察到肝脂肪变性显着减少 （5.5%）。与运动组 （1.3%，p = 0.02） 相比，IHTG 含量的这些有益变化显著不同，但与 ADF 组 （2.3%，p = 0.05） 相比没有差异。由于后一种比较略有显著性 （p = 0.05），因此需要更多的研究来了解与单独禁食相比，联合干预是否能更大程度地降低 IHTG 含量。IHTG 含量的变化与之前生活方式干预试验中观察到的变化相当。 18 19 20 例如，Cheng 及其同事 18 观察到，在患有 NAFLD 和糖尿病前期的成年人中，在卡路里限制 8 个月并结合有氧运动（每周 150 分钟）后，IHTG 含量绝对比基线减少了 5.5%。同样，Kantartzis 等人 20 证明，当 NAFLD 患者遵循低热量饮食结合运动（每周 180 分钟）9 个月时，IHTG 含量绝对比基线下降 4.6%。单独间歇性禁食也观察到肝脏脂肪含量和纤维化评分的改善。 14 15 21 此外，Holmer 等人 21 表明，与 3 个月后每日卡路里限制 （7.2%） 相比，每周禁食 2 天的 IHTG 绝对含量 （6.1%） 比基线降低相当。鉴于这些发现，对于难以计算卡路里的 NAFLD 患者来说，间歇性禁食可能是日常能量限制的合适替代方案。 有更多研究直接比较间歇性禁食与每日卡路里限制对 NAFLD 结局的影响。
We also examined the effect of these interventions on hepatic fibrosis scores and liver enzymes. Degree of liver fibrosis was estimated by the FIB-4 index. A FIB-4 score below 1.30 is considered as low risk for advanced fibrosis, while a score over 2.67 is considered as high risk for advanced fibrosis. At baseline, the mean FIB-4 score for all participants was 0.87, indicating low risk for advanced fibrosis. By the end of the study, changes in liver fibrosis score did not differ significantly between the groups. As for liver enzymes, ALT decreased by 6 U/L in the combination group versus controls. However, AST was not significantly different between groups by the end of the trial. Our findings for liver enzymes are consistent with other fasting studies conducted in patients with NAFLD. Holmer et al.21 observed decreases in ALT (−17 U/L) but no change in AST, despite a 6.1% decrease in absolute IHTG content, after 3 months of fasting on 2 days per week. Similarly, Johari et al.15 reported reductions in ALT (−25 U/L) without any change in AST, after 8 weeks of ADF, even though liver fat and fibrosis scores were improved (measured by ultrasound). While our findings are in line with previous reports, the general relevance of liver enzymes as diagnostic tests for NAFLD has been debated.22 In particular, ALT has been highly scrutinized since there is no clear link between ALT levels and degree of hepatic steatosis. For instance, in large cohort studies conducted in the US and Italy, 55%–79% of adults with fatty liver had normal ALT levels.23,24 Moreover, another study in patients with NAFLD showed no relationship between ALT concentrations and changes in steatosis, inflammation, hepatocyte ballooning, or degree of fibrosis over time.25 Contrary to these findings, others have shown that elevated ALT concentrations are significantly correlated with incidence of steatohepatitis and fibrosis in patients with obesity, NAFLD, and type 2 diabetes.26,27,28 In view of these equivocal findings, it remains unknown whether ALT has enough sensitivity and specificity to reliably diagnose fatty liver disease.
我们还检查了这些干预措施对肝纤维化评分和肝酶的影响。通过 FIB-4 指数估计肝纤维化程度。FIB-4 评分低于 1.30 被认为是晚期纤维化的低风险，而高于 2.67 分被认为是晚期纤维化的高风险。基线时，所有参与者的平均 FIB-4 评分为 0.87，表明晚期纤维化的风险较低。到研究结束时，两组之间肝纤维化评分的变化没有显着差异。至于肝酶，与对照组相比，联合组的 ALT 降低了 6 U/L。然而，到试验结束时，两组间 AST 没有显著差异。我们对肝酶的研究结果与在 NAFLD 患者中进行的其他空腹研究一致。Holmer 等人 21 观察到，尽管每周 2 天禁食 3 个月后，绝对 IHTG 含量下降了 6.1%，但 AST 没有变化。同样，Johari 等人 15 报告说，在 ADF 8 周后，ALT （-25 U/L） 降低，AST 没有任何变化，即使肝脏脂肪和纤维化评分有所改善（通过超声测量）。虽然我们的研究结果与以前的报告一致，但肝酶作为 NAFLD 诊断测试的一般相关性一直存在争议。 22 特别是，ALT 受到高度审查，因为 ALT 水平与肝脂肪变性程度之间没有明确的联系。例如，在美国和意大利进行的大型队列研究中，55%-79% 的脂肪肝成人患者的 ALT 水平正常。 23 24 此外，另一项针对 NAFLD 患者的研究表明，ALT 浓度与脂肪变性、炎症、肝细胞气球样变或纤维化程度随时间的变化之间没有关系。 25 与这些发现相反，其他人表明，ALT 浓度升高与肥胖、NAFLD 和 2 型糖尿病患者脂肪性肝炎和纤维化的发病率显著相关。 26 27 28 鉴于这些模棱两可的发现，ALT 是否具有足够的敏感性和特异性来可靠地诊断脂肪肝疾病仍然未知。
我们还检查了这些干预措施对肝纤维化评分和肝酶的影响。通过 FIB-4 指数估计肝纤维化程度。FIB-4 评分低于 1.30 被认为是晚期纤维化的低风险，而高于 2.67 分被认为是晚期纤维化的高风险。基线时，所有参与者的平均 FIB-4 评分为 0.87，表明晚期纤维化的风险较低。到研究结束时，两组之间肝纤维化评分的变化没有显着差异。至于肝酶，与对照组相比，联合组的 ALT 降低了 6 U/L。然而，到试验结束时，两组间 AST 没有显著差异。我们对肝酶的研究结果与在 NAFLD 患者中进行的其他空腹研究一致。Holmer 等人 21 观察到，尽管每周 2 天禁食 3 个月后，绝对 IHTG 含量下降了 6.1%，但 AST 没有变化。同样，Johari 等人 15 报告说，在 ADF 8 周后，ALT （-25 U/L） 降低，AST 没有任何变化，即使肝脏脂肪和纤维化评分有所改善（通过超声测量）。虽然我们的研究结果与以前的报告一致，但肝酶作为 NAFLD 诊断测试的一般相关性一直存在争议。 22 特别是，ALT 受到高度审查，因为 ALT 水平与肝脂肪变性程度之间没有明确的联系。例如，在美国和意大利进行的大型队列研究中，55%-79% 的脂肪肝成人患者的 ALT 水平正常。 23 24 此外，另一项针对 NAFLD 患者的研究表明，ALT 浓度与脂肪变性、炎症、肝细胞气球样变或纤维化程度随时间的变化之间没有关系。 25 与这些发现相反，其他人表明，ALT 浓度升高与肥胖、NAFLD 和 2 型糖尿病患者脂肪性肝炎和纤维化的发病率显著相关。 26 27 28 鉴于这些模棱两可的发现，ALT 是否具有足够的敏感性和特异性来可靠地诊断脂肪肝疾病仍然未知。
Body weight decreased in the combination group (−4.6%) versus the exercise group (−2.1%) and controls (−0.6%) but was not significantly different compared with the ADF group (−5.1%). The degree of weight loss noted with ADF (∼5%) is on par with what has been reported in other short-term trials conducted in people with obesity17,29 and those with NAFLD.14,15 Interestingly, the combination group did not lose more weight than the ADF group. This is somewhat surprising since these subjects were expending more energy than the ADF group by exercising 5 times per week but eating approximately the same number of calories. Thus, it would be expected that the net energy deficit by the combination group would be greater than that of the ADF group, which would in turn produce greater weight loss. It is unclear why this did not occur. However, it is possible that our participants were underreporting energy intake and that our food record data are inaccurate. For instance, the average daily caloric deficit reported by the combination and ADF groups was approximately 50% based on food record data. If the study participants were truly restricting energy intake by 50% per day, their weight loss would have been much greater (10%–15% from baseline). Since weight loss was closer to 5% by month 3, it is quite likely that our subjects were underreporting food intake, which is common in diet intervention trials.30,31 It is also interesting that our participants did not compensate for the lack of food on the fast day, by eating more on the feast day. This phenomenon has been reported in several other ADF trials.32,33,34,35 More specifically, it has been shown that participants eat either marginally less on the feast day,35 or just slightly more,17 relative to baseline intake. Future trials in this area should use gold-standard methods, such as the doubly labeled water technique,36 to assess changes in energy expenditure. This will help to elucidate how these interventions truly impact energy balance and weight regulation.
与运动组 （-2.1%） 和对照组 （-0.6%） 相比，联合组 （-4.6%） 的体重有所下降，但与 ADF 组 （-5.1%） 相比没有显著差异。ADF 观察到的体重减轻程度 （∼5%） 与在肥胖 17 患者 29 和 NAFLD 患者中进行的其他短期试验中报告的程度相当。 14 15 有趣的是，联合组并没有比 ADF 组减轻更多的体重。这有点令人惊讶，因为这些受试者每周锻炼 5 次，但摄入的卡路里数量大致相同，比 ADF 组消耗更多的能量。因此，可以预期组合组的净能量亏差将大于 ADF 组的净能量亏差，这反过来又会产生更大的体重损失。目前尚不清楚为什么没有发生这种情况。然而，我们的参与者可能少报了能量摄入量，并且我们的食物记录数据不准确。例如，根据食物记录数据，联合组和 ADF 组报告的平均每日热量赤字约为 50%。如果研究参与者真的每天限制 50% 的能量摄入，他们的体重减轻会大得多（比基线减轻 10%-15%）。由于到第 3 个月体重减轻接近 5%，因此我们的受试者很可能少报了食物摄入量，这在饮食干预试验中很常见。 30 31 同样有趣的是，我们的参与者并没有通过在节日当天吃得更多来弥补斋戒日的食物不足。这种现象在其他几项 ADF 试验中也有报道。 32 33 34 35 更具体地说，研究表明， 17 相对于基线摄入量，参与者在节日当天吃得略少， 35 或者略多。该领域的未来试验应使用金标准方法，例如双标记水技术， 36 以评估能量消耗的变化。这将有助于阐明这些干预措施如何真正影响能量平衡和体重调节。
与运动组 （-2.1%） 和对照组 （-0.6%） 相比，联合组 （-4.6%） 的体重有所下降，但与 ADF 组 （-5.1%） 相比没有显著差异。ADF 观察到的体重减轻程度 （∼5%） 与在肥胖 17 患者 29 和 NAFLD 患者中进行的其他短期试验中报告的程度相当。 14 15 有趣的是，联合组并没有比 ADF 组减轻更多的体重。这有点令人惊讶，因为这些受试者每周锻炼 5 次，但摄入的卡路里数量大致相同，比 ADF 组消耗更多的能量。因此，可以预期组合组的净能量亏差将大于 ADF 组的净能量亏差，这反过来又会产生更大的体重损失。目前尚不清楚为什么没有发生这种情况。然而，我们的参与者可能少报了能量摄入量，并且我们的食物记录数据不准确。例如，根据食物记录数据，联合组和 ADF 组报告的平均每日热量赤字约为 50%。如果研究参与者真的每天限制 50% 的能量摄入，他们的体重减轻会大得多（比基线减轻 10%-15%）。由于到第 3 个月体重减轻接近 5%，因此我们的受试者很可能少报了食物摄入量，这在饮食干预试验中很常见。 30 31 同样有趣的是，我们的参与者并没有通过在节日当天吃得更多来弥补斋戒日的食物不足。这种现象在其他几项 ADF 试验中也有报道。 32 33 34 35 更具体地说，研究表明， 17 相对于基线摄入量，参与者在节日当天吃得略少， 35 或者略多。该领域的未来试验应使用金标准方法，例如双标记水技术， 36 以评估能量消耗的变化。这将有助于阐明这些干预措施如何真正影响能量平衡和体重调节。
Whether these beneficial changes in hepatic steatosis are mediated by fasting or merely just weight loss remains unclear. Body weight reductions of 5%–10% have been shown to reduce, and even resolve, fatty liver disease.37,38 Since the combination group achieved ∼5% weight loss after 3 months, it can be speculated that these changes in weight played a role in the benefits observed. However, these subjects were also fasting for approximately 17–22 h on the fast day (i.e., midnight to 5:00–8:00 p.m.). Fasting diets induce the metabolic switch from glucose to fatty acid-derived ketone bodies for energy.39 Ketones regulate the expression of many proteins that optimize physiological function, thereby slowing aging and disease processes.39 However, in NAFLD, the role of ketones is less clear. It has been hypothesized that the combination of elevated liver fat and insulin resistance may predispose patients with NAFLD to increased ketogenesis by providing more substrate for ketone body production. However, increased levels of ketones may pose risk, as noted in a recent cohort study,40 which shows that augmented ketones were independently associated with higher all-cause mortality in NAFLD. While these findings are concerning, it is unknown whether ketones are the culprit in this association, or merely a reflection of an underlying mechanism.40 Moreover, how higher levels of ketones impact degree of hepatic steatosis is still unclear, with some studies showing increases in liver fat,41,42 decreases in liver fat,43,44 or no effect.45 Unfortunately, we did not measure circulating ketone bodies in this trial; therefore, we were not able to further explore these relationships.
肝脂肪变性的这些有益变化是由禁食介导的，还是仅仅由体重减轻介导的，目前尚不清楚。体重减轻 5%-10% 已被证明可以减少甚至解决脂肪肝疾病。 37 38 由于联合组在 3 个月后实现了 ∼5% 的体重减轻，因此可以推测这些体重变化在观察到的益处中发挥了作用。然而，这些受试者在禁食日（即午夜至下午 5：00-8：00）也禁食了大约 17-22 小时。禁食饮食会诱导从葡萄糖到脂肪酸衍生的酮体的代谢转变以获取能量。 39 酮调节许多蛋白质的表达，优化生理功能，从而减缓衰老和疾病过程。 39 然而，在 NAFLD 中，酮的作用不太清楚。据推测，肝脏脂肪升高和胰岛素抵抗的结合可能通过为酮体产生提供更多底物，使 NAFLD 患者易发生酮症增加。然而，正如最近的一项队列研究中所指出的那样，酮水平升高可能会带来风险， 40 该研究表明，增强的酮与 NAFLD 中较高的全因死亡率独立相关。虽然这些发现令人担忧，但尚不清楚酮是这种关联的罪魁祸首，还是仅仅反映了潜在机制。 40 此外，高水平的酮体如何影响肝脂肪变性的程度仍不清楚，一些研究表明肝脏脂肪增加、 41 42 肝脏脂肪减少或 43 44 没有影响。 45 不幸的是，我们在这项试验中没有测量循环中的酮体;因此，我们无法进一步探索这些关系。
肝脂肪变性的这些有益变化是由禁食介导的，还是仅仅由体重减轻介导的，目前尚不清楚。体重减轻 5%-10% 已被证明可以减少甚至解决脂肪肝疾病。 37 38 由于联合组在 3 个月后实现了 ∼5% 的体重减轻，因此可以推测这些体重变化在观察到的益处中发挥了作用。然而，这些受试者在禁食日（即午夜至下午 5：00-8：00）也禁食了大约 17-22 小时。禁食饮食会诱导从葡萄糖到脂肪酸衍生的酮体的代谢转变以获取能量。 39 酮调节许多蛋白质的表达，优化生理功能，从而减缓衰老和疾病过程。 39 然而，在 NAFLD 中，酮的作用不太清楚。据推测，肝脏脂肪升高和胰岛素抵抗的结合可能通过为酮体产生提供更多底物，使 NAFLD 患者易发生酮症增加。然而，正如最近的一项队列研究中所指出的那样，酮水平升高可能会带来风险， 40 该研究表明，增强的酮与 NAFLD 中较高的全因死亡率独立相关。虽然这些发现令人担忧，但尚不清楚酮是这种关联的罪魁祸首，还是仅仅反映了潜在机制。 40 此外，高水平的酮体如何影响肝脂肪变性的程度仍不清楚，一些研究表明肝脏脂肪增加、 41 42 肝脏脂肪减少或 43 44 没有影响。 45 不幸的是，我们在这项试验中没有测量循环中的酮体;因此，我们无法进一步探索这些关系。
Changes in body composition were also assessed. By the end of the trial, the combination group lost significantly more fat mass than the exercise group or control group. However, no change in lean mass was observed in the combination group relative to the other groups. Our findings are complementary to previous intermittent fasting studies. When fasting is applied alone, lean mass typically decreases by 10%–30% from baseline.17,29 However, when fasting is combined with endurance or resistance exercise, lean mass is maintained46,47 or increased.48,49 The maintenance or accretion of lean mass, or more specifically, skeletal muscle mass, has important implications for NAFLD. In a recent cohort study of approximately 13,000 subjects, skeletal muscle mass was negatively associated with NAFLD incidence and positively associated with NAFLD resolution.50 Skeletal muscle is also independently associated with the severity of hepatic steatosis and fibrosis in a dose-dependent manner in patients with NAFLD.51,52,53 Taken together, the lack of significant lean mass loss by the combination group likely played a role in the improvements noted in IHTG content. However, our study is limited in that it measured lean mass by dual energy X-ray absorptiometry (DXA), instead of skeletal muscle mass by MRI or computed tomography.54
还评估了身体成分的变化。到试验结束时，联合组比运动组或对照组损失的脂肪量明显更多。然而，相对于其他组，联合组没有观察到瘦体重的变化。我们的研究结果与之前的间歇性禁食研究相辅相成。当单独禁食时，瘦体重通常比基线减少 10%-30%。 17 29 然而，当禁食与耐力或阻力运动相结合时，瘦体重得以维持 46 47 或增加。 48 49 瘦体重的维持或增加，或者更具体地说，骨骼肌质量，对 NAFLD 具有重要意义。在最近一项针对大约 13,000 名受试者的队列研究中，骨骼肌质量与 NAFLD 发病率呈负相关，与 NAFLD 消退呈正相关。 50 在 NAFLD 患者中，骨骼肌也以剂量依赖性方式与肝脏脂肪变性和纤维化的严重程度独立相关。 51 52 53 综上所述，联合组没有显著的瘦肉质量损失，这可能是 IHTG 含量改善的原因。然而，我们的研究是有限的，因为它通过双能 X 射线吸收测定法 （DXA） 测量瘦体重，而不是通过 MRI 或计算机断层扫描测量骨骼肌质量。 54
还评估了身体成分的变化。到试验结束时，联合组比运动组或对照组损失的脂肪量明显更多。然而，相对于其他组，联合组没有观察到瘦体重的变化。我们的研究结果与之前的间歇性禁食研究相辅相成。当单独禁食时，瘦体重通常比基线减少 10%-30%。 17 29 然而，当禁食与耐力或阻力运动相结合时，瘦体重得以维持 46 47 或增加。 48 49 瘦体重的维持或增加，或者更具体地说，骨骼肌质量，对 NAFLD 具有重要意义。在最近一项针对大约 13,000 名受试者的队列研究中，骨骼肌质量与 NAFLD 发病率呈负相关，与 NAFLD 消退呈正相关。 50 在 NAFLD 患者中，骨骼肌也以剂量依赖性方式与肝脏脂肪变性和纤维化的严重程度独立相关。 51 52 53 综上所述，联合组没有显著的瘦肉质量损失，这可能是 IHTG 含量改善的原因。然而，我们的研究是有限的，因为它通过双能 X 射线吸收测定法 （DXA） 测量瘦体重，而不是通过 MRI 或计算机断层扫描测量骨骼肌质量。 54
The type, intensity, and duration of exercise necessary to elicit beneficials changes in NAFLD parameters is still uncertain. Both endurance and resistance exercise reduce hepatic steatosis by 20%–40% from baseline, independent of weight loss.55,56 Currently, no definitive exercise guidelines have been established for NAFLD. However, general recommendations include a structured exercise program, involving >150 min/week of moderate-intensity aerobic exercise, or >75 min/week of high-intensity exercise training for at least 3 months.57 Higher exercise intensity may be more effective for reducing liver fat,58,59,60 but findings are not consistent.61,62,63 Moreover, it is currently unknown whether adding resistance training to aerobic exercise would be more effective for improving NAFLD parameters, versus aerobic exercise alone.55,56,57 In the absence of clear guidelines, clinicians should emphasize the importance of exercise but leave type and intensity of the training regimen to the patient. Allowing patients with NAFLD to individualize their exercise programs may help increase long-term adherence to these lifestyle therapies.
引起 NAFLD 参数有益变化所需的运动类型、强度和持续时间仍不确定。耐力运动和阻力运动都可将肝脂肪变性从基线减少 20%-40%，这与体重减轻无关。 55 56 目前，尚未建立针对 NAFLD 的明确运动指南。然而，一般建议包括结构化运动计划，包括每周 >150 分钟的中等强度有氧运动，或每周 >75 分钟的高强度运动训练，持续至少 3 个月。 57 更高的运动强度可能更有效地减少肝脏脂肪， 58 59 60 但结果并不一致。 61 62 63 此外，目前尚不清楚在有氧运动中加入阻力训练是否比单独进行有氧运动更有效地改善 NAFLD 参数。 55 56 57 在没有明确指南的情况下，临床医生应强调锻炼的重要性，但将训练方案的类型和强度留给患者。允许 NAFLD 患者个性化他们的锻炼计划可能有助于提高对这些生活方式疗法的长期依从性。
引起 NAFLD 参数有益变化所需的运动类型、强度和持续时间仍不确定。耐力运动和阻力运动都可将肝脂肪变性从基线减少 20%-40%，这与体重减轻无关。 55 56 目前，尚未建立针对 NAFLD 的明确运动指南。然而，一般建议包括结构化运动计划，包括每周 >150 分钟的中等强度有氧运动，或每周 >75 分钟的高强度运动训练，持续至少 3 个月。 57 更高的运动强度可能更有效地减少肝脏脂肪， 58 59 60 但结果并不一致。 61 62 63 此外，目前尚不清楚在有氧运动中加入阻力训练是否比单独进行有氧运动更有效地改善 NAFLD 参数。 55 56 57 在没有明确指南的情况下，临床医生应强调锻炼的重要性，但将训练方案的类型和强度留给患者。允许 NAFLD 患者个性化他们的锻炼计划可能有助于提高对这些生活方式疗法的长期依从性。
Our findings also show the combination intervention improved glycemic control by lowering fasting insulin, insulin resistance, and increasing insulin sensitivity. The insulin-sensitizing effects of intermittent fasting have been well documented. For instance, Gabel and colleagues64 showed that fasting insulin and insulin resistance decreased by 52% and 53% from baseline, respectively, after 6 months of ADF in adults with insulin resistance and obesity. Likewise, Paravesh et al.65 reported 22% reductions in insulin resistance after 2 months of ADF in people with metabolic syndrome, relative to baseline. Aerobic exercise also has profound impacts on glycemic control. In a meta-analysis of 54 studies, aerobic exercise was shown to significantly reduce insulin resistance (measured by HOMA-IR) by 0.33 units in adults with obesity.66 Exercise also helps improve insulin sensitivity in patients with NAFLD.67,68,69 HbA1c, on the other hand, was not different between groups in this study. These findings are somewhat surprising considering the improvements in insulin sensitivity. However, it is likely that our intervention period was too short to see significant modifications, as HbA1c generally takes 3 months to change.70
我们的研究结果还表明，联合干预通过降低空腹胰岛素、胰岛素抵抗和增加胰岛素敏感性来改善血糖控制。间歇性禁食的胰岛素增敏作用已得到充分证明。例如，Gabel 及其同事 64 表明，患有胰岛素抵抗和肥胖的成年人在 ADF 治疗 6 个月后，空腹胰岛素和胰岛素抵抗分别从基线下降了 52% 和 53%。同样，Paravesh 等人 65 报告说，相对于基线，代谢综合征患者在 ADF 治疗 2 个月后胰岛素抵抗降低了 22%。有氧运动对血糖控制也有深远的影响。在对 54 项研究的荟萃分析中，有氧运动被证明可以显着降低肥胖成人的胰岛素抵抗（通过 HOMA-IR 测量）0.33 个单位。 66 运动还有助于提高 NAFLD 患者的胰岛素敏感性。 67 68 69 另一方面，在本研究中，HbA1c 在各组之间没有差异。考虑到胰岛素敏感性的改善，这些发现有些令人惊讶。然而，我们的干预期可能太短，没有看到明显的改变，因为 HbA1c 通常需要 3 个月才能改变。 70
我们的研究结果还表明，联合干预通过降低空腹胰岛素、胰岛素抵抗和增加胰岛素敏感性来改善血糖控制。间歇性禁食的胰岛素增敏作用已得到充分证明。例如，Gabel 及其同事 64 表明，患有胰岛素抵抗和肥胖的成年人在 ADF 治疗 6 个月后，空腹胰岛素和胰岛素抵抗分别从基线下降了 52% 和 53%。同样，Paravesh 等人 65 报告说，相对于基线，代谢综合征患者在 ADF 治疗 2 个月后胰岛素抵抗降低了 22%。有氧运动对血糖控制也有深远的影响。在对 54 项研究的荟萃分析中，有氧运动被证明可以显着降低肥胖成人的胰岛素抵抗（通过 HOMA-IR 测量）0.33 个单位。 66 运动还有助于提高 NAFLD 患者的胰岛素敏感性。 67 68 69 另一方面，在本研究中，HbA1c 在各组之间没有差异。考虑到胰岛素敏感性的改善，这些发现有些令人惊讶。然而，我们的干预期可能太短，没有看到明显的改变，因为 HbA1c 通常需要 3 个月才能改变。 70
BP was not significantly altered by the interventions in this 3-month trial. These findings are unexpected as BP generally improves by both intermittent fasting17 and aerobic exercise.71 However, it is possible that the degree of weight loss experienced by the combination group (4.6%), ADF group (5.1%), and exercise group (2.1%), was not sufficient to observe a significant change in BP. Body weight reductions of 7%–10% from baseline are usually necessary to see significant improvements in BP with diet and exercise interventions.72,73
在这项为期 3 个月的试验中，干预措施没有显着改变血压。这些发现是出乎意料的，因为血压通常通过间歇性禁食 17 和有氧运动得到改善。 71 然而，组合组 （4.6%）、ADF 组 （5.1%） 和运动组 （2.1%） 所经历的体重减轻程度可能不足以观察到血压的显着变化。通常需要从基线减轻 7%-10% 的体重才能看到饮食和运动干预的血压显着改善。 72 73
在这项为期 3 个月的试验中，干预措施没有显着改变血压。这些发现是出乎意料的，因为血压通常通过间歇性禁食 17 和有氧运动得到改善。 71 然而，组合组 （4.6%）、ADF 组 （5.1%） 和运动组 （2.1%） 所经历的体重减轻程度可能不足以观察到血压的显着变化。通常需要从基线减轻 7%-10% 的体重才能看到饮食和运动干预的血压显着改善。 72 73
Plasma lipids were also not significantly different between groups by the end of the study. Intermittent fasting generally has little effect on in LDL cholesterol, HDL cholesterol, or triglyceride concentrations in individuals with obesity17 or those with NAFLD,14,15 so our findings are in line with previous reports. On the other hand, aerobic exercise (>120 min/week) generally increases HDL cholesterol concentrations in individuals with obesity74,75 and NAFLD,76,77 so our findings are not in accordance with those studies. The lack of improvement in HDL cholesterol may be partly explained by baseline lipid levels. Improvements in HDL cholesterol with exercise are more likely to occur when HDL cholesterol is low (<36 mg/dL) at baseline.78 None of the groups had low HDL cholesterol at the onset of treatment (range 50–55 mg/dL), which may explain why no change in HDL cholesterol was observed.
到研究结束时，两组之间的血浆脂质也没有显着差异。间歇性禁食通常对肥胖 17 症或 NAFLD 患者的低密度脂蛋白胆固醇、高密度脂蛋白胆固醇或甘油三酯浓度影响不大， 14 15 因此我们的研究结果与以前的报告一致。另一方面，有氧运动（>120 分钟/周）通常会增加肥胖 74 75 和 NAFLD 患者的高密度脂蛋白胆固醇浓度， 76 77 因此我们的研究结果与这些研究不一致。HDL 胆固醇没有改善的部分原因可能是基线脂质水平。当基线时 HDL 胆固醇较低 （<36 mg/dL） 时，运动更可能改善 HDL 胆固醇。 78 在治疗开始时，没有一组的 HDL 胆固醇较低（范围 50-55 mg/dL），这可能解释了为什么没有观察到 HDL 胆固醇的变化。
到研究结束时，两组之间的血浆脂质也没有显着差异。间歇性禁食通常对肥胖 17 症或 NAFLD 患者的低密度脂蛋白胆固醇、高密度脂蛋白胆固醇或甘油三酯浓度影响不大， 14 15 因此我们的研究结果与以前的报告一致。另一方面，有氧运动（>120 分钟/周）通常会增加肥胖 74 75 和 NAFLD 患者的高密度脂蛋白胆固醇浓度， 76 77 因此我们的研究结果与这些研究不一致。HDL 胆固醇没有改善的部分原因可能是基线脂质水平。当基线时 HDL 胆固醇较低 （<36 mg/dL） 时，运动更可能改善 HDL 胆固醇。 78 在治疗开始时，没有一组的 HDL 胆固醇较低（范围 50-55 mg/dL），这可能解释了为什么没有观察到 HDL 胆固醇的变化。
We also examined the underlying role of hepatokines in mediating the effects observed. Hepatokines are proteins secreted by the liver that are known to directly affect glucose and insulin metabolism.79 In individuals with NAFLD, hepatokine secretion is altered, which adversely affects glucoregulatory systems and exacerbates hepatic steatosis.79 Fetuin-A, FGF-21, and selenoprotein P have recently emerged as hepatokines of interest due to their effects on insulin sensitivity. Fetuin-A is a glycoprotein secreted by the liver that is positively correlated with hepatic steatosis, NAFLD severity, and insulin resistance.80 This hepatokine disrupts tyrosine kinase receptor activity leading to impaired insulin signaling.80 FGF-21, on the other hand, has been shown to improve insulin sensitivity and glycemic control due to augmented basal glucose disposal and increased Akt phosphorylation (a key step in hepatic insulin and FGF-21 signaling).81 Considering these effects, FGF-21 analogs have recently emerged as potential therapeutic agents to treat hyperglycemia.82 Lastly, selenoprotein P is a hepatokine that disrupts glucose sensing in the β cell of the pancreas, inhibiting the secretion of insulin. In animal studies, inhibiting selenoprotein P expression was shown to improve insulin sensitivity and augment glucose tolerance.83,84
我们还检查了肝因子在介导观察到的效果中的潜在作用。肝因子是肝脏分泌的蛋白质，已知直接影响葡萄糖和胰岛素代谢。 79 在 NAFLD 患者中，肝激素分泌发生改变，这对葡萄糖调节系统产生不利影响并加剧肝脂肪变性。 79 Fetuin-A、FGF-21 和硒蛋白 P 由于对胰岛素敏感性的影响，最近已成为感兴趣的肝因子。胎球蛋白 A 是肝脏分泌的一种糖蛋白，与肝脂肪变性、NAFLD 严重程度和胰岛素抵抗呈正相关。 80 这种肝炎碱会破坏酪氨酸激酶受体活性，导致胰岛素信号传导受损。 80 另一方面，FGF-21 已被证明可以改善胰岛素敏感性和血糖控制，因为基础葡萄糖处理增加和 Akt 磷酸化增加（肝脏胰岛素和 FGF-21 信号传导的关键步骤）。 81 考虑到这些影响，FGF-21 类似物最近已成为治疗高血糖的潜在治疗剂。 82 最后，硒蛋白 P 是一种肝蛋白，可破坏胰腺β细胞中的葡萄糖感应，抑制胰岛素的分泌。在动物研究中，抑制硒蛋白 P 表达被证明可以提高胰岛素敏感性并增强葡萄糖耐量。 83 84
我们还检查了肝因子在介导观察到的效果中的潜在作用。肝因子是肝脏分泌的蛋白质，已知直接影响葡萄糖和胰岛素代谢。 79 在 NAFLD 患者中，肝激素分泌发生改变，这对葡萄糖调节系统产生不利影响并加剧肝脂肪变性。 79 Fetuin-A、FGF-21 和硒蛋白 P 由于对胰岛素敏感性的影响，最近已成为感兴趣的肝因子。胎球蛋白 A 是肝脏分泌的一种糖蛋白，与肝脂肪变性、NAFLD 严重程度和胰岛素抵抗呈正相关。 80 这种肝炎碱会破坏酪氨酸激酶受体活性，导致胰岛素信号传导受损。 80 另一方面，FGF-21 已被证明可以改善胰岛素敏感性和血糖控制，因为基础葡萄糖处理增加和 Akt 磷酸化增加（肝脏胰岛素和 FGF-21 信号传导的关键步骤）。 81 考虑到这些影响，FGF-21 类似物最近已成为治疗高血糖的潜在治疗剂。 82 最后，硒蛋白 P 是一种肝蛋白，可破坏胰腺β细胞中的葡萄糖感应，抑制胰岛素的分泌。在动物研究中，抑制硒蛋白 P 表达被证明可以提高胰岛素敏感性并增强葡萄糖耐量。 83 84
In this study, hepatokines did not change in any group after 3 months of intervention. These findings are somewhat surprising as the combination group experienced favorable reductions in hepatic steatosis, insulin resistance, and body weight. Nonetheless, it is possible that the degree of weight loss and liver fat reduction was not great enough to see changes in these hepatokines. Indeed, recent evidence suggests that a minimum of 7%–10% weight loss may be required.85,86 However, a positive correlation was observed between fetuin-A and HbA1c, and fetuin-A and fasting glucose levels. These results are in accordance with previous reports. For instance, in a sample of 3,790 men, fetuin-A was higher (309 ng/mL) in men with HbA1c greater than 7%, compared with those who had an HbA1c lower than 6.5% (290 ng/mL).87 Results from other trials, demonstrate that fetuin-A is positively correlated with fasting blood glucose in adults with new onset type 2 diabetes,88 and those with NAFLD.89 Results from our study and others further highlight the relationship between increased fetuin-A levels and the risk for developing type 2 diabetes and NAFLD. Future well-powered randomized controlled trials (RCTs) that examine how lifestyle interventions impact hepatokines are warranted.
在本研究中，干预 3 个月后，任何组的肝因子均无变化。这些发现有些令人惊讶，因为联合组在肝脂肪变性、胰岛素抵抗和体重方面都有良好的降低。尽管如此，体重减轻和肝脏脂肪减少的程度可能不足以看到这些肝因子的变化。事实上，最近的证据表明，可能需要至少减轻 7%-10% 的体重。 85 86 然而，观察到胎球蛋白 A 和 HbA1c 以及胎球蛋白 A 和空腹血糖水平呈正相关。这些结果与之前的报告一致。例如，在 3,790 名男性的样本中，与 HbA1c 低于 6.5% （290 ng/mL） 的男性相比，HbA1c 大于 7% 的男性的胎球蛋白-A 更高 （309 ng/mL）。 87 其他试验的结果表明，胎球蛋白-A 与新发 2 型糖尿病成人 88 和 NAFLD 患者的空腹血糖呈正相关。 89 我们的研究和其他研究的结果进一步强调了胎球蛋白 A 水平升高与患 2 型糖尿病和 NAFLD 的风险之间的关系。未来需要有把握度的随机对照试验 （RCT） 来研究生活方式干预如何影响肝因子。
在本研究中，干预 3 个月后，任何组的肝因子均无变化。这些发现有些令人惊讶，因为联合组在肝脂肪变性、胰岛素抵抗和体重方面都有良好的降低。尽管如此，体重减轻和肝脏脂肪减少的程度可能不足以看到这些肝因子的变化。事实上，最近的证据表明，可能需要至少减轻 7%-10% 的体重。 85 86 然而，观察到胎球蛋白 A 和 HbA1c 以及胎球蛋白 A 和空腹血糖水平呈正相关。这些结果与之前的报告一致。例如，在 3,790 名男性的样本中，与 HbA1c 低于 6.5% （290 ng/mL） 的男性相比，HbA1c 大于 7% 的男性的胎球蛋白-A 更高 （309 ng/mL）。 87 其他试验的结果表明，胎球蛋白-A 与新发 2 型糖尿病成人 88 和 NAFLD 患者的空腹血糖呈正相关。 89 我们的研究和其他研究的结果进一步强调了胎球蛋白 A 水平升高与患 2 型糖尿病和 NAFLD 的风险之间的关系。未来需要有把握度的随机对照试验 （RCT） 来研究生活方式干预如何影响肝因子。
Adherence to the ADF diet and exercise interventions was very good. Fast day energy intake in the combination group was 673 kcal/day (2,815 kJ), on average, which was 73 kcal (305 kJ) more than that prescribed. Likewise, fast day energy intake in the ADF group was 581 kcal/day (2,430 kJ/day), on average, which was 19 kcal (79 kJ) less than that prescribed. Our findings are complementary to what has been reported previously for short-term adherence to ADF.17,29,32 In addition, a high percent of subjects in the combination group (95%) and ADF group (85%) said that they would like to continue with the fasting protocol after the study was over. This bodes well for the longer-term feasibility of ADF in patients with NAFLD, but a >6-month RCT would be needed to confirm these assumptions. As for exercise adherence, attendance at the supervised sessions was consistently high, with participants attending 4 out of 5 sessions on average, over 3 months. Taken together, these findings suggest that patients with NAFLD may not find it difficult to follow a lifestyle intervention that combines ADF with exercise for short durations (up to 3 months). However, previous trials have shown that adherence to both intermittent fasting32,90 and aerobic exercise91 wanes after 6 months. Thus, it will be important to examine whether the high level of adherence can be sustained for longer periods of time in this population group.
对 ADF 饮食和运动干预的依从性非常好。联合组的禁食日能量摄入量平均为 673 kcal/天 （2,815 kJ），比规定的多 73 kcal （305 kJ）。同样，ADF 组的快速日能量摄入平均为 581 kcal/天（2,430 kJ/天），比规定的少 19 kcal （79 kJ）。我们的研究结果与之前报道的短期 ADF 依从性相辅相成。 17 29 32 此外，联合组 （95%） 和 ADF 组 （85%） 中高比例的受试者表示，他们希望在研究结束后继续禁食方案。这预示着 ADF 在 NAFLD 患者中的长期可行性，但需要 >6 个月的 RCT 来证实这些假设。至于运动依从性，参加监督课程的出席率一直很高，参与者在 3 个月内平均参加了 5 节课中的 4 节。综上所述，这些发现表明，NAFLD 患者可能并不觉得遵循短期 ADF 与运动相结合的生活方式干预并不困难（长达 3 个月）。然而，以前的试验表明，对间歇性禁食 32 90 和有氧运动 91 的依从性在 6 个月后都会减弱。因此，重要的是要检查该人群的高依从性是否可以维持更长的时间。
对 ADF 饮食和运动干预的依从性非常好。联合组的禁食日能量摄入量平均为 673 kcal/天 （2,815 kJ），比规定的多 73 kcal （305 kJ）。同样，ADF 组的快速日能量摄入平均为 581 kcal/天（2,430 kJ/天），比规定的少 19 kcal （79 kJ）。我们的研究结果与之前报道的短期 ADF 依从性相辅相成。 17 29 32 此外，联合组 （95%） 和 ADF 组 （85%） 中高比例的受试者表示，他们希望在研究结束后继续禁食方案。这预示着 ADF 在 NAFLD 患者中的长期可行性，但需要 >6 个月的 RCT 来证实这些假设。至于运动依从性，参加监督课程的出席率一直很高，参与者在 3 个月内平均参加了 5 节课中的 4 节。综上所述，这些发现表明，NAFLD 患者可能并不觉得遵循短期 ADF 与运动相结合的生活方式干预并不困难（长达 3 个月）。然而，以前的试验表明，对间歇性禁食 32 90 和有氧运动 91 的依从性在 6 个月后都会减弱。因此，重要的是要检查该人群的高依从性是否可以维持更长的时间。
Dropout rates in the combination group (0%) and ADF group (5%) were minimal, but the dropout rate in the exercise group was moderately high (25%). This dropout rate may have induced selection bias.92 Upon closer examination of the exercise dropouts, these individuals tended to be heavier (BMI 41 kg/m2) than the rest of the sample (BMI 36 kg/m2). This excess body weight may have made it more difficult for these participants to perform the exercise, which could have contributed to them dropping out. It is also possible that some participants in the exercise group may have wanted to participate in the intermittent fasting intervention. After finding out that they were not randomized to the fasting protocol, they may have lost motivation to participate in the study, which may have led them to drop out. However, since no formal exit survey was performed in our trial, the precise reason for the greater dropouts in the exercise group remains unknown. This highlights the need for future studies to perform a comprehensive exit interview in dropout subjects to see what led them to terminate their participation.
组合组 （0%） 和 ADF 组 （5%） 的退出率最低，但运动组的退出率中等高 （25%）。这种退出率可能诱发了选择偏倚。 92 在仔细检查运动退出者后，这些个体往往比其他样本 （BMI 36 kg/m2） 更重 （BMI 36 kg/m2）。这种超重可能使这些参与者更难进行锻炼，这可能导致他们退出。运动组中的一些参与者也可能想参加间歇性禁食干预。在发现他们没有被随机分配到禁食方案后，他们可能已经失去了参与研究的动力，这可能导致他们退出。然而，由于我们的试验中没有进行正式的退出调查，因此运动组辍学率较高的确切原因仍然未知。这突出了未来研究需要对辍学受试者进行全面的离职面谈，以了解是什么导致他们终止参与。
组合组 （0%） 和 ADF 组 （5%） 的退出率最低，但运动组的退出率中等高 （25%）。这种退出率可能诱发了选择偏倚。 92 在仔细检查运动退出者后，这些个体往往比其他样本 （BMI 36 kg/m2） 更重 （BMI 36 kg/m2）。这种超重可能使这些参与者更难进行锻炼，这可能导致他们退出。运动组中的一些参与者也可能想参加间歇性禁食干预。在发现他们没有被随机分配到禁食方案后，他们可能已经失去了参与研究的动力，这可能导致他们退出。然而，由于我们的试验中没有进行正式的退出调查，因此运动组辍学率较高的确切原因仍然未知。这突出了未来研究需要对辍学受试者进行全面的离职面谈，以了解是什么导致他们终止参与。
In conclusion, the results of this randomized controlled trial demonstrate that ADF combined with aerobic exercise is an effective lifestyle therapy to reduce IHTG content versus exercise alone and controls. However, more research will be required to inform whether the combination intervention produces greater reductions in IHTG content versus fasting alone. The combination therapy also produced significant decreases in body weight, fat mass, waist circumference, ALT levels, fasting insulin, insulin resistance, and significant increases in insulin sensitivity, versus controls. Compliance to the ADF and exercise protocols was shown to be very good and 93% of subjects randomized completed the full protocol. While these preliminary findings offer promise for the use of ADF combined with aerobic exercise to improve NAFLD outcomes, future trials will be needed to examine whether these benefits can be sustained over longer durations of time.
总之，这项随机对照试验的结果表明，与单独运动和对照组相比，ADF 联合有氧运动是一种有效的生活方式疗法，可以减少 IHTG 含量。然而，需要更多的研究来了解与单独禁食相比，联合干预是否能更大程度地降低 IHTG 含量。与对照组相比，联合疗法还显著降低了体重、脂肪量、腰围、ALT 水平、空腹胰岛素、胰岛素抵抗，并显着增加了胰岛素敏感性。对 ADF 和运动方案的依从性被证明非常好，93% 的随机受试者完成了完整的方案。虽然这些初步发现为使用 ADF 联合有氧运动来改善 NAFLD 结局提供了希望，但需要未来的试验来检验这些益处是否可以在更长的时间内持续。
总之，这项随机对照试验的结果表明，与单独运动和对照组相比，ADF 联合有氧运动是一种有效的生活方式疗法，可以减少 IHTG 含量。然而，需要更多的研究来了解与单独禁食相比，联合干预是否能更大程度地降低 IHTG 含量。与对照组相比，联合疗法还显著降低了体重、脂肪量、腰围、ALT 水平、空腹胰岛素、胰岛素抵抗，并显着增加了胰岛素敏感性。对 ADF 和运动方案的依从性被证明非常好，93% 的随机受试者完成了完整的方案。虽然这些初步发现为使用 ADF 联合有氧运动来改善 NAFLD 结局提供了希望，但需要未来的试验来检验这些益处是否可以在更长的时间内持续。
Limitations of the study 研究的局限性
Our study has several limitations. First, the combination intervention produced beneficial changes in key NAFLD parameters, but it did not achieve a reduction in IHTG content and ALT levels into the normal range. Second, the intervention period was short (3 months). The long-term effects of intermittent fasting alone or combined with exercise on NAFLD outcomes warrants investigation. Third, we did not follow up with the participants to see whether they were still following the interventions after the study was over. Fourth, the generalizability of our findings is questionable. Based on baseline IHTG content (range: 16%–18%, where 5%–33% is considered mild steatosis93,94), and liver fibrosis score, it would appear as though our sample was at an early stage of NAFLD development. Thus, it is unclear whether our findings can be extrapolated to patients with a more severe form of the disease. Our participants were also highly adherent to both the diet and exercise interventions. This suggests that our subjects were perhaps a highly motivated subgroup of patients with NAFLD. Whether or not individuals with a more advanced stage of the disease would be just as compliant with this intensive lifestyle therapy remains unknown. Fifth, baseline values for certain secondary outcomes were numerically different between groups. More specifically, energy intake, ALT, and insulin resistance were all higher “numerically” (but not statistically) at the beginning of the study in the combination group compared with controls. This could have increased the likelihood for observing larger mean absolute differences in the combination group. Thus, these findings should be interpreted with caution, as regression to the mean could be a possible cause of this observed change.95
我们的研究有几个局限性。首先，联合干预对关键 NAFLD 参数产生了有益的变化，但并未将 IHTG 含量和 ALT 水平降低到正常范围内。其次，干预期短（3 个月）。单独间歇性禁食或联合运动对 NAFLD 结局的长期影响值得研究。第三，我们没有对受试者进行随访，看看他们在研究结束后是否仍在接受干预。第四，我们的研究结果的普遍性值得怀疑。根据基线 IHTG 含量（范围：16%-18%，其中 5%-33% 被认为是轻度脂肪变性 93 94 ）和肝纤维化评分，我们的样本似乎处于 NAFLD 发展的早期阶段。因此，目前尚不清楚我们的研究结果是否可以外推到患有更严重疾病的患者。我们的参与者对饮食和运动干预也都高度依从。这表明我们的受试者可能是 NAFLD 患者的一个高度积极的亚组。疾病更晚期的个体是否会同样依从这种强化生活方式疗法仍然未知。第五，某些次要结局的基线值在组间存在数值差异。更具体地说，与对照组相比，联合组在研究开始时的能量摄入、ALT 和胰岛素抵抗在“数字上”（但不是统计学上）都更高。这可能增加了在组合组中观察到较大平均绝对差异的可能性。因此，应谨慎解释这些发现，因为回归均值可能是观察到的变化的可能原因。 95
我们的研究有几个局限性。首先，联合干预对关键 NAFLD 参数产生了有益的变化，但并未将 IHTG 含量和 ALT 水平降低到正常范围内。其次，干预期短（3 个月）。单独间歇性禁食或联合运动对 NAFLD 结局的长期影响值得研究。第三，我们没有对受试者进行随访，看看他们在研究结束后是否仍在接受干预。第四，我们的研究结果的普遍性值得怀疑。根据基线 IHTG 含量（范围：16%-18%，其中 5%-33% 被认为是轻度脂肪变性 93 94 ）和肝纤维化评分，我们的样本似乎处于 NAFLD 发展的早期阶段。因此，目前尚不清楚我们的研究结果是否可以外推到患有更严重疾病的患者。我们的参与者对饮食和运动干预也都高度依从。这表明我们的受试者可能是 NAFLD 患者的一个高度积极的亚组。疾病更晚期的个体是否会同样依从这种强化生活方式疗法仍然未知。第五，某些次要结局的基线值在组间存在数值差异。更具体地说，与对照组相比，联合组在研究开始时的能量摄入、ALT 和胰岛素抵抗在“数字上”（但不是统计学上）都更高。这可能增加了在组合组中观察到较大平均绝对差异的可能性。因此，应谨慎解释这些发现，因为回归均值可能是观察到的变化的可能原因。 95
Lastly, since our study began in January 2020, it was impacted by the COVID-19 pandemic. It is likely that the regular activity level of our participants decreased since they had to stay at home for several months. Based on the pedometer data, there were no significant changes in steps per day in any group from the beginning to the end of the trial. However, our study is limited in that the pedometer was only worn at baseline and month 3; therefore, we failed to capture weekly changes in activity levels. In addition, our supervised exercise program changed considerably because of the pandemic. At the beginning of the study (early 2020), the exercise sessions were conducted at the research center and supervised by the study coordinator. However, when the pandemic began, we had to shift all the exercise sessions to home-based programs where subjects used their own exercise equipment or watched online exercise videos. Even though the sessions were still supervised via video conference, using different modalities of exercise may have introduced some variability into the intervention.
最后，由于我们的研究于 2020 年 1 月开始，它受到了 COVID-19 大流行的影响。我们的参与者的正常活动水平很可能下降了，因为他们不得不在家呆了几个月。根据计步器数据，从试验开始到结束，任何组每天的步数都没有显着变化。然而，我们的研究是有限的，因为计步器仅在基线和第 3 个月佩戴;因此，我们无法捕捉到活动水平的每周变化。此外，由于大流行，我们的监督锻炼计划发生了很大变化。在研究开始时（2020 年初），锻炼课程在研究中心进行，并由研究协调员监督。然而，当大流行开始时，我们不得不将所有锻炼课程转移到家庭计划，受试者使用自己的健身器材或观看在线锻炼视频。尽管这些会议仍然通过视频会议进行监督，但使用不同的运动方式可能会给干预带来一些可变性。
最后，由于我们的研究于 2020 年 1 月开始，它受到了 COVID-19 大流行的影响。我们的参与者的正常活动水平很可能下降了，因为他们不得不在家呆了几个月。根据计步器数据，从试验开始到结束，任何组每天的步数都没有显着变化。然而，我们的研究是有限的，因为计步器仅在基线和第 3 个月佩戴;因此，我们无法捕捉到活动水平的每周变化。此外，由于大流行，我们的监督锻炼计划发生了很大变化。在研究开始时（2020 年初），锻炼课程在研究中心进行，并由研究协调员监督。然而，当大流行开始时，我们不得不将所有锻炼课程转移到家庭计划，受试者使用自己的健身器材或观看在线锻炼视频。尽管这些会议仍然通过视频会议进行监督，但使用不同的运动方式可能会给干预带来一些可变性。
STAR★Methods ★STAR 方法
Key resources table 关键资源表
| REAGENT or RESOURCE 试剂或资源 | SOURCE | IDENTIFIER |
|---|---|---|
| Critical commercial assays 关键商业检测 | ||
| Fetuin A Human ELISA Kit 胎球蛋白 A 人 ELISA 试剂盒 | Thermofisher-Invitrogen Thermofisher-Invitrogen 公司 | EHAHSG |
| FGF-21 Human ELISA Kit FGF-21 人 ELISA 试剂盒 | Ray Biotech 雷生物科技 | ELH-FGF21-1 |
| Selenoprotein P Human ELISA Kit 硒蛋白 P 人 ELISA 试剂盒 | MyBioSource | MBS760712 |
| Software and algorithms 软件和算法 | ||
| R software R 软件 | R Foundation for Statistical Computing 用于统计计算的 R 基础 | https://www.r-project.org |
Resource availability 资源可用性
Lead contact 牵头联系人
Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact, Krista Varady (varady@uic.edu).
更多信息以及资源和试剂请求应直接发送至首席联系人 Krista Varady （varady@uic.edu） 并由其完成。
更多信息以及资源和试剂请求应直接发送至首席联系人 Krista Varady （varady@uic.edu） 并由其完成。
Materials availability 材料可用性
This study did not generate new unique reagents.
这项研究没有产生新的独特试剂。
这项研究没有产生新的独特试剂。
Experimental model and subject details
实验模型和主题详细信息
Human subjects 人类受试者
Participants were recruited from the Hepatology Clinic at the University of Illinois Chicago Medical Center. Subjects (mean age 44 ± 13 y; 81% female, 19% male) were enrolled in the study between January 2020 and March 2022. Participants were recruited in four non-overlapping rounds (approximately 20 subjects per round). Individuals between the ages of 18 and 65 years with obesity (body mass index (BMI) between 30 and 60 kg/m2) were screened via a questionnaire and ALT blood test. Women who had an ALT greater than 17 U/L96 and men who had an ALT greater than 25 U/L96 were invited to have their IHTG content quantified by magnetic resonance imaging proton density fat fraction (MRI-PDFF).97 Those who had ultra-sonography or biopsy diagnosed NAFLD were also invited to confirm their diagnosis by MRI-PDFF. Participants were included in the study if the MRI-PDFF exam revealed that IHTG content was at least 5% of liver weight.12 Participants were excluded if they had a history of acute or chronic viral hepatitis, drug-induced liver diseases, or autoimmune hepatitis. Women who consumed more than a mean of 70 g of ethanol (5 alcoholic drinks per week) and men who consumed more than 140 g of ethanol (10 drinks per week) in the past 6 months were also excluded. In addition, patients were excluded if they had a history of diabetes, cardiovascular disease, or chronic kidney disease. Patients who were weight unstable, i.e., more than 4 kg weight loss or gain in the past 3 months, or who had a medical condition that would preclude them from participating in an exercise program, were also excluded. The protocol was approved by the Office for the Protection of Research Subjects at the University of Illinois at Chicago, and informed consent was obtained from all participants.
参与者是从伊利诺伊大学芝加哥医学中心的肝病诊所招募的。受试者 （平均年龄 44 ± 13 岁;81% 为女性，19% 为男性） 在 2020 年 1 月至 2022 年 3 月期间被纳入研究。参与者分四轮非重叠招募（每轮约 20 名受试者）。通过问卷调查和 ALT 血液测试筛选年龄在 18 至 65 岁之间的肥胖个体 （体重指数 （BMI） 在 30 至 60 kg/m2 之间）。邀请 ALT 大于 17 U/L 96 的女性和 ALT 大于 25 U/L 96 的男性通过磁共振成像质子密度脂肪分数 （MRI-PDFF） 量化其 IHTG 含量。 97 那些通过超声检查或活检诊断为 NAFLD 的人也被邀请通过 MRI-PDFF 确认他们的诊断。如果 MRI-PDFF 检查显示 IHTG 含量至少为肝脏重量的 5%，则参与者将被纳入研究。 12 如果参与者有急性或慢性病毒性肝炎、药物性肝病或自身免疫性肝炎病史，则被排除在外。在过去 6 个月内平均饮用超过 70 克乙醇（每周 5 杯酒精饮料）的女性和饮用超过 140 克乙醇（每周 10 杯）的男性也被排除在外。此外，如果患者有糖尿病、心血管疾病或慢性肾病病史，则被排除在外。体重不稳定的患者，即过去 3 个月内体重减轻或增加超过 4 公斤，或患有会妨碍他们参加锻炼计划的医疗状况的患者，也被排除在外。 该方案得到了伊利诺伊大学芝加哥分校研究对象保护办公室的批准，并获得了所有参与者的知情同意。
参与者是从伊利诺伊大学芝加哥医学中心的肝病诊所招募的。受试者 （平均年龄 44 ± 13 岁;81% 为女性，19% 为男性） 在 2020 年 1 月至 2022 年 3 月期间被纳入研究。参与者分四轮非重叠招募（每轮约 20 名受试者）。通过问卷调查和 ALT 血液测试筛选年龄在 18 至 65 岁之间的肥胖个体 （体重指数 （BMI） 在 30 至 60 kg/m2 之间）。邀请 ALT 大于 17 U/L 96 的女性和 ALT 大于 25 U/L 96 的男性通过磁共振成像质子密度脂肪分数 （MRI-PDFF） 量化其 IHTG 含量。 97 那些通过超声检查或活检诊断为 NAFLD 的人也被邀请通过 MRI-PDFF 确认他们的诊断。如果 MRI-PDFF 检查显示 IHTG 含量至少为肝脏重量的 5%，则参与者将被纳入研究。 12 如果参与者有急性或慢性病毒性肝炎、药物性肝病或自身免疫性肝炎病史，则被排除在外。在过去 6 个月内平均饮用超过 70 克乙醇（每周 5 杯酒精饮料）的女性和饮用超过 140 克乙醇（每周 10 杯）的男性也被排除在外。此外，如果患者有糖尿病、心血管疾病或慢性肾病病史，则被排除在外。体重不稳定的患者，即过去 3 个月内体重减轻或增加超过 4 公斤，或患有会妨碍他们参加锻炼计划的医疗状况的患者，也被排除在外。 该方案得到了伊利诺伊大学芝加哥分校研究对象保护办公室的批准，并获得了所有参与者的知情同意。
Experimental design
The study was a 3-month randomized, controlled, parallel-arm trial designed to compare the effects of ADF combined with aerobic exercise, to each intervention alone, on IHTG content and metabolic disease risk factors in patients with NAFLD. Participants were randomized in a 1:1:1:1 ratio to one of four intervention groups: ADF combined with exercise, ADF alone, exercise alone, or no-intervention control group (Figure S1).
ADF protocol
Participants assigned to the combination group and ADF group were instructed to consume 600 calories as a dinner (between 5:00 pm and 8:00 pm) on fast days and eat food as desired on alternating feast days. The feast and fast days began at midnight each day. As such, on fast days, subjects fasted for approximately 17-20 hours (from midnight to 5:00 pm or 8:00 pm). During the fasting period on fast days, participants were encouraged to drink plenty of water and were permitted to consume calorie free drinks such as black coffee, tea, and diet soda in moderation. These participants were provided with fast day meals during the first month of the trial and received dietary counseling thereafter. The provided fast day meals were in accordance with the American Diabetes Association guidelines98 for macronutrient intake, with 30%, 55%, and 15% of energy as fat, carbohydrate and protein, respectively. The exercise group and control group participants were asked to maintain their regular eating habits and were not provided with any food or dietary counseling.
Exercise protocol
Participants assigned to the combination group and exercise group participated in a moderate-intensity aerobic exercise program five times per week for 3 months. All exercise sessions were supervised by study staff. Exercise was performed using treadmills, stationary bikes, or elliptical machines at the research center. The maximum predicted heart rate was calculated as 210/min (220/min for men) minus the participant’s age.99 Heart rates were monitored by an activity monitor worn on the wrist. Training intensity gradually increased over the first four weeks of the study from 65 to 80% of their maximum predicted heart rate (equivalent to 8.0 to 10.0 metabolic equivalents). The participants were instructed to exercise at this intensity for 60 minutes per session. During the peak of the COVID-19 pandemic, participants transitioned to an at-home exercise program using their own treadmills, stationary bikes, elliptical machines, or by watching online aerobic exercise videos. These at-home sessions were supervised by study staff via video conference. Participants in the ADF and control groups did not participate in the exercise intervention and were instructed to not change their physical activity habits.
Control group protocol
Control participants were instructed to maintain their body weight throughout the trial, and not to change their eating or physical activity habits. Controls received no food or dietary counseling but visited the research center at the same frequency as the intervention participants to provide outcome measurements. Controls who completed the 3-month trial received free weight loss counseling at the end of the study.
Method details
Intrahepatic triglyceride (IHTG) content by MRI-PDFF
The primary outcome of the study was absolute percent change in IHTG content from baseline to month 3. The IHTG content was measured using MRI-PDFF.97 MRI scans were performed at the Center for Magnetic Resonance Research at the University of Illinois Medical Center. MRI-PDFF was utilized with a 3.0-Tesla MRI scanner (SIEMENS) for the baseline and follow-up liver fat estimations. Fat-water separation images of the liver were acquired using a T1volumetric interpolated breath-hold examination (VIBE) Dixon sequence with the following parameter settings: TE1 2.5ms; TE2 3.7ms; repetition time 5.47ms; 5° flip angle; ±504.0kHz per pixel receiver bandwidth; and a slice thickness of 3.0 mm. The fat content was calculated in an irregular-shaped ROI covering the entire liver in 21 consecutive slices (max-area centered) of each participant placed by a trained technician manually. MRI-PDFF maps for all segments were generated by placing circular ROIs with diameter of 20mm centrally in each of the eight liver segments. The average fat content values were calculated for the entire liver. The technician performing the MRI-PDFF measurements was blinded to participant group assignment.
Body weight and body composition
Body weight measurements were taken with subjects wearing light clothing and without shoes using a digital scale at home each week. Body weight was also measured at the research center at baseline and month 3. Height was assessed using a wall-mounted stadiometer at baseline. BMI will be assessed as kg/m2. Dual energy X-ray absorptiometry (DXA) was performed on all subjects at baseline and month 3 to assess fat mass, fat free mass, and visceral fat mass (iDXA, GE Inc).
Metabolic disease risk factors
Twelve-hour fasting blood samples were collected at baseline and month 3. Blood was centrifuged for 15 min at 520 x g and 4°C to separate plasma from red cells and was stored at -80°C. Plasma metabolic disease risk factors were assessed at baseline and month 3. Plasma total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, fasting glucose, fasting insulin, HbA1c, ALT, and AST concentrations were measured by a commercial lab (Medstar, IL). Insulin resistance (IR) was calculated by the HOMA (Homeostasis Model Assessment) method: [HOMA-IR = Fasting insulin (μlU/ml) × Fasting glucose (mg/dL) / 405].100 Insulin sensitivity was measured by the Quantitative insulin sensitivity check index (QUICKI) and calculated as: 1 / [log [Insulin (μlU/ml)] + log [Glucose (mg/dl)].101 Blood pressure and heart rate was assessed after a 10-minute rest at baseline and month 3 using a blood pressure cuff. Degree of liver fibrosis was estimated using the Fibrosis-4 (FIB-4) index: Age (years) × AST (IU/L)/(√ALT (IU/L) × Platelet count (109/L)).102
Hepatokines
Plasma levels of fetuin-A, FGF-21, and selenoprotein P were measured by ELISA (Invitrogen, Frederick, MD; RayBio Tech, Norcross, GA, and MyBioSource Inc., San Diego, CA) on a Bio Rad Microplate reader (Bio-Rad Laboratories; Hercules, CA) in duplicate.
Adherence to the intervention and dietary intake
Adherence with the diet intervention and dietary intake was assessed at baseline and month 3 using the NIH web-based system, Automated Self-administered 24-hour Dietary Assessment Tool (ASA24).103 Participants following the ADF diet were considered “adherent” when actual energy intake on the fast day, determined via food records, was not significantly different from the prescribed energy goal for that day (600 kcal; 2500 kJ). Participants following the exercise program were considered adherent if they attended 80% or more of the supervised exercise sessions (a mean of 4 of 5 per week). All participants were required to wear a pedometer (Fitbit Alta) for 7 days to record their regular physical activity (excluding the exercise intervention program) at baseline and at month 3. On the last of the study, the combination and ADF group were asked if they would be willing to continue with the ADF diet after the study was over. The percent of subjects willing to continue the fasting intervention was calculated based on these survey findings.
Quantification and statistical analysis
Power and sample size
For the sample size calculation, we estimated that IHTG content would be reduced by 5.0% in the combination group, 2.5% in the ADF group, 2.5% in the exercise group, and 0% in the control group, by month 3. These estimations were derived from a pilot trial conducted by our lab. We calculated that 17 participants per group would provide 90% power to detect a significant difference in IHTG content between the combination group and the three other groups using one-way ANOVA with α = 0.05. We anticipated a dropout rate of 15%. Thus, we aimed to recruit 80 participants (20 per group) assuming that 68 participants (17 per group) would complete the trial.
Randomization
Participants were randomized in a 1:1:1:1 ratio to one of four intervention groups: ADF combined with exercise, ADF alone, exercise alone, or no-intervention control group (Figure S1). Randomization was performed by a stratified random sampling procedure by sex, age (18-42 y/ 43-65 y), BMI (30.0-45.0 kg/m2 / 45.1-60.0 kg/m2), and IHTG content (5.0-17.5%/ 17.6-30.0%). Due to the nature of the interventions, the study could not be blinded. However, study staff involved in outcome ascertainment were blinded as to the subjects’ group assignments.
Statistical analyses
Data are shown as mean (95% CI) unless otherwise noted. A two-tailed P value of less than 0.05 was considered statistically significant. We conducted an intention-to-treat analysis, which included data from all 80 participants who underwent randomization. Results are reported by intention-to-treat analysis unless indicated otherwise.
A linear mixed model was used to assess time, group, and time∗group effects for each outcome. Linear mixed models for longitudinal data analysis account for missing outcome data using maximum likelihood principles. Thus, these models provide unbiased estimates of time and treatment effects under a missing at random assumption. Group is included in the model to account for baseline differences in the outcome variable between treatment groups. The inclusion of time in the model allows for changes in the outcome over time that are unrelated to the intervention (e.g., regression to the mean, Hawthorne effect). In models for body weight, which was measured at 12 time points, time was modeled with cubic splines. This strategy allowed for estimation of time and group effects (and their interaction) without imposing a linear time trend. The decision to model time with splines was based on a priori rationale for possibly non-linear intervention effects over time (e.g., weight plateau effect, declining compliance) rather than empirical evidence of non-linearity. The interaction terms provide estimates of the 12-week intervention effects, here defined as the effect of assignment to the ADF, exercise, or control compared to the combination group. Estimated changes from baseline and P values for intervention effects based on the linear mixed models are shown in Table 2.
For each outcome variable, linear modelling assumptions were assessed with residual diagnostics. To account for the potential for non-uniform variances (heteroskedasticity) between treatment groups due to random chance, CIs and P values (i.e., body weight percent, ALT, and HOMA-IR) were calculated using robust variance estimators (sandwich estimators) as needed.104,105,106 The analyses were performed using R software (version 4.3.1).
Additional resources
Prior to enrolling participants, the trial was preregistered on clinicaltrials.gov (NCT04004403).
Acknowledgments
The authors would like to thank the study participants for their time and effort in participating in the trial. This study was supported by R01DK119783 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding: National Institutes of Health, NIDDK (R01DK119783).
Author contributions
M.E. designed the research, conducted the clinical trial, and wrote the manuscript. K.G., S.C., F.K., S.L., and V.P. assisted with the conduction of the clinical trial. S.K. assisted with recruitment. S.J.A. performed the statistical analysis. K.A.V., Z.S., L.T.-H., and J.M.H. designed the research and wrote the manuscript. All authors helped interpret the data, revised the manuscript for critical content, and approved the final version of the manuscript.
Declaration of interests
K.A.V. received author fees from Hachette Book Group for the book The Every Other Day Diet.
Inclusion and diversity
We support inclusive, diverse, and equitable conduct of research.
Supplemental information (3)
Document S1. Figures S1 and S2 and Tables S1
Data S1. Unprocessed data underlying the display items in the manuscript, related to Figures 2, 3, and 4
Document S2. Article plus supplemental information
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