Effects of PPAR Ligands on Ectopic Fat Accumulation and Inflammation

NCT ID: NCT00470262

Last Updated: 2016-07-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 27 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-01-31
• Study Completion Date: 2014-06-30

Brief 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 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.

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.

Conditions

Metabolic Syndrome X; Prediabetic State

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Fenofibrate 145 mg PO QD and Pioglitazone 45 mg PO QD

Treatment with pioglitazone and fenofibrate in subjects with pre diabetes

Group Type: OTHER

Fenofibrate 145mg PO QD

Intervention Type: DRUG

Subjects will be randomized to either fenofibrates or combination of both fenofibrate and pioglitazone

Pioglitazone 45 mg PO QD

Intervention Type: DRUG

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

Fenofibrate 145 mg PO QD

Treatment with fenofibrate in subjects with pre diabetes

Group Type: OTHER

Fenofibrate 145mg PO QD

Intervention Type: DRUG

Subjects will be randomized to either fenofibrates or combination of both fenofibrate and pioglitazone

Interventions

Fenofibrate 145mg PO QD

Subjects will be randomized to either fenofibrates or combination of both fenofibrate and pioglitazone

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

Tricor; Actos

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

VA Office of Research and Development

FED

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Neda Rasouli, MD

Role: PRINCIPAL_INVESTIGATOR

VA Eastern Colorado Health Care System, Denver

Locations

VA Eastern Colorado Health Care System, Denver

Denver, Colorado, United States

Countries

United States

References

Ipsen EO, Madsen KS, Chi Y, Pedersen-Bjergaard U, Richter B, Metzendorf MI, Hemmingsen B. Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus. Cochrane Database Syst Rev. 2020 Nov 19;11(11):CD013516. doi: 10.1002/14651858.CD013516.pub2.

Reference Type: DERIVED

PMID: 33210751 (View on PubMed)

Other Identifiers

09-0710

Identifier Type: OTHER

Identifier Source: secondary_id

ENDA-020-06S

Identifier Type: -

Identifier Source: org_study_id