Effect of Endoplasmic Reticulum Stress on Metabolic Function

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

NA

Total Enrollment

101 participants

Study Classification

INTERVENTIONAL

Study Start Date

2008-02-29

Study Completion Date

2014-12-31

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Insulin Resistance Diabetes Obesity

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

SINGLE

Participants

Study Groups

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Placebo

Subjects will be given a placebo rather than tauroursodeoxycholic acid.

Group Type PLACEBO_COMPARATOR

placebo

Intervention Type OTHER

7 pills daily for 4 weeks

tauroursodeoxycholic acid

Subjects will receive tauroursodeoxycholic acid for four weeks.

Group Type EXPERIMENTAL

tauroursodeoxycholic acid

Intervention Type DRUG

1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner.

PBA

Subjects will receive sodium phenylbutyrate for four weeks.

Group Type EXPERIMENTAL

sodium phenylbutyrate

Intervention Type DRUG

20g/day for four weeks.

Interventions

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tauroursodeoxycholic acid

1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner.

Intervention Type DRUG

placebo

7 pills daily for 4 weeks

Intervention Type OTHER

sodium phenylbutyrate

20g/day for four weeks.

Intervention Type DRUG

Other Intervention Names

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TUDCA PBA

Eligibility Criteria

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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

Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes