Effect of Intermittent Calorie Restriction on NAFLD Patients With Disorders of Glucose Metabolism

• ClinicalTrials.gov Identifier: NCT04283942
• Recruitment Status: Completed
• First Posted: February 25, 2020
• Last Update Posted: August 10, 2022
• Sponsor: Shanghai Zhongshan Hospital
• Information provided by (Responsible Party): Hua Bian, Shanghai Zhongshan Hospital

Study Description

Brief Summary:

This study is designed to observe the effect of 5:2 intermittent calorie restriction (fasting 2 days each week) on liver fat content in NAFLD patients with abnormal blood glucose.

Condition or disease	Intervention/treatment	Phase
Non-Alcoholic Fatty Liver Disease (NAFLD); Disorders of Glucose Metabolism; Type 2 Diabetes; Impaired Glucose Regulation	Behavioral: Intermittent calorie restriction; Behavioral: 25kcal/kg/d diet	Not Applicable

Detailed Description:

Intermittent caloric restriction (ICR) can effectively reduce weight and facilitate blood glucose control, but whether it can be applied for clinical treatment to non-alcoholic fatty liver disease (NAFLD) patients remains unclear. What's more, in order to investigate whether the mechanism of glucose-lowering effect of ICR is related to the decrease of liver fat content, we intend to carry out this study in NAFLD patients with abnormal glucose metabolism. It is an open-labeled randomized trial designed to observe the effect of 5:2 intermittent calorie restriction (fasting 2 days each week) on liver fat content in NAFLD patients with abnormal blood glucose. 50 patients will be randomly divided into ICR group and control group for 12 weeks of intervention. ICR group: during the 2-day fasting-mimicking period each week, the food based on plant ingredients will be served (4 pieces of nutrition bars / day, 1:2:1 for breakfast, lunch and dinner, 124.4kcal / piece, 497.2kcal / day in total). In the rest 5 days each week, subjects are allowed ad libitum to their usual food. Control group: under the guidance of nutritionist, subjects have to learn the method of food calories calculation. The daily calories intake for control group should be: 25 kcal / kg × standard weight [kg, male: height (cm) - 105, female: height (cm) - 100]. Daily food diary is required in both groups. During the experiment, all subjects should maintain their exercise routine. The use of drugs affecting blood glucose and fatty liver should be avoided. After 12 weeks of intervention, the changes of liver fat content were evaluated by magnetic resonance spectroscopy (MRS). The effects of ICR on body weight, blood glucose and body fat distribution will also be evaluated. Both groups will be followed up on their changes of weight 4 weeks after intervention.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

Patients were randomly divided into intermittent calorie restriction group and control group for 12 weeks of intervention. Both groups will be followed up 4 weeks after intervention.

ICR group: during the 2-day fasting-mimicking period each week, the food based on plant ingredients will be served (4 pieces of nutrition bars / day, 1:2:1 for breakfast, lunch and dinner, 124.4kcal/piece, 497.2kcal / day in total). In the rest 5 days each week, subjects are allowed ad libitum to their usual food.

Control group: under the guidance of nutritionist, subjects have to learn the method of food calories calculation. For each day, the daily calories intake = 25 kcal / kg × standard weight [kg, estimated by height (cm) - 100].

• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effect of Intermittent Calorie Restriction on Non-alcoholic Fatty Liver Disease Patients With Disorders of Glucose Metabolism
• Actual Study Start Date: July 30, 2020
• Actual Primary Completion Date: July 25, 2021
• Actual Study Completion Date: July 25, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Intermittent Calorie Restriction (ICR); Eat only instant nutrition bar in two consecutive days each week, 4 sticks / day, 1 for breakfast, 2 for lunch, 1 for dinner. And the total caloric intake is 497.2kcal/day. In the rest 5 days each week, subjects are allowed ad libitum to their usual food.	Behavioral: Intermittent calorie restriction; Intermittent calorie restriction is a new strategy of reducing weight and improving health. The most common ICR methods include alternative day calorie restriction (ACR) and 5:2 intermittent fasting (fasting 2 days each week). The food consumption in non-fasting day is not limited. We plan to apply the 5:2 intermittent fasting. Intermittent caloric restriction can effectively reduce weight, improve body composition (i.e., reduce fat content while maintaining lean body weight), reduce risk factors of cardiovascular disease (including reducing blood pressure, improving blood lipid level, reducing oxidative stress), and also facilitate blood glucose control (by increasing insulin sensitivity and improving the function of islet β cells).; Other Name: Intermittent fasting
Control; Followed by NAFLD guidelines' recommendation of 25 kcal / kg / day, we only ask them to adjust their daily diet. No experimental foods or drugs are supplied.	Behavioral: 25kcal/kg/d diet; For each day, the daily calories intake = 25 kcal / kg × standard weight [kg, estimated by height (cm) - 100].

Outcome Measures

Primary Outcome Measures :

1. Change of liver fat content in % [ Time Frame: 12 weeks ]
   Change of liver fat content in %

Secondary Outcome Measures :

1. Change of weight [ Time Frame: 12 weeks ]
   Change of weight in kilograms
2. Change of blood glucose: fasting blood glucose [ Time Frame: 12 weeks ]
   Change of fasting blood glucose in mmol/L
3. Change of blood glucose: 2h postload blood glucose [ Time Frame: 12 weeks ]
   Change of 2h postload blood glucose in mmol/L
4. Change of HbA1c [ Time Frame: 12 weeks ]
   Change of HbA1c in %
5. Change of liver enzymes: alanine aminotransferase [ Time Frame: 12 weeks ]
   Change of alanine aminotransferase in U/L
6. Change of liver enzymes: aspartate aminotransferase [ Time Frame: 12 weeks ]
   Change of aspartate aminotransferase in U/L
7. Change of liver enzymes: γ-glutamyl transpeptidase [ Time Frame: 12 weeks ]
   Change of γ-glutamyl transpeptidase in U/L
8. Change of lipid profile: total cholesterol [ Time Frame: 12 weeks ]
   Change of total cholesterol in mmol/L
9. Change of lipid profile: triglyceride [ Time Frame: 12 weeks ]
   Change of triglyceride in mmol/L
10. Change of lipid profile: high-density lipoprotein-cholesterol [ Time Frame: 12 weeks ]
    Change of high-density lipoprotein-cholesterol in mmol/L
11. Change of lipid profile: low-density lipoprotein-cholesterol [ Time Frame: 12 weeks ]
    Change of low-density lipoprotein-cholesterol in mmol/L
12. Change of lipid profile: free fatty acid [ Time Frame: 12 weeks ]
    Change of free fatty acid in mmol/L

Other Outcome Measures:

1. Change of body fat percentage [ Time Frame: 12 weeks ]
   measured by InBody520, body fat percentage in % adipose tissue [SAT])
2. Change of skeletal muscle mass [ Time Frame: 12 weeks ]
   measured by InBody520, skeletal muscle mass in kilograms
3. Change of abdominal adiposity [ Time Frame: 12 weeks ]
   measured by MRI, visceral adipose tissue and subcutaneous adipose tissue, all in square centimetres.
4. Change of liver stiffness measure of liver transient elastography [ Time Frame: 12 weeks ]
   Change of liver stiffness measure of liver transient elastography, in kPa
5. Change of insulin sensitivity [ Time Frame: 12 weeks ]
   Change of HOMA-IR (fasting glucose in mmol/L x fasting insulin in μU/mL)/22.5)
6. Change of fasting insulin [ Time Frame: 12 weeks ]
   Change of fasting insulin in μU/mL
7. Change of brain functional MRI [ Time Frame: 12 weeks ]
   Brain functional MRI will be used to evaluate the neural activity of the brain

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age 18-70
2. diagnosed as fatty liver
3. BMI≥24 kg/m2

4. The diagnostic criteria for abnormal glucose metabolism are as follows (meeting at least one):

   1. Impaired glucose regulation: fasting blood glucose ≥ 5.6 mmol / L, postprandial blood glucose ≥ 7.8 mmol / L or HbA1c ≥ 5.7%.
   2. Diabetes mellitus: diabetic symptoms + plasma glucose concentration ≥ 11.1 mmol / L at any time or fasting plasma glucose concentration ≥ 7.0 mmol / L or OGTT 2 h plasma glucose concentration ≥ 11.1 mmol / L.

Exclusion Criteria:

1. Type 1 diabetes, gestational diabetes and other special types of diabetes
2. Poor blood glucose control, HbA1c > 8.5% within 3 months
3. Had antidiabetic drugs in the past month
4. Serum ALT was more than 6 times of normal upper limit
5. Excessive alcohol consumption (definition: in the past 6 months, alcohol intake: men > 140g, women > 70g)
6. Other liver diseases: such as acute and chronic viral hepatitis, drug-induced hepatitis, immune hepatitis, liver cirrhosis, liver cancer, etc
7. Had drugs that may affect NAFLD in the past three months, such as vitamin E
8. Biliary diseases: biliary obstructive diseases, etc
9. Other diseases affecting glycolipid metabolism: hyperthyroidism, hypothyroidism, Cushing's syndrome, etc
10. Chronic kidney disease (serum creatinine ≥ 2.0mg/dl)
11. Life expectancy of no more than 5 years
12. Already pregnant or plan to be pregnant in the near future
13. Mental illness
14. Other conditions affecting follow-up
15. Participated in other clinical trials in the past 4 weeks
16. Absent of informed consent

Contacts and Locations

Locations

China

Zhongshan Hospital, Fudan University

Shanghai, China

Sponsors and Collaborators

Shanghai Zhongshan Hospital

Investigators

• Principal Investigator: Hua Bian; Shanghai Zhongshan Hospital
• Study Director: Xin Gao; Shanghai Zhongshan Hospital

More Information

Publications:

Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016 Jul;64(1):73-84. doi: 10.1002/hep.28431. Epub 2016 Feb 22.

Fan JG, Kim SU, Wong VW. New trends on obesity and NAFLD in Asia. J Hepatol. 2017 Oct;67(4):862-873. doi: 10.1016/j.jhep.2017.06.003. Epub 2017 Jun 19.

Fan JG. Epidemiology of alcoholic and nonalcoholic fatty liver disease in China. J Gastroenterol Hepatol. 2013 Aug;28 Suppl 1:11-7. doi: 10.1111/jgh.12036.

Wang FS, Fan JG, Zhang Z, Gao B, Wang HY. The global burden of liver disease: the major impact of China. Hepatology. 2014 Dec;60(6):2099-108. doi: 10.1002/hep.27406. Epub 2014 Oct 29.

Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002 Apr 18;346(16):1221-31. doi: 10.1056/NEJMra011775. No abstract available.

Ballestri S, Zona S, Targher G, Romagnoli D, Baldelli E, Nascimbeni F, Roverato A, Guaraldi G, Lonardo A. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol. 2016 May;31(5):936-44. doi: 10.1111/jgh.13264.

Vozarova B, Stefan N, Lindsay RS, Saremi A, Pratley RE, Bogardus C, Tataranni PA. High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes. Diabetes. 2002 Jun;51(6):1889-95. doi: 10.2337/diabetes.51.6.1889.

Armstrong MJ, Adams LA, Canbay A, Syn WK. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology. 2014 Mar;59(3):1174-97. doi: 10.1002/hep.26717. Epub 2014 Jan 16.

Musso G, Gambino R, Tabibian JH, Ekstedt M, Kechagias S, Hamaguchi M, Hultcrantz R, Hagstrom H, Yoon SK, Charatcharoenwitthaya P, George J, Barrera F, Hafliethadottir S, Bjornsson ES, Armstrong MJ, Hopkins LJ, Gao X, Francque S, Verrijken A, Yilmaz Y, Lindor KD, Charlton M, Haring R, Lerch MM, Rettig R, Volzke H, Ryu S, Li G, Wong LL, Machado M, Cortez-Pinto H, Yasui K, Cassader M. Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLoS Med. 2014 Jul 22;11(7):e1001680. doi: 10.1371/journal.pmed.1001680. eCollection 2014 Jul.

Huang MA, Greenson JK, Chao C, Anderson L, Peterman D, Jacobson J, Emick D, Lok AS, Conjeevaram HS. One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study. Am J Gastroenterol. 2005 May;100(5):1072-81. doi: 10.1111/j.1572-0241.2005.41334.x.

Sundfor TM, Svendsen M, Tonstad S. Intermittent calorie restriction-a more effective approach to weight loss? Am J Clin Nutr. 2018 Nov 1;108(5):909-910. doi: 10.1093/ajcn/nqy288. No abstract available.

Wei M, Brandhorst S, Shelehchi M, Mirzaei H, Cheng CW, Budniak J, Groshen S, Mack WJ, Guen E, Di Biase S, Cohen P, Morgan TE, Dorff T, Hong K, Michalsen A, Laviano A, Longo VD. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med. 2017 Feb 15;9(377):eaai8700. doi: 10.1126/scitranslmed.aai8700.

Cheng CW, Villani V, Buono R, Wei M, Kumar S, Yilmaz OH, Cohen P, Sneddon JB, Perin L, Longo VD. Fasting-Mimicking Diet Promotes Ngn3-Driven beta-Cell Regeneration to Reverse Diabetes. Cell. 2017 Feb 23;168(5):775-788.e12. doi: 10.1016/j.cell.2017.01.040.

Johari MI, Yusoff K, Haron J, Nadarajan C, Ibrahim KN, Wong MS, Hafidz MIA, Chua BE, Hamid N, Arifin WN, Ma ZF, Lee YY. A Randomised Controlled Trial on the Effectiveness and Adherence of Modified Alternate-day Calorie Restriction in Improving Activity of Non-Alcoholic Fatty Liver Disease. Sci Rep. 2019 Aug 2;9(1):11232. doi: 10.1038/s41598-019-47763-8. Erratum In: Sci Rep. 2020 Jun 25;10(1):10599.

Schubel R, Nattenmuller J, Sookthai D, Nonnenmacher T, Graf ME, Riedl L, Schlett CL, von Stackelberg O, Johnson T, Nabers D, Kirsten R, Kratz M, Kauczor HU, Ulrich CM, Kaaks R, Kuhn T. Effects of intermittent and continuous calorie restriction on body weight and metabolism over 50 wk: a randomized controlled trial. Am J Clin Nutr. 2018 Nov 1;108(5):933-945. doi: 10.1093/ajcn/nqy196.

Liu M, Yan HM, Gao X, Gao J. [Association of abnormality of liver enzymes and metabolic syndrome in patients with nonalcoholic fatty liver disease]. Zhonghua Yi Xue Za Zhi. 2007 Jan 23;87(4):253-5. Chinese.

• Responsible Party: Hua Bian, Director, Shanghai Zhongshan Hospital
• ClinicalTrials.gov Identifier: NCT04283942
• Other Study ID Numbers: B2019-256R
• First Posted: February 25, 2020
• Last Update Posted: August 10, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Hua Bian, Shanghai Zhongshan Hospital:

Non-Alcoholic Fatty Liver Disease; Type 2 Diabetes

Additional relevant MeSH terms:

Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Diabetes Mellitus; Metabolic Diseases; Endocrine System Diseases; Digestive System Diseases