Thiazolidinediones

Thiazolidinediones, or glitazones, are insulin-sensitizing agents that are selective ligands of the nuclear transcription factor peroxisome proliferator-activated receptor g (PPAR-g). An insulin sensitizer has the potential to target insulin resistance directly, a key underlying factor in the pathogenesis of T2DM. Insulin resistance also contributes to dyslipidemia, abnormal coagulation, altered fibrinolysis, and hypertension.

Rosiglitazone and pioglitazone (Figure 7) are the two thiazolidinediones approved by the FDA for use in the USA. In January 1997, troglitazone was the first thiazolidinedione to receive FDA approval. However, it was withdrawn from use in March 2000 due to hepatotoxicity. Rosiglitazone and pioglitazone were approved for use in 1999 and do not appear to have the same hepatic profile as their predecessor.

6.19.6.4.5.1 Mechanisms of action

The peroxisome proliferator-activated receptors (PPARs) are a subset of the 48-member nuclear-receptor superfamily and directly regulate gene expression. To date, three PPARs have been identified, PPAR-a, PPAR-S (also known as PPAR-b), and PPAR-g.

PPAR-a expression67 is primarily found in the liver, heart, skeletal muscle, and smooth muscle cells of the vascular wall (Table 8). PPAR-a activation regulates gene transcription directly, influencing lipoprotein metabolism, fatty acid uptake and oxidation, and some anti-inflammatory products. PPAR-a agonists have also been shown to prevent or slow the progression of atherosclerosis in animal models68 and in humans.69 Common ligands for PPAR-a are the fibrates, including fenofibrate, bezafibrate, ciprofibrate, and gemfibrozil.

Table 8 Target organs of PPAR action

Liver Skeletal muscle Adipose tissue

Lipoprotein metabolism

* Decreased apolipoprotein C-III

Increased apolipoprotein A-I, II

Fatty acid uptake

* Increased fatty acid transport protein-1

* Increased fatty acid translocase/CD36

Fatty acid catabolism

* Increased CPT I, II

Decreased inflammation

* Decreased C-reactive protein (ag)

Fatty acid catabolism (PPAR-<x)

* Increased CPT I, II

Glucose uptake (PPAR-y)

* Increased GLUT4

• Increased phosphatidyl 3-kinase

Adipocyte differentiation

Fatty acid uptake and storage

• Increased fatty acid transport protein-1

• Increased acyl-co-enzyme A synthetase

Intravascular lipolysis

• Increased lipoprotein lipase

Glucose uptake

• Increased GLUT4

• Increased phosphatidyl 3-kinase

• Increased insulin-receptor substrates IRS-1 and IRS-2

• Increased CAP

• Increased glycerol kinase

Other effects

• Increased adiponectin

Adhesion molecules

* Decreased intercellular adhesion molecule-1 (y)

* Decreased vascular-cell adhesion molecule-1 (ay)

Inflammation

* Increased nuclear factor kB (a)

* Decreased cyclooxygenase-

Decreased endothelin (ay) Cholesterol efflux

* Increased ABCA1 (aby)

* Increased scavenger receptor-Bl (ay)

Other

* Decreased iNOS (y)

* Decreased interleukin-6

* Decreased tissue factor (a)

ABC, ATP-binding cassette; CAP, Cbl-associated protein; CPT, carnitine palmitoyl transferase; HSD, hydroxysteroid dehydrogenase; iNOS, inducible nitric oxide synthase; MCP, monocyte chemoattractant protein; MMP, matrix metalloproteinase; PDK, pyruvate dehydrogenase kinase.

Adapted from Yki-Jarvinen, H. N. Engl. J. Med. 2004, 351, 1106-1118. Copyright © 2006 Massachusetts Medical Society. All rights reserved.

PPAR-S (also known as PPAR-b) expression is highest in adipose tissue, brain, and skin cells. Although not targeted pharmacologically yet, PPAR-S has been shown to delay wound closure and alter myelination.

PPAR-g expression is primarily found in adipose tissue, pancreatic b-cells, vascular endothelial cells, and macrophages. Tissues with high PPAR-g expression generally have lower expression of PPAR-a, and vice versa. PPAR-g activation regulates adipocyte differentiation, fatty acid uptake and storage, intravascular lipolysis, and glucose uptake.

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