Effects of PPAR Ligands on Ectopic Fat Accumulation and Inflammation

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT00470262
First received: May 4, 2007
Last updated: January 23, 2014
Last verified: January 2014
  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
Drug: Pioglitazone and Fenofibrate

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 Department of Veterans Affairs:

Primary Outcome Measures:
  • Ectopic fat accumulation after 3 months of therapy [ Time Frame: 3 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Adipose tissue inflammation [ Time Frame: 3 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 300
Study Start Date: January 2007
Estimated Study Completion Date: December 2014
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Arm 1
Treatment with pioglitazone and fenofibrate in subjects with pre diabetes
Drug: Fenofibrate
Subjects will be randomized to either fenofibrates or combination of both fenofibrate and pioglitazone
Drug: Pioglitazone and Fenofibrate
Subjects will be randomized to either fenofibrates or combination of both fenofibrate and pioglitazone
Arm 2
Treatment with fenofibrate in subjects with pre diabetes
Drug: Fenofibrate
Subjects will be randomized to either fenofibrates or combination of both fenofibrate and pioglitazone
Drug: Pioglitazone and Fenofibrate
Subjects will be randomized to either fenofibrates or combination of both fenofibrate and pioglitazone

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. We 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, we 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 our 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
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
Investigators
Principal Investigator: Neda Rasouli, MD VA Eastern Colorado Health Care System, Denver
  More Information

No publications provided

Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT00470262     History of Changes
Other Study ID Numbers: ENDA-020-06S, 09-0710
Study First Received: May 4, 2007
Last Updated: January 23, 2014
Health Authority: United States: Federal Government

Keywords provided by Department of Veterans Affairs:
fatty acid oxidation complex
fenofibrate
Inflammation
Peroxisome Proliferator-Activated Receptors
pioglitazone
Prediabetic State
insulin resistance

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

ClinicalTrials.gov processed this record on September 11, 2014