De Novo Lipogenesis, Lipid and Carbohydrate Metabolism in Non-alcoholic Fatty Liver Disease (LINC)

February 12, 2020 updated by: University of California, San Francisco

The worldwide epidemic of obesity is paralleled with increased cases of non-alcoholic liver disease (liver fat accumulation) and diabetes. Fat belongs in the adipose tissue, and if excess fat accumulates in the liver or muscle, these tissues cannot use sugar efficiently. It has been discovered that when large quantities of fructose (a sugar present in soft drinks) are consumed, the conversion of carbohydrate (CHO) to fat in the liver increases.

We hypothesize that: 1) subjects with fatty liver have a higher CHO uptake and conversion to fat in their liver when compared to matched control subjects with normal liver fat content; and that: 2) when subjects with fatty liver are fed a diet limiting fructose and simple sugars will decrease their liver CHO fat content. This reduction in liver fat will normalize the way the liver responds to sugar and insulin, reversing the pre-diabetic state.

The measurement of these parameters will be done using state-of-the-art techniques such as safe non-radioactive isotope tracers and non-invasive magnetic resonance spectroscopy.

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Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Non-alcoholic fatty liver disease (NAFLD) is the most common liver ailment in developed countries. Fatty liver - steatosis - affects up to one third of the population. Its prevalence is rising and seems to parallel the global increase in obesity and type-2 diabetes. The etiology of NAFLD in humans is not well understood. We propose that the hepatic conversion of carbohydrates (CHO) to lipids (de novo lipogenesis, DNL) is a key factor in the accumulation of excess liver fat and the accompanying dyslipidemia and hepatic insulin resistance; and that suppressing DNL by diet will reduce liver fat and improve both lipid and carbohydrate metabolism in patients with steatosis. These hypotheses are based on studies in which we and others have established that fractional hepatic DNL can vary dramatically depending on the diet and/or health status of a subject; and, in particular, that dietary fructose is a potent lipogenic stimulus. In this proposal we will perform CRC-based studies to compare the rates of DNL and very low density lipoprotein (VLDL) kinetics in steatotic and matched non-steatotic controls and evaluate their relationship to lipid profiles and hepatic and whole-body insulin resistance and overall carbohydrate metabolism (Aim1). The steatotic individuals whose habitual intake of fructose and other simple sugars exceeds 15% of total energy intake will then be randomized to consume one of two low-fat diets that differ only in CHO type to determine whether diet-induced changes in DNL affect liver fat flux and content and hepatic, whole-body insulin sensitivity, and overall carbohydrate metabolism (Aim 2). We hypothesize that a diet that is rich in complex CHO will achieve greater decreases in DNL and liver fat than one that contains typical amounts of simple CHO, including fructose. This dietary intervention study includes a 6-week 25% energy restriction outpatient phase to promote moderate weight loss and improve insulin sensitivity, followed by a two weeks weight maintenance with the last 4 days as an inpatient stay during which all of the studies performed at baseline (Aim 1) will be repeated. State-of-the-art stable isotope techniques will be used to assess hepatic DNL, apoB100 turnover, VLDL-triglyceride (TG) fluxes, and lipolysis under fasting and fed conditions. Hepatic and extra-hepatic insulin sensitivity will be measured using hyperinsulinemic-euglycemic clamps and stable isotope studies of endogenous glucose production and glycogen flux. Liver and muscle fat will be measured by proton magnetic resonance spectroscopy (MRS), visceral fat by magnetic resonance imaging (MRI), and whole-body composition by dual-energy X-ray absorptiometry (DEXA). These studies will allow us to evaluate the importance of DNL as a mechanism modulating liver fat content and flux, and the significance of CHO quality in dietary guidance for steatotic patients.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
41

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Vallejo, California, United States, 94592
        • Touro University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • In the steatotic subjects, steatosis will be diagnosed by MRS or liver biopsy in which >33% of the hepatocytes will contain fat. Non-steatotic controls will not have biopsies since they are not medically warranted; thus, to ensure they do not have steatosis they will undergo MRS during screening and have a total lipid: unsuppressed water < 0.05.

Exclusion Criteria:

  • Habitual consumption of alcohol > 20 g/day for men and 10 g/day for women
  • Confirmed HIV-1 infection, Hgb <13 g/dL for males and <12 g/dL for females
  • Abnormal hepatitis B or C serology
  • Diabetes or current use of any antidiabetic or hypolipidemic agents
  • Presence of metal-containing substances in the body (e.g. a fragment in the eye, aneurysm clips, ear implants, spinal nerve stimulators or a pacemaker)
  • Weight over 350 pounds or severe claustrophobia, which would preclude the MR studies
  • Any condition that would preclude adherence to the protocol or the ability to provide informed consent
  • Change in body weight >5% within the preceding 6 months (by self-report)
  • Known intolerance, allergy or hypersensitivity to fructose
  • Pregnancy or lactation (for women); OR
  • Any other condition that, in the opinion of the investigators, would put the subject at risk.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: 1
Weight loss diet - normal diet
Other: Dietary intervention (calorie restricted diet)
Participants in Aim 2 will receive a calorie restricted diet. This group will receive all their food for approximately 8 weeks which is the similar composition of their current diet.
Other: Dietary intervention (calorie restricted diet)
Participants in Aim 2 will receive a calorie restricted diet. This group will receive all their food for approximately 8 weeks which is lower in simple sugars, specifically fructose.
Experimental: 2
Weight loss diet - low in simple sugars (specifically fructose)
Other: Dietary intervention (calorie restricted diet)
Participants in Aim 2 will receive a calorie restricted diet. This group will receive all their food for approximately 8 weeks which is the similar composition of their current diet.
Other: Dietary intervention (calorie restricted diet)
Participants in Aim 2 will receive a calorie restricted diet. This group will receive all their food for approximately 8 weeks which is lower in simple sugars, specifically fructose.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Stable isotopic and magnetic resonance measures to determine the changes in lipid and carbohydrate metabolism after dietary intervention
Time Frame: approximately 8 weeks
approximately 8 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
DEXA, insulin sensitivity and energy expenditure changes due to dietary intervention
Time Frame: 8 weeks
8 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of California, San Francisco

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
American Diabetes Association
Touro University

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Jean-Marc Schwarz, PhD, Touro University and UCSF

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 1, 2007

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
October 12, 2012

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
October 12, 2012

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 9, 2008

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 11, 2008

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 14, 2008

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
February 17, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 12, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • R01DK078133-01 (U.S. NIH Grant/Contract)
  • NIH R01DK078133-01A1
  • ADA 1-08-CR-56

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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