Effect of Endoplasmic Reticulum Stress on Metabolic Function

Not Applicable

Completed

Interventions: Other: placebo
Drug: sodium phenylbutyrate
Drug: tauroursodeoxycholic acid

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.

Recruitment & 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

Arm && Interventions

Group	Intervention	Description
Placebo	placebo	Subjects will be given a placebo rather than tauroursodeoxycholic acid.
PBA	sodium phenylbutyrate	Subjects will receive sodium phenylbutyrate for four weeks.
tauroursodeoxycholic acid	tauroursodeoxycholic acid	Subjects will receive tauroursodeoxycholic acid for four weeks.

Primary Outcome Measures

Name	Time	Method
Body Composition	Baseline and four weeks	Fat mass (%)

Secondary Outcome Measures

Name	Time	Method
Insulin Sensitivity in the Liver	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	Baseline and four weeks