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Effect of Endoplasmic Reticulum Stress on Metabolic Function (TUDCA/PBA)

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ClinicalTrials.gov Identifier: NCT00771901
Recruitment Status : Completed
First Posted : October 15, 2008
Results First Posted : May 29, 2018
Last Update Posted : May 29, 2018
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine

Study Description
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Brief Summary:

Normally, the hormone insulin works to help keep blood sugar normal. However, as a person gains weight, insulin does not work as well and blood sugar tends to be a little higher than normal. This is called "insulin resistance".

Two investigational drugs (not approved by the Food and Drug Administration) for the treatment of high lipid levels or insulin resistance are being examined in this study: one drug is called tauroursodeoxycholic acid (TUDCA), the other is called sodium phenylbutyrate (PBA). This study is designed to test if TUDCA and/or PBA is effective in people who are obese with insulin resistance and high lipids. We hypothesize that pharmacologically-induced decreases in ER stress will improve insulin action and hepatic lipid metabolism in obese subjects.


Condition or disease Intervention/treatment Phase
Insulin Resistance Diabetes Obesity Drug: tauroursodeoxycholic acid Other: placebo Drug: sodium phenylbutyrate Not Applicable

Detailed Description:

A 4-week randomized, controlled trial will be conducted to evaluate the following specific aims in obese subjects:

Determine the effect of treatment with TUDCA or PBA on:

  1. Body fat distribution: a) intrahepatic triglyceride (IHTG) content, b) intramyocellular triglyceride (IMTG) content, and c) intra-abdominal fat content, assessed by using magnetic resonance spectroscopy and magnetic resonance imaging.
  2. In vivo insulin sensitivity in adipose tissue (suppression of lipolysis), liver (suppression of glucose production), and skeletal muscle (stimulation of glucose uptake), assessed by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotope tracer infusion.
  3. VLDL-triglyceride (TG) and VLDL-apolipoprotein-B100 (apoB-100) secretion rates, assessed by stable isotopically labeled tracer infusion methods.
  4. Skeletal muscle intracellular insulin signaling, fatty acid oxidation, and markers of inflammation, assessed by evaluating skeletal muscle biopsies ex vivo.
  5. Adipose tissue insulin signaling, ER stress, and inflammation, assessed by evaluating adipose tissue biopsies ex vivo.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 101 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Basic Science
Official Title: Effect of Endoplasmic Reticulum Stress on Metabolic Function
Actual Study Start Date : February 2008
Actual Primary Completion Date : December 2014
Actual Study Completion Date : December 2014
Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Placebo
Subjects will be given a placebo rather than tauroursodeoxycholic acid.
 Other: placebo
7 pills daily for 4 weeks
Experimental: tauroursodeoxycholic acid
Subjects will receive tauroursodeoxycholic acid for four weeks.
 Drug: tauroursodeoxycholic acid
1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner.
Other Name: TUDCA
Experimental: PBA
Subjects will receive sodium phenylbutyrate for four weeks.
 Drug: sodium phenylbutyrate
20g/day for four weeks.
Other Name: PBA


Outcome Measures
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Primary Outcome Measures :
  1. Body Composition [ Time Frame: Baseline and four weeks ]
    Fat mass (%)


Secondary Outcome Measures :
  1. Insulin Sensitivity in the Liver [ Time Frame: Baseline and four weeks ]
    HISI (hepatic insulin sensitivity index). HISI is the inverse of the product of endogenous glucose production and plasma insulin concentration and provides an index of how well circulating insulin controls the amount of glucose supplied by the liver. A higher number is indicative of greater insulin sensitivity.

  2. VLDL-triglyceride (TG) Concentration [ Time Frame: Baseline and four weeks ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • BMI range 30 to 45
  • sedentary (defined as regular exercise < 1 h per week or < 2 x/week for the last 6 months)

Exclusion Criteria:

  • active or previous infection with hepatitis B or C
  • liver diseases
  • history of alcohol abuse
  • current alcohol consumption > 20 g/day
  • severe hypertriglyceridemia ( > 400 mg/dL)
  • active peptic ulcer disease
  • taking cholestyramine or oral contraceptives
  • women who are pregnant or lactating
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00771901


Locations
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United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Investigators
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Principal Investigator: Samuel Klein, MD Washington University School of Medicine
More Information
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Publications of Results:

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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00771901    
Other Study ID Numbers: 07-1114
First Posted: October 15, 2008    Key Record Dates
Results First Posted: May 29, 2018
Last Update Posted: May 29, 2018
Last Verified: April 2018
Keywords provided by Washington University School of Medicine:
obesity
insulin resistance
type II diabetes
Additional relevant MeSH terms:
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Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Tauroursodeoxycholic acid
4-phenylbutyric acid
 Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Cholagogues and Choleretics
Gastrointestinal Agents