Effect of Endoplasmic Reticulum Stress on Metabolic Function

Study Overview
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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.

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: 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. 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. VLDL-triglyceride (TG) and VLDL-apolipoprotein-B100 (apoB-100) secretion rates, assessed by stable isotopically labeled tracer infusion methods. Skeletal muscle intracellular insulin signaling, fatty acid oxidation, and markers of inflammation, assessed by evaluating skeletal muscle biopsies ex vivo. Adipose tissue insulin signaling, ER stress, and inflammation, assessed by evaluating adipose tissue biopsies ex vivo.

Official Title
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Effect of Endoplasmic Reticulum Stress on Metabolic Function

Conditions
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Insulin Resistance, Diabetes, Obesity

Intervention / Treatment
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* Drug: tauroursodeoxycholic acid
* Other: placebo
* Drug: sodium phenylbutyrate


Participation Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subjects will be given a placebo rather than tauroursodeoxycholic acid. | Other: placebo<br>* 7 pills daily for 4 weeks<br>|
| Experimental: tauroursodeoxycholic acid<br>Subjects will receive tauroursodeoxycholic acid for four weeks. | Drug: tauroursodeoxycholic acid<br>* 1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner.<br>* Other names: TUDCA;|
| Experimental: PBA<br>Subjects will receive sodium phenylbutyrate for four weeks. | Drug: sodium phenylbutyrate<br>* 20g/day for four weeks.<br>* Other names: PBA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body Composition | Fat mass (%) | Baseline and four weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Sensitivity in the Liver | 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. | Baseline and four weeks | 
| VLDL-triglyceride (TG) Concentration |  | Baseline and four weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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obesity, insulin resistance, type II diabetes