Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

Effects of PPAR Ligands on Ectopic Fat Accumulation and Inflammation

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development
ClinicalTrials.gov Identifier:
NCT00470262
First received: May 4, 2007
Last updated: June 9, 2016
Last verified: June 2016
  Purpose

The relationship between obesity and insulin resistance is known, however the mechanism(s) associating obesity with insulin resistance is not well understood. Inflammation and accumulation of fat in non fat tissue (like muscle) are conditions found on obesity which could be the potential link between obesity and insulin resistance. This study is designed to test the effects of two different drugs on numerous features of the obesity and insulin resistance in subjects with impaired glucose tolerance. Impaired glucose tolerance is a condition where blood sugar is too high after drinking a sugary drink containing 75 grams of sugar. Impaired glucose tolerant subjects are insulin resistant and at risk of developing diabetes. The drugs to be used are fenofibrate and pioglitazone. Fenofibrate is used to reduce the amount of fat (triglycerides) in the blood while pioglitazone is routinely used to make the body more sensitive to insulin in patients with diabetes. The purpose of this study is to compare the effects of either of these two medications (pioglitazone and fenofibrate) alone or the combination of both on fat accumulation in body (muscle) and inflammation. The amount of fat accumulation in muscle is thought to affect insulin sensitivity. In addition, the changes in the level of proteins produced by fat tissues will be studied in response to the two medications in this study. These proteins are thought to be involved in diabetes and insulin resistance.

These studies are designed to examine fundamental clinical mechanisms underlying the metabolic syndrome and diabetes.


Condition Intervention
Metabolic Syndrome X
Prediabetic State
Drug: Fenofibrate 145mg PO QD
Drug: Pioglitazone 45 mg PO QD

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Effects of PPAR Ligands on Ectopic Fat Accumulation and Inflammation in Subjects With Impaired Glucose Tolerance

Resource links provided by NLM:


Further study details as provided by VA Office of Research and Development:

Primary Outcome Measures:
  • Insulin Sensitivity [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Insulin sensitivity was measure through frequently sampled intravenous glucose tolerance test. Subjects presented to research center fasting. Blood samples were collected at -21, -11, and -1 minutes. At time t=0 initiates the start of the IVGTT and the injection of glucose into the non-sampling arm. The glucose dose was calculated as 11.4g/m2 of body surface area, given as a 50% dextrose solution. This glucose injection was administered over 60 seconds or less. At time t=20 minutes, an insulin dose of 0.04u/kg was administered over 30 seconds. Blood samples were collected at times t=2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 40, 50, 70, 90, 100, 120, 140, 160, and 180. If blood sugar did not return to a steady state the test was continued to t= 210 or t= 240.


Secondary Outcome Measures:
  • IMCL [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Intramyocellular lipid was measured using immunohistochemistry (using oil Red O staining) in muscle biopsy specimens. Oil red O-stained muscle sections were magnified with an Olympus Provis (Tokyo, Japan) light microscope, and images were digitally captured by using a connected charge-coupled device camera (Sony, Tokyo, Japan). Fiber-typed and oil red O-stained fibers were matched. The oil red O staining intensity of either type 1 or 2 muscle fibers was quantified using National Institutes of Health Image program (http://rsb.info.nih.gov/nih-image/). By adjusting a density threshold, the software was set to recognize the presence of one fat droplet only if its highlighted surface was exceeding 0.40 μm2 or larger. Muscle lipid content was calculated by total area of lipid droplets in a given muscle fiber divided by the total area of the same fiber. The mean number of fibers analyzed per sample was 40 for type 1 and 2 muscle fibers


Enrollment: 27
Study Start Date: January 2007
Study Completion Date: June 2014
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Fenofibrate 145 mg PO QD and Pioglitazone 45 mg PO QD
Treatment with pioglitazone and fenofibrate in subjects with pre diabetes
Drug: Fenofibrate 145mg PO QD
Subjects will be randomized to either fenofibrates or combination of both fenofibrate and pioglitazone
Other Name: Tricor
Drug: Pioglitazone 45 mg PO QD
Subjects will be randomized to either fenofibrate 145 mg PO QD or a combination of both fenofibrate 145 mg PO QD and pioglitazone 45 mg PO QD
Other Name: Actos
Fenofibrate 145 mg PO QD
Treatment with fenofibrate in subjects with pre diabetes
Drug: Fenofibrate 145mg PO QD
Subjects will be randomized to either fenofibrates or combination of both fenofibrate and pioglitazone
Other Name: Tricor

Detailed Description:

The correlation between obesity, inflammation and ectopic fat accumulation is well recognized; however, the mechanism(s) responsible for obesity induced insulin resistance is not well understood. The investigators will focus on lipotoxicity and inflammation as the link between obesity and insulin resistance. The factors leading to inflammation and ectopic lipid accumulation in obesity and the best intervention to reverse this pathophysiology are not clear. In this study, the investigators will examine inflammation in adipose tissue and muscle lipid mechanism in response to Peroxisome Proliferator Activated Receptors (PPAR) and ligands have synergistic anti-inflammatory effects in adipose tissue and activation of PPAR and decrease muscle lipid oxidation and redistribution of lipid from muscle to adipocytes respectively. The combination of both medications will be particularly effective in reducing inflammation and muscle lipid accumulation.

In this study, IGT subjects will be randomized to treatment with PPAR ligand (fenofibrate), PPAR ligand (pioglitazone) or combination of both for 10 weeks. Baseline studies will include assessment of body composition, insulin sensitivity, muscle and fat biopsies. All studies will be repeated after treatment with fenofibrate, pioglitazone or combination of both.

Specific Aims (SA) are as follows:

SA 1. Insulin sensitivity and Intramyocellular lipid (IMCL) from muscle biopsy specimens will be measured in response to different treatments (PPAR , and combination of both ligands).

SA 2. The rate of fatty acid oxidation and the number of mitochondria in muscle will be measured in response to PPAR ligands.

SA 3. The anti-inflammatory effects of PPAR and ligands will be studied by the measurement of the number of adipose tissue macrophages and the rate of macrophages apoptosis in fat biopsy specimens. In addition, the plasma levels and expression of proinflammatory proteins will be studied in response to different treatment.

SA 4. The rate of SUMOylation of PPAR (a novel mechanism regulating anti-inflammatory effects of PPAR ligands) will be studied in response to PPAR , ligand or combination of both.

These studies are designed to examine fundamental clinical mechanisms underlying the metabolic syndrome and diabetes.

Potential Impact on Veterans Health Care: The national obesity/diabetes epidemic is magnified in the VA, and the cost of caring for these patients is enormous. This study will provide data on the mechanism of action of these drugs, which will improve the investigators' understanding of these drugs, impaired glucose tolerance, and treatment of metabolic syndrome. From the clinical perspective, this study uses drugs to treat patients with IGT, which is rapidly becoming recognized as a "disease" because of its association with coronary artery disease risk factors, and because of its high rate of progression to T2DM. If these drugs were shown to improve the care of patients, then they would eventually be a cost savings to the VA, either by choosing the less expensive drug, or by using the drug that delays the progression of the disease, and improves the care of the patient by preventing complications.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Impaired glucose tolerance and/or impaired fasting glucose and/or metabolic syndrome
  • Age 18-65
  • BMI 28-38

Exclusion Criteria:

  • Renal insufficiency: creatinine.1.4
  • Liver disease: ALT.2x normal, congestive heart failure, history of documented coronary artery disease, concomitant use HMG CoA-reductase inhibitors (statins)
  • Concurrent use of ASA, steroids and other anti-inflammatory agents
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00470262

Locations
United States, Colorado
VA Eastern Colorado Health Care System, Denver
Denver, Colorado, United States, 80220
Sponsors and Collaborators
VA Office of Research and Development
Investigators
Principal Investigator: Neda Rasouli, MD VA Eastern Colorado Health Care System, Denver
  More Information

Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT00470262     History of Changes
Other Study ID Numbers: ENDA-020-06S  09-0710 
Study First Received: May 4, 2007
Results First Received: June 27, 2014
Last Updated: June 9, 2016
Health Authority: United States: Federal Government

Keywords provided by VA Office of Research and Development:
fatty acid oxidation complex
fenofibrate
Inflammation
Peroxisome Proliferator-Activated Receptors
pioglitazone
Prediabetic State
insulin resistance

Additional relevant MeSH terms:
Inflammation
Metabolic Syndrome X
Prediabetic State
Pathologic Processes
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Diabetes Mellitus
Endocrine System Diseases
Pioglitazone
Fenofibrate
Hypoglycemic Agents
Physiological Effects of Drugs
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents

ClinicalTrials.gov processed this record on September 29, 2016