Plasma Lipids-Dependent Vitamin E Metabolism During Dynamic Hyperlipidemia

Study Description:

A controlled interventional study of effects of postprandial hypertriglyceridemia from three consecutive high-fat vitamin E-stripped meals on the dynamics of plasma vitamin E concentrations in subjects with baseline normo- and hyperlipidemia, to explore the concept of vitamin E sequestration by fats in plasma.

Objectives:

Primary Objective: Compare effects of postprandial hypertriglyceridemia (PHTG) on plasma/lipoprotein vitamin E dynamics in subjects between baseline normo- and hyperlipidemia.

Secondary Objectives: Compare effects of postprandial hypertriglyceridemia (PHTG) on other fat-soluble vitamins (gamma-tocopherol, phylloquinone [K1]; menaquinone [K2]; 25-OH vitamin D; retinol [A]) and related vitamers (beta-carotene, lycopene lutein/zeaxanthin) between subjects with baseline normo- and hyperlipidemia.

Tertiary/Exploratory Objectives:

• Compare effects of individual high-fat meals on the dynamics of vitamin E, gamma-tocopherol, phylloquinone [K1], menaquinone [K2], 25-OH vitamin D, retinol [A], and other carotenoids between subjects with baseline normo- and hyperlipidemia.
• Compare effects of postprandial hypertriglyceridemia (PHTG) and resultant vitamin E dynamics on: red blood cell (RBC) membrane

deformability, fluidity, and oxygen exchange capacity (pO2, p50); RBC vitamin E, plasma vitamin C, plasma dehydroascorbic acid;

fasting glucose and insulin; oxidized LDL, coenzyme Q10, and plasma cytokine/adipokine profile between subjects with baseline normo- and hyperlipidemia;

• Explore effects of postprandial hypertriglyceridemia on small RNAs including microRNAs, tRNAs, and PIWI-interacting RNAs.
• Explore the influence of genetic variance on the metabolism of vitamin E and other fat-soluble vitamins and related vitamers in subjects with baseline normo- and hyperlipidemia.

Endpoints:

Primary Endpoint: AUC (Area Under the Curve) of vitamin E plasma from hour 1 to hour 23, by cohort.

Secondary Endpoints: AUC of gamma-tocopherol, phylloquinone [K1], menaquinone [K2], 25-OH vitamin D and retinol [A] from hour 1 to hour 23, by cohort.

Tertiary/Exploratory Endpoints:

• Between the timepoints that reflect consuming 3 high-fat meals, AUC of vitamin E, gamma-tocopherol, phylloquinone [K1], menaquinone [K2], 25-OH vitamin D, retinol [A], and other carotenoids will be separately calculated for each participant.
• Over the course of inpatient visit, RBC membrane deformability/fluidity, pO2, p50, RBC vitamin E, plasma vitamin C, plasma dehydroascorbic acid, blood glucose, insulin, c-peptide, oxidized LDL, coenzyme Q10 and serum cytokine/adipokine profiles in each subject.
• Over the course of inpatient visit, small RNAs including microRNAs, tRNAs, and PIWI-interacting RNAs.
• Genetic variance (single nucleotide polymorphisms, SNPs)- dependent change in lipid-soluble vitamin dynamics over the course of inpatient visit in each subject.

• INCLUSION CRITERIA:

Cohort 1

• Males and females aged 18 to 65 years.
• BMI 18.5 26.9 kg/m^2 .
• Able to understand the study procedures and provide written consent, and willing to comply with all scheduled follow-up visits and assessments.
• Normotensive and not on antihypertensive medications, blood pressure 90-129/60-84.
• Not on glucose-lowering or lipid-lowering medications.
• At screening, laboratory values meet all of the following:

• HbA1c < 5.7%,
• Fasting triglycerides < 150 mg/dL
• LDL < 100 mg/dL

• Liver fat < 2%.

Cohort 2

• Males and females aged 18 to 65 years.
• BMI > 26.0 to < 36.0 kg/m2.
• Able to understand the study procedures and provide written informed consent, and willing to comply with all scheduled follow-up visits and assessments.
• At screening, laboratory values meet all of the following:

• HbA1c <= 7.5%
• Fasting triglycerides < 500 mg/dL
• LDL < 190 mg/dL
• Willing to discontinue oral glucose-lowering medications (metformin) and oral lipidlowering medications for 4 to 10 weeks prior to the inpatient visit, if applicable.
• Liver fat < 2%.

Exclusion criteria

• Women who are pregnant or currently breastfeeding.
• Subjects younger than 18 years old. This age group has a broad spectrum of hormonal profiles due to development and puberty, which significantly increases the heterogenicity of study subjects.
• Subjects older than 65 years. This age group has significantly increased risk of cardiovascular diseases. To minimize the risk from temporarily suspending lipid- and glucose-lowering medications and the stress from serial blood draws, these individuals are excluded.
• Heavy alcohol use within past 12 months (males: >2 drinks per day or >14 drinks per week; females: >1 drink per day or >7 drinks per week).
• Current smoker, or former smoker who quit smoking less than 15 years ago.
• Subjects with weight changes greater than 20% of baseline body weight (self-reported or documented within past 12 months) over the past 3 months at outpatient visit 1, or change from outpatient visit 1 during screening.
• Subjects with lactose intolerance who are unwilling to take lactase.
• Subjects with type 1 diabetes.
• Subjects with hemoglobin <11 g/dL or hematocrit <33%.
• Subjects with clinically significant abnormal liver function test results.
• Subjects with liver fat >= 2% on abdominal MRI.
• Subjects with a history of pancreatitis, diabetes ketoacidosis, hyperosmolar hyperglycemic state, advanced atherosclerosis, cardiovascular diseases, kidney diseases, or liver diseases.
• Subjects with fat malabsorption, including a history of gastrointestinal surgery, pancreatic insufficiency, inflammatory bowel disease, celiac disease, moderate-to-severe irritable bowel syndrome, or pathologic mutations impacting lipoprotein metabolism.
• Subjects on glucocorticoids for more than 1 week (not including topical glucocorticoids) within past 3 months.
• Subjects with HIV.
• Subjects with uncontrolled psychiatric and/or behavioral disorders.
• Subjects taking diabetes medications other than metformin.
• Subjects with anticipated surgery during the study period.
• Subjects with severe medication-resistant claustrophobia.
• Subjects who are unwilling to stop medications, vitamins, and/or dietary supplements that investigators have requested to be held.
• Subjects participating in any other clinical study without informing investigators.
• Any other reason or clinical condition that the investigators judge would interfere with study participation and/or be unsafe for the participant or staff member.