Effect of Endoplasmic Reticulum Stress on Metabolic Function

Obesity Clinical Trial

— TUDCA/PBA  

Official title:

Effect of Endoplasmic Reticulum Stress on Metabolic Function

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00771901
• Other study ID #: 07-1114
• Status: Completed
• Phase: N/A
• Start date: February 2008
• Est. completion date: December 2014

Study information

• Verified date: April 2018
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 101
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes
• Insulin Resistance
• Obesity

Intervention

Drug:
• tauroursodeoxycholic acid
1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner.

Other:
• placebo
7 pills daily for 4 weeks

Drug:
• sodium phenylbutyrate
20g/day for four weeks.

Locations

Country	Name	City	State
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. Diabe — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Body Composition	Fat mass (%)	Baseline and four weeks
Secondary	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
Secondary	VLDL-triglyceride (TG) Concentration		Baseline and four weeks