Effects of PPAR Ligands on Ectopic Fat Accumulation and Inflammation in Subjects With Impaired Glucose Tolerance
Information source: Department of Veterans Affairs
Information obtained from ClinicalTrials.gov on February 12, 2009
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Metabolic Syndrome X; Prediabetic State
Intervention: Fenofibrate (Drug); Pioglitazone (Drug); Pioglitazone and Fenofibrate (Drug)
Phase: N/A
Status: Not yet recruiting
Sponsored by: Department of Veterans Affairs Official(s) and/or principal investigator(s):
Neda Rasouli, MD, Principal Investigator, Affiliation: VA Affiliation: Central Arkansas Veterans Healrhcare System
Overall contact:
Regina G Dennis, BA, Phone: 501-257-5893, Email: RCDennis@uams.edu
Summary
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 proglitazone. 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. Th 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.
Clinical Details
Official title: Effects of PPAR Ligands on Ectopic Fat Accumulation and Inflammation in Subjects With Impaired Glucose Tolerance
Study design: Prevention, Randomized, Open Label, Uncontrolled, Parallel Assignment, Efficacy Study
Primary outcome: Ectopic fat accumulation
Secondary outcome: Adipose tissue inflammation
Detailed description:
The correlation between obesity, inflammation and ectopic fat accumulation is wel 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) α and γ ligands have synergistic
anti-inflammatory effects in adipose tissue and activation of PPAR α and γ 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 α ligand (fenofibrate),
PPAR γ 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 α, γ 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 α and γ 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 γ, α 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
Minimum age: 35 Years.
Maximum age: 65 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Impaired glucose tolerance
- Age 35-65
- 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
Locations and Contacts
Regina G Dennis, BA, Phone: 501-257-5893, Email: RCDennis@uams.edu
Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205, United States
Additional Information
Related publications: Rasouli N, Raue U, Miles LM, Lu T, Di Gregorio GB, Elbein SC, Kern PA. Pioglitazone improves insulin sensitivity through reduction in muscle lipid and redistribution of lipid into adipose tissue. Am J Physiol Endocrinol Metab. 2005 May;288(5):E930-4. Epub 2005 Jan 4. Bodles AM, Varma V, Yao-Borengasser A, Phanavanh B, Peterson CA, McGehee RE Jr, Rasouli N, Wabitsch M, Kern PA. Pioglitazone induces apoptosis of macrophages in human adipose tissue. J Lipid Res. 2006 Sep;47(9):2080-8. Epub 2006 Jun 23.
Ending date: October 2010
Last updated: May 4, 2007
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