Effect of Intermittent Calorie Restriction on MASLD Patients With Abnormal Glucose Metabolism

Effect of Intermittent Calorie Restriction on Metabolic Dysfunction-Associated Steatotic Liver Disease Patients With Abnormal Glucose Metabolism

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04283942

Enrollment

Registered

2020-02-25

Start date

2020-07-30

Completion date

2021-07-25

Last updated

2024-09-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Fatty Liver Disease, Impaired Glucose Regulation, Type 2 Diabetes

Keywords

Metabolic dysfunction-associated steatotic liver disease, Type 2 Diabetes

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 MASLD patients with abnormal blood glucose.

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 metabolic dysfunction-associated steatotic liver disease (MASLD) patients remains unclear. We intend to carry out this study in MASLD 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 MASLD patients with abnormal blood glucose. 60 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 (continuous calorie restriction, CCR): 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 × \[height (cm) - 100\] kg. 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) and Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF). The effects of ICR on body weight, blood glucose and body fat will also be evaluated. Both groups will be followed up on their changes of weight 4 weeks after intervention.

Interventions

BEHAVIORALIntermittent calorie restriction (ICR)

Participants in ICR group were instructed to ensure 2 successive days of fasting-mimicking and 5 days of recovery per week. On fasting-mimicking days, the participants were instructed to consume approximately 500 kcal/day and they were provided with plant-based meal replacement to improve adherence and ensured adequate intake of micronutrients. In the rest 5 days of recovery per week, participants were allowed to consume their usual diet. Participants will receive dietary counseling from experienced nutritionists and eat a balanced diet (macronutrient distribution of approximately 10-15% protein, 55-65% carbohydrate and 20-30% fat).They are required to write daily dietary log. Besides, they are required to maintain their exercise routines and record their daily steps using a unified pedometer (Redmi Smart Band, Xiaomi Corporation, China). The use of drugs affecting blood glucose and LFC will be avoided.

BEHAVIORALContinuous calorie restriction (CCR)

Participants in CCR group were instructed to consume the prescribed calories (25 kcal / kg × \[height (cm) - 100\] kg) every day by eating conventional food without time restriction. Participants will receive dietary counseling from experienced nutritionists and eat a balanced diet (macronutrient distribution of approximately 10-15% protein, 55-65% carbohydrate and 20-30% fat).They are required to write daily dietary log. Besides, they are required to maintain their exercise routines and record their daily steps using a unified pedometer (Redmi Smart Band, Xiaomi Corporation, China). The use of drugs affecting blood glucose and LFC will be avoided.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

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: continuous calorie restriction (CCR). Under the guidance of nutritionist, subjects have to learn the method of food calories calculation. For each day, the daily calories intake is limited to 25 kcal / kg × standard weight \[kg, estimated by height (cm) - 100\].

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

Healthy volunteers

Inclusion criteria

* Age 18-70 * Diagnosed as fatty liver by ultrasound or magnetic resonance imaging * BMI ≥ 24 kg/m2 * abnormal glucose metabolism: (meeting at least one): 1. Impaired glucose regulation: fasting blood glucose ≥ 100 mg/dL, postprandial blood glucose ≥ 140 mg/dL or HbA1c ≥ 5.7% 2. Diabetes mellitus: diabetic symptoms + plasma glucose concentration ≥ 200 mg/dL at any time or fasting plasma glucose concentration ≥ 100 mg/dL or OGTT 2 h plasma glucose concentration ≥ 200 mg/dL

Exclusion criteria

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

Design outcomes

Primary

Measure	Time frame	Description
Change of Liver Fat Content in %	From baseline to week 12	Change of liver fat content in %.

Secondary

Measure	Time frame	Description
Change of Blood Glucose: Fasting Blood Glucose	From baseline to week 12	Change of fasting blood glucose in mg/dL.
Change of Blood Glucose: 2h Postload Blood Glucose	From baseline to week 12	Change of 2h postload blood glucose in mg/dL.
Change of HbA1c	From baseline to week 12	Change of HbA1c in %.
Change of Liver Enzymes: Alanine Aminotransferase	From baseline to week 12	Change of alanine aminotransferase in U/L.
Change of Liver Enzymes: Aspartate Aminotransferase	From baseline to week 12	Change of aspartate aminotransferase in U/L.
Change of Liver Enzymes: γ-glutamyl Transpeptidase	From baseline to week 12	Change of γ-glutamyl transpeptidase in U/L.
Change of Lipid Profile: Total Cholesterol	From baseline to week 12	Change of total cholesterol in mg/dL.
Change of Lipid Profile: Triglyceride	From baseline to week 12	Change of triglyceride in mg/dL.
Change of Weight	From baseline to week 12	Change of weight in kilograms.
Change of Lipid Profile: Low-density Lipoprotein-cholesterol	From baseline to week 12	Change of low-density lipoprotein-cholesterol in mg/dL.
Change of Lipid Profile: Free Fatty Acid	From baseline to week 12	Change of free fatty acid in mg/dL.
Change of Lipid Profile: High-density Lipoprotein-cholesterol	From baseline to week 12	Change of high-density lipoprotein-cholesterol in mg/dL.

Other

Measure	Time frame	Description
Change of Lean Mass	From baseline to week 12	measured by bioimpedance analyzer, skeletal muscle mass in kilograms.
Change of Abdominal Adipose Tissue Area	From baseline to week 12	measured by MRI, including visceral adipose and subcutaneous adipose, all in square centimeter.
Change of Liver Stiffness Measure of Liver Transient Elastography	From baseline to week 12	Change of liver stiffness measure of liver transient elastography, in kPa.
Change of Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Index	From baseline to week 12	Change of HOMA-IR index from baseline to week 12. HOMA-IR index was calculated as fasting serum insulin (μU/ml) × fasting plasma glucose (mmol/l)/22.5. A HOMA-IR index higher than 75th quartile of non diabetes subjects is considered to be insulin resistance. However, due to differences in race, gender and research subjects, there is currently no recognized cut-off point. The cut-off values of HOMA-IR reported in previous studies varied greatly. A study on Caucasian non diabetes population showed that the cut-off value is 2.29. And a Chinese study proposed that the cut-off value of population over 40 years old in Shanghai was 4.31 for men and 4.51 for women.
Change of Fasting Insulin	From baseline to week 12	Change of fasting insulin in μU/mL.
Change of Fat Mass	From baseline to week 12	measured by bioimpedance analyzer, fat mass in kilograms.

Countries

China

Participant flow

Participants by arm

Arm	Count
Intermittent Calorie Restriction (ICR) Intermittent calorie restriction (ICR): Participants in ICR group were instructed to ensure 2 successive days of fasting-mimicking and 5 days of recovery per week. On fasting-mimicking days, the participants were instructed to consume approximately 500 kcal/day and they were provided with plant-based meal replacement to improve adherence and ensured adequate intake of micronutrients. In the rest 5 days of recovery per week, participants were allowed to consume their usual diet. Participants will receive dietary counseling from experienced nutritionists and eat a balanced diet (macronutrient distribution of approximately 10-15% protein, 55-65% carbohydrate and 20-30% fat). They are required to write daily dietary log. Besides, they are required to maintain their exercise routines and record their daily steps using a unified pedometer (Redmi Smart Band, Xiaomi Corporation, China). The use of drugs affecting blood glucose and LFC will be avoided.	30
Control (Continuous Calorie Restriction, CCR) Continuous calorie restriction (CCR): Participants in CCR group were instructed to consume the prescribed calories (25 kcal / kg × \[height (cm) - 100\] kg) every day by eating conventional food without time restriction. Participants will receive dietary counseling from experienced nutritionists and eat a balanced diet (macronutrient distribution of approximately 10-15% protein, 55-65% carbohydrate and 20-30% fat). They are required to write daily dietary log. Besides, they are required to maintain their exercise routines and record their daily steps using a unified pedometer (Redmi Smart Band, Xiaomi Corporation, China). The use of drugs affecting blood glucose and LFC will be avoided.	30
Total	60

Baseline characteristics

Characteristic	Total	Intermittent Calorie Restriction (ICR)	Control (Continuous Calorie Restriction, CCR)
2h postprandial plasma glucose	188.5 mg/dL STANDARD_DEVIATION 78.1	205.9 mg/dL STANDARD_DEVIATION 74.2	171.2 mg/dL STANDARD_DEVIATION 79.6
Age, Continuous	47.9 years STANDARD_DEVIATION 10.9	49.3 years STANDARD_DEVIATION 10.7	46.5 years STANDARD_DEVIATION 11.1
Alanine aminotransferase	44.3 U/L STANDARD_DEVIATION 32.1	51.5 U/L STANDARD_DEVIATION 38.6	37.1 U/L STANDARD_DEVIATION 22.4
Aspartate aminotransferase	28.3 U/L STANDARD_DEVIATION 15.2	32.3 U/L STANDARD_DEVIATION 18.3	24.3 U/L STANDARD_DEVIATION 10.2
Body mass index	30.0 kg/m2 STANDARD_DEVIATION 4.5	29.0 kg/m2 STANDARD_DEVIATION 3.2	31.1 kg/m2 STANDARD_DEVIATION 5.3
Comorbidities Hyperlipidaemia	14 Participants	8 Participants	6 Participants
Comorbidities Hypertension	19 Participants	11 Participants	8 Participants
Comorbidities Impaired glucose regulation	36 Participants	16 Participants	20 Participants
Comorbidities Type 2 diabetes	24 Participants	14 Participants	10 Participants
Concomitant drug use Anti-hypertensive	14 Participants	8 Participants	6 Participants
Concomitant drug use Anti-lipidaemic	6 Participants	4 Participants	2 Participants
Controlled attenuation parameter	317.9 dB/m STANDARD_DEVIATION 43.1	315.7 dB/m STANDARD_DEVIATION 43.9	320.2 dB/m STANDARD_DEVIATION 42.9
Diastolic blood pressure	81.8 mmHg STANDARD_DEVIATION 10.6	82.1 mmHg STANDARD_DEVIATION 11.1	81.4 mmHg STANDARD_DEVIATION 10.2
Duration of MASLD	9.2 years STANDARD_DEVIATION 8.1	9.7 years STANDARD_DEVIATION 8.8	8.6 years STANDARD_DEVIATION 7.5
Fasting insulin	21.3 μU/mL STANDARD_DEVIATION 13.8	19.0 μU/mL STANDARD_DEVIATION 11.8	23.5 μU/mL STANDARD_DEVIATION 15.4
Fasting plasma glucose	113.8 mg/dL STANDARD_DEVIATION 19.6	115.6 mg/dL STANDARD_DEVIATION 22	111.8 mg/dL STANDARD_DEVIATION 17.1
Fat mass	29.8 kg STANDARD_DEVIATION 8.9	27.9 kg STANDARD_DEVIATION 7.2	31.8 kg STANDARD_DEVIATION 10.1
Free fatty acids	15.5 mg/dL STANDARD_DEVIATION 5.7	17.2 mg/dL STANDARD_DEVIATION 5.9	14.1 mg/dL STANDARD_DEVIATION 4.8
HbA1c	6.1 % STANDARD_DEVIATION 0.7	6.2 % STANDARD_DEVIATION 0.8	5.9 % STANDARD_DEVIATION 0.6
HDL cholesterol	45.3 mg/dL STANDARD_DEVIATION 10.8	44.8 mg/dL STANDARD_DEVIATION 6.9	45.9 mg/dL STANDARD_DEVIATION 13.9
Height	167.2 cm STANDARD_DEVIATION 8.7	165.4 cm STANDARD_DEVIATION 8.3	168.9 cm STANDARD_DEVIATION 8.8
Homeostasis model assessment of insulin resistance (HOMA-IR) index	6.0 index STANDARD_DEVIATION 4.1	5.5 index STANDARD_DEVIATION 4	6.4 index STANDARD_DEVIATION 4.2
LDL cholesterol	108.9 mg/dL STANDARD_DEVIATION 28.2	107.3 mg/dL STANDARD_DEVIATION 30.1	110.0 mg/dL STANDARD_DEVIATION 26.6
Lean mass	54.1 kg STANDARD_DEVIATION 11.7	51.5 kg STANDARD_DEVIATION 10	57 kg STANDARD_DEVIATION 12.8
Liver fat content by 1H-MRS	38.1 % STANDARD_DEVIATION 16	37.7 % STANDARD_DEVIATION 16.2	38.5 % STANDARD_DEVIATION 16.1
Liver fat content by Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) Couinaud Segment 1	13.1 % STANDARD_DEVIATION 7.1	13.1 % STANDARD_DEVIATION 7.2	13.1 % STANDARD_DEVIATION 7.3
Liver fat content by Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) Couinaud Segment 2	13.1 % STANDARD_DEVIATION 7.1	12.9 % STANDARD_DEVIATION 6.8	13.4 % STANDARD_DEVIATION 7.7
Liver fat content by Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) Couinaud Segment 3	13.7 % STANDARD_DEVIATION 7.4	13.5 % STANDARD_DEVIATION 7.3	13.9 % STANDARD_DEVIATION 7.7
Liver fat content by Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) Couinaud Segment 4	13.6 % STANDARD_DEVIATION 7.3	13.4 % STANDARD_DEVIATION 7.2	13.9 % STANDARD_DEVIATION 7.6
Liver fat content by Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) Couinaud Segment 5	14.1 % STANDARD_DEVIATION 7.8	13.9 % STANDARD_DEVIATION 7.6	14.5 % STANDARD_DEVIATION 8.3
Liver fat content by Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) Couinaud Segment 6	13.7 % STANDARD_DEVIATION 7.7	13.6 % STANDARD_DEVIATION 7.6	13.9 % STANDARD_DEVIATION 8
Liver fat content by Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) Couinaud Segment 7	14.1 % STANDARD_DEVIATION 7.4	13.9 % STANDARD_DEVIATION 7.3	14.4 % STANDARD_DEVIATION 7.8
Liver fat content by Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) Couinaud Segment 8	14.4 % STANDARD_DEVIATION 7.6	14.0 % STANDARD_DEVIATION 7.3	14.9 % STANDARD_DEVIATION 8.1
Liver fat content by Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) Whole liver	14.0 % STANDARD_DEVIATION 7.5	13.7 % STANDARD_DEVIATION 7.3	14.3 % STANDARD_DEVIATION 7.9
Liver stiffness	6.0 kPa STANDARD_DEVIATION 1.7	6.2 kPa STANDARD_DEVIATION 1.8	5.8 kPa STANDARD_DEVIATION 1.4
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	60 Participants	30 Participants	30 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	0 Participants	0 Participants	0 Participants
Region of Enrollment China	60 participants	30 participants	30 participants
Sex: Female, Male Female	24 Participants	14 Participants	10 Participants
Sex: Female, Male Male	36 Participants	16 Participants	20 Participants
Subcutaneous adipose area	325.4 cm2 STANDARD_DEVIATION 105.2	315.5 cm2 STANDARD_DEVIATION 82.4	335.5 cm2 STANDARD_DEVIATION 125.2
Systolic blood pressure	134.8 mmHg STANDARD_DEVIATION 16.8	135.4 mmHg STANDARD_DEVIATION 17.2	134.3 mmHg STANDARD_DEVIATION 16.6
Total cholesterol	186.1 mg/dL STANDARD_DEVIATION 31.7	182.6 mg/dL STANDARD_DEVIATION 33.2	189.6 mg/dL STANDARD_DEVIATION 29.7
Triglycerides	168.2 mg/dL STANDARD_DEVIATION 114.2	152.2 mg/dL STANDARD_DEVIATION 68.1	184.1 mg/dL STANDARD_DEVIATION 146
Visceral adipose area	195.0 cm2 STANDARD_DEVIATION 55.8	194.4 cm2 STANDARD_DEVIATION 56.4	195.7 cm2 STANDARD_DEVIATION 56.2
Waist circumference	98.9 cm STANDARD_DEVIATION 10.6	97.6 cm STANDARD_DEVIATION 7.5	100.3 cm STANDARD_DEVIATION 13
Weight	84.0 kg STANDARD_DEVIATION 16.5	79.4 kg STANDARD_DEVIATION 11.4	88.6 kg STANDARD_DEVIATION 19.5
γ-Glutamyl transpeptidase	37.9 U/L STANDARD_DEVIATION 22.4	39.6 U/L STANDARD_DEVIATION 24.6	36.2 U/L STANDARD_DEVIATION 20.3

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 30	0 / 30
other Total, other adverse events	8 / 30	0 / 30
serious Total, serious adverse events	0 / 30	0 / 30