Non-Alcoholic Fatty Liver Disease, Obesity
Conditions
Brief summary
Approximately 65% of obese individuals have non-alcoholic fatty liver disease (NAFLD), and this condition is strongly related to the development of insulin resistance and diabetes. Innovative lifestyle strategies to treat NAFLD are critically needed. The proposed research will demonstrate that alternate day fasting (ADF) combined with exercise is an effective non-pharmacological therapy to treat NAFLD.
Detailed description
Nonalcoholic fatty liver disease (NAFLD) is characterized by an accumulation of fat in the liver (not resulting from excessive alcohol consumption). Approximately 65% of obese individuals have NAFLD, and this condition is strongly related to the development of insulin resistance and type 2 diabetes. While certain pharmacological agents have been shown to reduce liver fat (i.e. thiazolidinediones), there is mounting concern regarding the safety and weight-gaining effects of these compounds. In light of this, recent research has focused on non-pharmacological lifestyle therapies to reduce hepatic steatosis, such as daily calorie restriction combined with aerobic exercise. Evidence from clinical trials suggest that this combination is an effective lifestyle therapy improve liver fat content and hepatic insulin sensitivity. More recently, it's been shown that intermittent fasting may produce even greater improvements in hepatic steatosis and hepatic insulin sensitivity, when compared to conventional calorie restriction. For instance, intrahepatic lipid accumulation was lower and insulin sensitivity was higher in mice fasted every other day, when compared to mice who were energy restricted every day. Moreover, data from human trials show that adults with obesity experience greater decreases in insulin and insulin resistance with intermittent fasting versus daily restriction. These findings suggest that intermittent fasting may be a more effective diet therapy to reduce hepatic steatosis and improve insulin sensitivity, when compared to daily calorie restriction. Although these findings are very promising, these data still require confirmation by a randomized controlled clinical trial.
Interventions
OTHERExercise
The exercise intervention involves supervised aerobic exercise program 5 times per week, 40-60 min per session, 60-85% HRmax.
The diet involves consuming 600 kcal on the fast day and eat ad libitum at home on alternating feed days.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Illinois at Chicago
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Age between 18 to 65 years old * BMI between 30.0 and 59.9 kg/m2 * NAFLD (hepatic steatosis ≥ 5% confirmed by MRI-PDFF) * Sedentary (\<20 min, 2x/week of light activity at 3-4 metabolic equivalents (METs) for 3 mo prior to study)
Exclusion criteria
* Have chronic liver disease other than NAFLD (hepatitis B or C, primary biliary cirrhosis, sclerosing cholangitis, autoimmune hepatitis, hemochromatosis, Wilson's disease, α1-antitrypsin deficiency) * Consume excessive amounts of alcohol women: 70 g of ethanol (5 alcoholic drinks per week) and men 140 g of ethanol (10 drinks per week) in the past 6 months) * Have a history of known cardiovascular, pulmonary or renal disease * Diagnosed T1DM or T2DM * Are not weight stable for 3 months prior to the beginning of study (weight gain or loss \> 4 kg) * Are claustrophobic or have implanted metallic/electrical devices (e.g. cardiac pacemaker, neuro-stimulator) * Are taking drugs that induce steatosis (e.g. corticosteroids, estrogens, methotrexate, Ca channel blockers) * Are taking drugs that benefit NAFLD (e.g. betaine, pioglitazone, rosiglitazone, metformin, or gemifibrozil) * Are taking drugs that influence study outcomes (weight loss medications) * Are perimenopausal or have an irregular menstrual cycle (menses that does not appear every 27-32 days) * Are pregnant, or trying to become pregnant * Are smokers
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hepatic Steatosis | Change from week 1 to week 12 | Hepatic steatosis will be measured by magnetic resonance imaging (MRI-PDFF) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Alanine Aminotransferase (ALT) | Change from week 1 to week 12 | Measured by a commercial lab (Medstar, Inc) |
| Change in Aspartate Aminotransferase (AST) | Change from week 1 to week 12 | Measured by a commercial lab (Medstar, Inc) |
| Change in Fasting Glucose | Change from week 1 to week 12 | Measured by a commercial lab (Medstar, Inc) |
| Change in Body Weight | Change from week 1 to week 12 | Measured by digital scale |
| Change in Insulin Resistance | Change from week 1 to week 12 | Measured by Homeostatic model assessment of insulin resistance (HOMA-IR). The HOMA-IR value was calculated using the formula: \[HOMA-IR = glucose (mg/dL) × insulin (mU/L)/405\]. Interpretation of HOMA-IR Scores: \< 1.0: Normal insulin sensitivity; 1.0-1.9: Mild insulin resistance; \> 2.0: Moderate to severe insulin resistance. |
| Change in HbA1c | Change from week 1 to week 12 | Measured by a commercial lab (Medstar, Inc) |
| Change in Fasting Insulin | Change from week 1 to week 12 | Measured by a commercial lab (Medstar, Inc) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Alternate Day Fasting These participants will consume 600 kcal on the fast day and eat ad libitum at home on alternating feed days.
Alternate day fasting: The diet involves consuming 600 kcal on the fast day and eat ad libitum at home on alternating feed days. | 20 |
| Exercise These participants will participate in a supervised aerobic exercise program 5 times per week, 40-60 min per session, 60-85% HRmax.
Exercise: The exercise intervention involves supervised aerobic exercise program 5 times per week, 40-60 min per session, 60-85% HRmax. | 20 |
| Combination Alternate Day Fasting Plus Exercise These participants will consume 600 kcal on the fast day and eat ad libitum at home on alternating feed days. They will also participate in a supervised aerobic exercise program 5 times per week, 40-60 min per session, 60-85% HRmax.
Alternate day fasting: The diet involves consuming 600 kcal on the fast day and eat ad libitum at home on alternating feed days.
Exercise: The exercise intervention involves supervised aerobic exercise program 5 times per week, 40-60 min per session, 60-85% HRmax. | 20 |
| Control Controls will be instructed to maintain their weight throughout the trial, and not to change eating or physical activity habits. | 20 |
| Total | 80 |
Baseline characteristics
| Characteristic | Control | Total | Exercise | Combination Alternate Day Fasting Plus Exercise | Alternate Day Fasting |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 80 Participants | 20 Participants | 20 Participants | 20 Participants |
| Age, Continuous | 44 years STANDARD_DEVIATION 12 | 44 years STANDARD_DEVIATION 13 | 44 years STANDARD_DEVIATION 13 | 44 years STANDARD_DEVIATION 13 | 44 years STANDARD_DEVIATION 16 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 7 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 24 Participants | 6 Participants | 7 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 49 Participants | 14 Participants | 12 Participants | 10 Participants |
| Region of Enrollment United States | 20 participants | 80 participants | 20 participants | 20 participants | 20 participants |
| Sex: Female, Male Female | 16 Participants | 65 Participants | 16 Participants | 17 Participants | 16 Participants |
| Sex: Female, Male Male | 4 Participants | 15 Participants | 4 Participants | 3 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 0 / 20 | 0 / 20 | 0 / 20 | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 | 0 / 20 | 0 / 20 |
Outcome results
Primary
Change in Hepatic Steatosis
Hepatic steatosis will be measured by magnetic resonance imaging (MRI-PDFF)
Time frame: Change from week 1 to week 12
Population: Adults with obesity and NAFLD
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Alternate Day Fasting | Change in Hepatic Steatosis | -2.25 liver fat percentage |
| Exercise | Change in Hepatic Steatosis | -1.3 liver fat percentage |
| Combination Alternate Day Fasting Plus Exercise | Change in Hepatic Steatosis | -5.48 liver fat percentage |
| Control | Change in Hepatic Steatosis | -0.17 liver fat percentage |
Secondary
Change in Alanine Aminotransferase (ALT)
Measured by a commercial lab (Medstar, Inc)
Time frame: Change from week 1 to week 12
Population: Adults with obesity and NAFLD
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Alternate Day Fasting | Change in Alanine Aminotransferase (ALT) | -11.24 U/L |
| Exercise | Change in Alanine Aminotransferase (ALT) | -0.70 U/L |
| Combination Alternate Day Fasting Plus Exercise | Change in Alanine Aminotransferase (ALT) | -5.97 U/L |
| Control | Change in Alanine Aminotransferase (ALT) | 0.65 U/L |
Secondary
Change in Aspartate Aminotransferase (AST)
Measured by a commercial lab (Medstar, Inc)
Time frame: Change from week 1 to week 12
Population: Adults with obesity and NAFLD
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Alternate Day Fasting | Change in Aspartate Aminotransferase (AST) | -5.39 U/L |
| Exercise | Change in Aspartate Aminotransferase (AST) | .34 U/L |
| Combination Alternate Day Fasting Plus Exercise | Change in Aspartate Aminotransferase (AST) | -1.59 U/L |
| Control | Change in Aspartate Aminotransferase (AST) | -0.33 U/L |
Secondary
Change in Body Weight
Measured by digital scale
Time frame: Change from week 1 to week 12
Population: Adults with obesity and NAFLD
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Alternate Day Fasting | Change in Body Weight | -4.45 kg |
| Exercise | Change in Body Weight | -1.79 kg |
| Combination Alternate Day Fasting Plus Exercise | Change in Body Weight | -4.18 kg |
| Control | Change in Body Weight | -0.52 kg |
Secondary
Change in Fasting Glucose
Measured by a commercial lab (Medstar, Inc)
Time frame: Change from week 1 to week 12
Population: Adults with obesity and NAFLD
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Alternate Day Fasting | Change in Fasting Glucose | -5.14 mg/dl |
| Exercise | Change in Fasting Glucose | -2.12 mg/dl |
| Combination Alternate Day Fasting Plus Exercise | Change in Fasting Glucose | -5.28 mg/dl |
| Control | Change in Fasting Glucose | .62 mg/dl |
Secondary
Change in Fasting Insulin
Measured by a commercial lab (Medstar, Inc)
Time frame: Change from week 1 to week 12
Population: Adults with obesity and NAFLD
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Alternate Day Fasting | Change in Fasting Insulin | -7.41 uIU/mL |
| Exercise | Change in Fasting Insulin | -3.93 uIU/mL |
| Combination Alternate Day Fasting Plus Exercise | Change in Fasting Insulin | -9.59 uIU/mL |
| Control | Change in Fasting Insulin | 1.22 uIU/mL |
Secondary
Change in HbA1c
Measured by a commercial lab (Medstar, Inc)
Time frame: Change from week 1 to week 12
Population: Adults with obesity and NAFLD
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Alternate Day Fasting | Change in HbA1c | -.12 percentage of glycosylated hemoglobin |
| Exercise | Change in HbA1c | .02 percentage of glycosylated hemoglobin |
| Combination Alternate Day Fasting Plus Exercise | Change in HbA1c | -0.08 percentage of glycosylated hemoglobin |
| Control | Change in HbA1c | .04 percentage of glycosylated hemoglobin |
Secondary
Change in Insulin Resistance
Measured by Homeostatic model assessment of insulin resistance (HOMA-IR). The HOMA-IR value was calculated using the formula: \[HOMA-IR = glucose (mg/dL) × insulin (mU/L)/405\]. Interpretation of HOMA-IR Scores: \< 1.0: Normal insulin sensitivity; 1.0-1.9: Mild insulin resistance; \> 2.0: Moderate to severe insulin resistance.
Time frame: Change from week 1 to week 12
Population: Adults with obesity and NAFLD
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Alternate Day Fasting | Change in Insulin Resistance | -1.8 index |
| Exercise | Change in Insulin Resistance | -1.25 index |
| Combination Alternate Day Fasting Plus Exercise | Change in Insulin Resistance | -2.55 index |
| Control | Change in Insulin Resistance | 0.49 index |