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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 28, 2018
Last Update Posted : May 28, 2018
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine

October 10, 2008
October 15, 2008
September 15, 2017
May 28, 2018
May 28, 2018
February 2008
December 2014   (Final data collection date for primary outcome measure)
Body Composition [ Time Frame: Baseline and four weeks ]
Fat mass (%)
Determine the effect of treatment with TUDCA on body fat distribution. [ Time Frame: four weeks ]
Complete list of historical versions of study NCT00771901 on ClinicalTrials.gov Archive Site
  • 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.
  • VLDL-triglyceride (TG) Concentration [ Time Frame: Baseline and four weeks ]
  • Determine the effect of TUDCA on in vivo insulin sensitivity [ Time Frame: four weeks ]
  • Determine the effect of TUDCA on hepatic VLDL-triglyceride (TG) and VLDL-apolipoprotein-B100 (apoB-100) secretion rates [ Time Frame: four weeks ]
  • Determine the effect of TUDCA on skeletal muscle intracellular insulin signaling, fatty acid oxidation, and markers of inflammation, assessed by evaluating skeletal muscle biopsies ex vivo. [ Time Frame: four weeks ]
  • Determine the effect of TUDCA on Adipose tissue insulin signaling, ER stress, and inflammation, assessed by evaluating adipose tissue biopsies ex vivo. [ Time Frame: four weeks ]
Not Provided
Not Provided
 
Effect of Endoplasmic Reticulum Stress on Metabolic Function
Effect of Endoplasmic Reticulum Stress on Metabolic Function

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.

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.
Interventional
Not Applicable
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Basic Science
  • Insulin Resistance
  • Diabetes
  • Obesity
  • 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
  • Other: placebo
    7 pills daily for 4 weeks
  • Drug: sodium phenylbutyrate
    20g/day for four weeks.
    Other Name: PBA
  • Placebo Comparator: Placebo
    Subjects will be given a placebo rather than tauroursodeoxycholic acid.
    Intervention: Other: placebo
  • Experimental: tauroursodeoxycholic acid
    Subjects will receive tauroursodeoxycholic acid for four weeks.
    Intervention: Drug: tauroursodeoxycholic acid
  • Experimental: PBA
    Subjects will receive sodium phenylbutyrate for four weeks.
    Intervention: Drug: sodium phenylbutyrate
Kars M, Yang L, Gregor MF, Mohammed BS, Pietka TA, Finck BN, Patterson BW, Horton JD, Mittendorfer B, Hotamisligil GS, Klein S. Tauroursodeoxycholic Acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes. 2010 Aug;59(8):1899-905. doi: 10.2337/db10-0308. Epub 2010 Jun 3.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
101
30
December 2014
December 2014   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years to 65 Years   (Adult, Older Adult)
Yes
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT00771901
07-1114
No
Not Provided
Not Provided
Washington University School of Medicine
Washington University School of Medicine
Not Provided
Principal Investigator: Samuel Klein, MD Washington University School of Medicine
Washington University School of Medicine
April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP