Clinical trial NCT00771901: Effect of Endoplasmic Reticulum Stress on Metabolic Function
Official title: Effect of Endoplasmic Reticulum Stress on Metabolic Function
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Insulin Resistance
Diabetes
Obesity
Keywords: obesity
insulin resistance
type II diabetes
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2008-10-15
Enrollment: 101
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility 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

Primary outcomes:
measure: Body Composition
timeFrame: Baseline and four weeks
Secondary outcomes:
measure: Insulin Sensitivity in the Liver
timeFrame: Baseline and four weeks
measure: VLDL-triglyceride (TG) Concentration
timeFrame: Baseline and four weeks
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Samuel Klein, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.