Effects of PPAR Ligands on Ectopic Fat Accumulation and Inflammation
Condition: Metabolic Syndrome X; Prediabetic State
MeSH terms: Metabolic Syndrome; Prediabetic State; Inflammation
Study type: Interventional

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.
    

Intervention name(s): Fenofibrate 145mg PO QD; Pioglitazone 45 mg PO QD
Intervention type(s): Drug; Drug
Intervention description(s): Subjects will be randomized to either fenofibrates or combination of both fenofibrate and pioglitazone; 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 intervention name(s): Tricor; Actos
Intervention MeSH terms: Pioglitazone; Fenofibrate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: fatty acid oxidation complex; fenofibrate; Inflammation; Peroxisome Proliferator-Activated Receptors; pioglitazone; Prediabetic State; insulin resistance