Effect of Endoplasmic Reticulum Stress on Metabolic Function
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.
Allocation: Randomized, Control: Placebo Control, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Basic Science
tauroursodeoxycholic acid, placebo, sodium phenylbutyrate
Washington University School of Medicine
Washington University School of Medicine
Results (where available)
- Source: http://clinicaltrials.gov/show/NCT00771901
- Information obtained from ClinicalTrials.gov on January 06, 2011
Medical and Biotech [MESH] Definitions
A syndrome with excessively high INSULIN levels in the BLOOD. It may cause HYPOGLYCEMIA. Etiology of hyperinsulinism varies, including hypersecretion of a beta cell tumor (INSULINOMA); autoantibodies against insulin (INSULIN ANTIBODIES); defective insulin receptor (INSULIN RESISTANCE); or overuse of exogenous insulin or HYPOGLYCEMIC AGENTS.
Diminished effectiveness of INSULIN in lowering blood sugar levels: requiring the use of 200 units or more of insulin per day to prevent HYPERGLYCEMIA or KETOSIS. It can be caused by the presence of INSULIN ANTIBODIES or the abnormalities in insulin receptors (RECEPTOR, INSULIN) on target cell surfaces. It is often associated with OBESITY; DIABETIC KETOACIDOSIS; INFECTION; and certain rare conditions. (from Stedman, 25th ed)
THIAZOLES with two keto oxygens. Members are insulin-sensitizing agents which overcome INSULIN RESISTANCE by activation of the peroxisome proliferator activated receptor gamma (PPAR-gamma).
A 51-amino acid pancreatic hormone that plays a major role in the regulation of glucose metabolism, directly by suppressing endogenous glucose production (GLYCOGENOLYSIS; GLUCONEOGENESIS) and indirectly by suppressing GLUCAGON secretion and LIPOLYSIS. Native insulin is a globular protein comprised of a zinc-coordinated hexamer. Each insulin monomer containing two chains, A (21 residues) and B (30 residues), linked by two disulfide bonds. Insulin is used as a drug to control insulin-dependent diabetes mellitus (DIABETES MELLITUS, TYPE 1).
The trihydrate sodium salt of acetic acid, which is used as a source of sodium ions in solutions for dialysis and as a systemic and urinary alkalizer, diuretic, and expectorant.
OBJECTIVES: I. Assess the safety and efficacy of sodium phenylbutyrate, sodium benzoate, sodium phenylacetate, and dietary intervention in patients with urea cycle disorders.
OBJECTIVES: I. Determine the optimum dose of tauroursodeoxycholic acid (TUDCA) required to achieve maximal bioavailability for patients with cystic fibrosis-associated liver disease. II....
Subjects will be screened with a 2 hour oral glucose tolerance test. After this screening visit, their insulin resistance will be measured. Subjects will then be given either alpha lipoi...
The purpose of this study is to evaluate the safety, tolerability and clinical impact of 15-grams daily of sodium phenylbutyrate (phenylbutyrate) in Huntington's disease and to lay the gro...
The purpose of this study is to identify the maximum tolerated dosage of sodium phenylbutyrate in children with spinal muscular atrophy types II or III; and to determine if the drug has an...
OBJECTIVE: The aim of this study was to assess whether the administration of Diamel could improve any of the components of metabolic syndrome (MS), as well as insulin resistance and sensitivity METHOD...
Free-fatty acids (FFAs) are well-characterized factor for causing production of inflammatory factors and insulin resistance in adipocytes. Using cultured adipocytes, we demonstrate that FFAs can activ...
To explore the molecular mechanism of puerarin (Pue) in improving insulin resistance through observing its effect on the insulin resistance of 3T3-Li lipocyte induced by free fatty acid (FFA).
Inborn errors of urea metabolism result in hyperammonemia. Treatment of urea cycle disorders can effectively lower plasma ammonium levels and results in survival in the majority of patients. Available...
Background: Increased carotid restenosis due to revascularization therapy is associated with insulin resistance. We hypothesize that glucose control using acarbose may attenuate intimal hyperplasia in...