Non-alcoholic Fatty Liver, Metabolic Syndrome
Conditions
Keywords
Vitamin E, Metabolic syndrome, Liver disease, Non-alcoholic liver steatohepatitis, Fatty liver, Dairy consumption
Brief summary
This study is conducted to investigate if vitamin E status in healthy individuals and individuals with metabolic syndrome can be improved by dairy fat. The investigators hypothesize that full-fat dairy will substantially increase the bioavailability of alpha-tocopherol, a form of vitamin E. The results of this study will contribute to the application of dairy fat as a simple and effective strategy for improving vitamin E status, which is partly due to poor vitamin E intake. By completing this study, the investigators anticipate developing new dietary recommendations to achieve adequate vitamin E status through the regular consumption of dairy fat paired with foods containing vitamin E.
Detailed description
Nonalcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome and affects \>70 million Americans. Weight loss and vitamin E supplementation are leading strategies for preventing and/or treating NASH. However, the long-term success of weight loss is limited and \>92% of Americans fail to meet dietary recommendations for vitamin E. Thus, the objective is to define the extent to which dairy fat facilitates adequate vitamin E status in individuals with metabolic syndrome, a population at high-risk for NASH, by improving α-tocopherol bioavailability. The central hypothesis is that full-fat dairy will substantially increase alpha-tocopherol (a-T) bioavailability to the extent needed to facilitate production of alpha-carboxyethyl-hydroxy-chromanol (a-CEHC), a metabolite of a-T that predict a-T status. The will therefore complete the following specific aims: 1) define milk fat-mediated improvements in a-T bioavailability, and 2) define dairy fat-mediated improvements in a-T status. This study involves a randomized crossover study design where healthy adults and those with metabolic syndrome (n = 10/group) will ingest deuterium-labeled a-T (15 mg) with 1 cup of either fat-free milk, low-fat milk, whole milk, or soy milk. Urine and blood samples will be collected at timed intervals prior to and following milk consumption. Blood will be collected at timed intervals over 72 h, and plasma will be analyzed by liquid chromatography with mass spectrometry to determine pharmacokinetic parameters by measuring labeled and unlabeled a-T and a-CEHC. Risk to participants is expected to be minimal and will be outlined in the informed consent form in clear and simple terms. Upon successful completion of this study, it is expected to show that a-T bioavailability increases in a milk fat-dependent manner and that dairy milk compared with soy milk significantly improves a-T bioavailability. The results are expected to provide timely evidence demonstrating the amount and type of fat needed to achieve optimal vitamin E status specifically in a population of significant public health concern. Overall, these studies will fill a substantial knowledge gap regarding the importance of dairy fat in contributing to optimal health and provide a simple dietary approach to ameliorate poor vitamin E status among a significant proportion of Americans.
Interventions
OTHERFat-Free Milk
Fat-free milk ingestion with 15 mg deuterium-labeled alpha-tocopherol.
OTHERLow-Fat Milk
Low-fat milk ingestion with 15 mg deuterium-labeled alpha-tocopherol.
OTHERFull-Fat Milk
Full-fat milk ingestion with 15 mg deuterium-labeled alpha-tocopherol.
OTHERSoy Milk
Soy milk ingestion with 15 mg deuterium-labeled alpha-tocopherol.
Sponsors
Ohio State University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* specific criteria of the metabolic syndrome: large waist circumference (\>102 or \>89 cm for men and women, respectively), high fasting triglycerides (150-300 mg/dL), low fasting HDL (\<40 and \<50 mg/dL for men and women, respectively), high blood pressure (\>130/85 mm Hg) and high fasting glucose (110-180 mg/dL) * BMI: \>30 kg/m2, * non-dietary supplement users for \>2-mo * no use of medications known to affect lipid metabolism * no history of gastrointestinal disorders * resting blood pressure \<140 mm Hg * not taking any medications that control hypertension
Exclusion criteria
* lactose-intolerance * excessive alcohol consumption (\>3 drinks/d) * \>5 h/wk of aerobic activity * women who are pregnant, lactating, or have initiated or changed birth control in the past 3-mo * plasma alpha-tocopherol \>20 μmol/L.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve 0-72 h (Deuterium Labeled Alpha-tocopherol) | 0, 3, 6, 9, 12, 24, 36, 48, and 72 h post test meal | — |
| Cmax | 0-72 h post-meal | Maximal plasma concentration of deuterium labelled alpha-tocopherol |
| Tmax | 0-72 h post-meal | Time to maximal plasma concentration of deuterium labelled alpha-tocopherol |
| Elimination Rate | 0-72 h post-meal | Rate of plasma elimination of deuterium labelled alpha-tocopherol |
| Estimated Absorption (% Dose) | 0-72 h post-meal | Absorption of deuterium labelled alpha-tocopherol |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Participants As a randomized crossover study design, participants were stratified by health status (healthy versus metabolic syndrome) and received fat-free milk, low-fat milk, full-fat milk, and soy milk in a randomized order. | 10 |
| Metabolic Syndrome Participants As a randomized crossover study design, participants were stratified by health status (healthy versus metabolic syndrome) and received fat-free milk, low-fat milk, full-fat milk, and soy milk in a randomized order. | 10 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 1 (Cross-over Arm 1) | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Healthy Participants | Metabolic Syndrome Participants |
|---|---|---|---|
| Age, Continuous | 31.6 years STANDARD_DEVIATION 4.7 | 30.3 years STANDARD_DEVIATION 4 | 32.8 years STANDARD_DEVIATION 5.1 |
| alpha-tocopherol | 4.13 umol/mmol lipid STANDARD_DEVIATION 0.93 | 22.2 umol/L STANDARD_DEVIATION 3.9 | 3.71 umol/mmol lipid STANDARD_DEVIATION 0.85 |
| Body mass index | 30.2 kg/m2 STANDARD_DEVIATION 10.2 | 22.6 kg/m2 STANDARD_DEVIATION 2.2 | 37.7 kg/m2 STANDARD_DEVIATION 9.4 |
| Diastolic Blood Pressure | 76.5 mmHg STANDARD_DEVIATION 9.2 | 74.0 mmHg STANDARD_DEVIATION 7.9 | 79.0 mmHg STANDARD_DEVIATION 10.1 |
| Glucose | 98.4 mg/dL STANDARD_DEVIATION 13.9 | 89.2 mg/dL STANDARD_DEVIATION 6.2 | 107.6 mg/dL STANDARD_DEVIATION 4.2 |
| HDL cholesterol | 48.6 mg/dL STANDARD_DEVIATION 12.6 | 56.0 mg/dL STANDARD_DEVIATION 9.9 | 41.2 mg/dL STANDARD_DEVIATION 10.8 |
| Sex: Female, Male Female | 10 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Male | 10 Participants | 5 Participants | 5 Participants |
| Systolic Blood Pressure | 123.5 mmHg STANDARD_DEVIATION 18.1 | 118.8 mmHg STANDARD_DEVIATION 9.5 | 128.2 mmHg STANDARD_DEVIATION 23.6 |
| Triglyceride | 117.4 mg/dL STANDARD_DEVIATION 62.8 | 82.0 mg/dL STANDARD_DEVIATION 30.4 | 152.7 mg/dL STANDARD_DEVIATION 68.1 |
| Waist Circumference | 95.7 cm STANDARD_DEVIATION 27 | 75.2 cm STANDARD_DEVIATION 6.5 | 116.1 cm STANDARD_DEVIATION 23.7 |
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 | — / — | — / — | — / — | — / — |
| 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
Area Under the Curve 0-72 h (Deuterium Labeled Alpha-tocopherol)
Time frame: 0, 3, 6, 9, 12, 24, 36, 48, and 72 h post test meal
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Fat-Free Milk Ingestion | Area Under the Curve 0-72 h (Deuterium Labeled Alpha-tocopherol) | Healthy Participants | 103 umol/L x h | Standard Error 7 |
| Acute Fat-Free Milk Ingestion | Area Under the Curve 0-72 h (Deuterium Labeled Alpha-tocopherol) | Metabolic Syndrome Participants | 86 umol/L x h | Standard Error 8 |
| Acute Low-Fat Milk Ingestion | Area Under the Curve 0-72 h (Deuterium Labeled Alpha-tocopherol) | Metabolic Syndrome Participants | 84 umol/L x h | Standard Error 7 |
| Acute Low-Fat Milk Ingestion | Area Under the Curve 0-72 h (Deuterium Labeled Alpha-tocopherol) | Healthy Participants | 115 umol/L x h | Standard Error 8 |
| Acute Full-Fat Milk Ingestion | Area Under the Curve 0-72 h (Deuterium Labeled Alpha-tocopherol) | Healthy Participants | 102 umol/L x h | Standard Error 8 |
| Acute Full-Fat Milk Ingestion | Area Under the Curve 0-72 h (Deuterium Labeled Alpha-tocopherol) | Metabolic Syndrome Participants | 81 umol/L x h | Standard Error 7 |
| Acute Soy Milk Ingestion | Area Under the Curve 0-72 h (Deuterium Labeled Alpha-tocopherol) | Healthy Participants | 102 umol/L x h | Standard Error 5 |
| Acute Soy Milk Ingestion | Area Under the Curve 0-72 h (Deuterium Labeled Alpha-tocopherol) | Metabolic Syndrome Participants | 74 umol/L x h | Standard Error 11 |
Primary
Cmax
Maximal plasma concentration of deuterium labelled alpha-tocopherol
Time frame: 0-72 h post-meal
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Fat-Free Milk Ingestion | Cmax | Healthy | 2.67 umol/L | Standard Error 0.2 |
| Acute Fat-Free Milk Ingestion | Cmax | Metabolic Syndrome | 2.14 umol/L | Standard Error 0.2 |
| Acute Low-Fat Milk Ingestion | Cmax | Metabolic Syndrome | 2.01 umol/L | Standard Error 0.19 |
| Acute Low-Fat Milk Ingestion | Cmax | Healthy | 2.98 umol/L | Standard Error 0.18 |
| Acute Full-Fat Milk Ingestion | Cmax | Healthy | 2.55 umol/L | Standard Error 0.21 |
| Acute Full-Fat Milk Ingestion | Cmax | Metabolic Syndrome | 1.98 umol/L | Standard Error 0.16 |
| Acute Soy Milk Ingestion | Cmax | Healthy | 2.67 umol/L | Standard Error 0.13 |
| Acute Soy Milk Ingestion | Cmax | Metabolic Syndrome | 1.88 umol/L | Standard Error 0.27 |
Primary
Elimination Rate
Rate of plasma elimination of deuterium labelled alpha-tocopherol
Time frame: 0-72 h post-meal
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Fat-Free Milk Ingestion | Elimination Rate | Healthy | 0.022 mmol/L/h | Standard Error 0.001 |
| Acute Fat-Free Milk Ingestion | Elimination Rate | Metabolic Syndrome | 0.019 mmol/L/h | Standard Error 0.001 |
| Acute Low-Fat Milk Ingestion | Elimination Rate | Metabolic Syndrome | 0.020 mmol/L/h | Standard Error 0.001 |
| Acute Low-Fat Milk Ingestion | Elimination Rate | Healthy | 0.024 mmol/L/h | Standard Error 0.001 |
| Acute Full-Fat Milk Ingestion | Elimination Rate | Healthy | 0.023 mmol/L/h | Standard Error 0.001 |
| Acute Full-Fat Milk Ingestion | Elimination Rate | Metabolic Syndrome | 0.021 mmol/L/h | Standard Error 0.001 |
| Acute Soy Milk Ingestion | Elimination Rate | Healthy | 0.023 mmol/L/h | Standard Error 0.001 |
| Acute Soy Milk Ingestion | Elimination Rate | Metabolic Syndrome | 0.022 mmol/L/h | Standard Error 0.001 |
Primary
Estimated Absorption (% Dose)
Absorption of deuterium labelled alpha-tocopherol
Time frame: 0-72 h post-meal
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Fat-Free Milk Ingestion | Estimated Absorption (% Dose) | Healthy | 27.8 % dose | Standard Error 1.4 |
| Acute Fat-Free Milk Ingestion | Estimated Absorption (% Dose) | Metabolic Syndrome | 26.6 % dose | Standard Error 1.8 |
| Acute Low-Fat Milk Ingestion | Estimated Absorption (% Dose) | Metabolic Syndrome | 26.0 % dose | Standard Error 2.5 |
| Acute Low-Fat Milk Ingestion | Estimated Absorption (% Dose) | Healthy | 32.4 % dose | Standard Error 1.6 |
| Acute Full-Fat Milk Ingestion | Estimated Absorption (% Dose) | Healthy | 28.4 % dose | Standard Error 1.3 |
| Acute Full-Fat Milk Ingestion | Estimated Absorption (% Dose) | Metabolic Syndrome | 25.6 % dose | Standard Error 1.9 |
| Acute Soy Milk Ingestion | Estimated Absorption (% Dose) | Healthy | 28.1 % dose | Standard Error 0.88 |
| Acute Soy Milk Ingestion | Estimated Absorption (% Dose) | Metabolic Syndrome | 24.62 % dose | Standard Error 2.72 |
Primary
Tmax
Time to maximal plasma concentration of deuterium labelled alpha-tocopherol
Time frame: 0-72 h post-meal
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Fat-Free Milk Ingestion | Tmax | Metabolic Syndrome | 12 h | Standard Error 0 |
| Acute Fat-Free Milk Ingestion | Tmax | Healthy | 12 h | Standard Error 0 |
| Acute Low-Fat Milk Ingestion | Tmax | Healthy | 12 h | Standard Error 0 |
| Acute Low-Fat Milk Ingestion | Tmax | Metabolic Syndrome | 12 h | Standard Error 0 |
| Acute Full-Fat Milk Ingestion | Tmax | Metabolic Syndrome | 12 h | Standard Error 0 |
| Acute Full-Fat Milk Ingestion | Tmax | Healthy | 13.2 h | Standard Error 1.2 |
| Acute Soy Milk Ingestion | Tmax | Metabolic Syndrome | 12 h | Standard Error 0 |
| Acute Soy Milk Ingestion | Tmax | Healthy | 12 h | Standard Error 0 |