Effect of Endoplasmic Reticulum Stress on Metabolic Function (TUDCA/PBA)

• Determine the effect of TUDCA or PBA on in vivo insulin sensitivity [ Time Frame: four weeks ] [ Designated as safety issue: No ]
• Determine the effect of TUDCA or PBA on hepatic VLDL-triglyceride (TG) and VLDL-apolipoprotein-B100 (apoB-100) secretion rates [ Time Frame: four weeks ] [ Designated as safety issue: No ]
• Determine the effect of TUDCA or PBA on skeletal muscle intracellular insulin signaling, fatty acid oxidation, and markers of inflammation, assessed by evaluating skeletal muscle biopsies ex vivo. [ Time Frame: four weeks ] [ Designated as safety issue: No ]
• Determine the effect of TUDCA or PBA on Adipose tissue insulin signaling, ER stress, and inflammation, assessed by evaluating adipose tissue biopsies ex vivo. [ Time Frame: four weeks ] [ Designated as safety issue: No ]

• Determine the effect of TUDCA on in vivo insulin sensitivity [ Time Frame: four weeks ] [ Designated as safety issue: No ]
• Determine the effect of TUDCA on hepatic VLDL-triglyceride (TG) and VLDL-apolipoprotein-B100 (apoB-100) secretion rates [ Time Frame: four weeks ] [ Designated as safety issue: No ]
• Determine the effect of TUDCA on skeletal muscle intracellular insulin signaling, fatty acid oxidation, and markers of inflammation, assessed by evaluating skeletal muscle biopsies ex vivo. [ Time Frame: four weeks ] [ Designated as safety issue: No ]
• Determine the effect of TUDCA on Adipose tissue insulin signaling, ER stress, and inflammation, assessed by evaluating adipose tissue biopsies ex vivo. [ Time Frame: four weeks ] [ Designated as safety issue: No ]

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.

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. Hepatic 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.

• Insulin Resistance
• Diabetes
• Obesity

• Drug: tauroursodeoxycholic acid
  1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner.
  Other Name: TUDCA
• Other: placebo
  7 pills daily for 4 weeks
• Drug: sodium phenylbutyrate
  20g/day for four weeks.
  Other Name: PBA

• Placebo Comparator: Placebo
  Subjects will be given a placebo rather than tauroursodeoxycholic acid.
  Intervention: Other: placebo
• Experimental: tauroursodeoxycholic acid
  Subjects will receive tauroursodeoxycholic acid for four weeks.
  Intervention: Drug: tauroursodeoxycholic acid
• Experimental: PBA
  Subjects will receive sodium phenylbutyrate for four weeks.
  Intervention: Drug: sodium phenylbutyrate

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