Rosiglitazone: A PPAR-γ Full Agonist of the Thiazolidinedione Class for Management of Type II Diabetes
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A 73-year-old, obese female patient was admitted to the emergency department presenting with fatigue, pink frothing phlegm, cyanosis, and dyspnea. The patient had a medical history of type II diabetes, hypertension and congestive heart disease for almost 10 years. Four weeks after initiation of rosiglitazone, her cardiovascular system examination revealed that her heart rate was rhythmic, but tachycardic. There was pretibial edema (4+) on the lower extremities bilaterally. Based on clinical and laboratory findings, the physician diagnosed acute pulmonary edema likely due to rosiglitazone use.
Rosiglitazone was discontinued.
Type II diabetes mellitus (DM) is a condition of decreased sensitivity to insulin. Medications like Rosiglitazone, classified as Thiazolidinediones (TZDs), have been used for type II DM-associated conditions including hyperglycemia, insulin resistance, and obesity. Rosiglitazone targets peroxisome proliferator active receptor gamma (PPAR-γ) to promote [transcription of genes that control] glucose and lipid metabolism when insulin is present. TZDs have proven to help improve insulin sensitivity, but complications have resulted in discontinuation of these medications. Development of a drug that targets PPAR-γ without severe adverse reactions could be the next step in diabetic treatment.
Rosiglitazone acts as a full PPAR-γ agonist and may be utilized by patients with type II diabetes mellitus. Rosiglitazone targets PPAR-γ, a nuclear hormone receptor that initiates transcription. It decreases insulin resistance by increased transcription of GLUT4 transporters in adipose and skeletal tissues. This improves utilization of glucose10 and may help treat type II diabetes.
An important part of the PPAR-γ structure is its ligand binding pocket (LBP) in which agonists bind, creating a conformational change in the receptor. This change makes the binding site for favorable for co-activators, which activates transcription.
PPAR-γ binds:
-Thiazolidinediones, such as rosiglitazone, when insulin is present.
-Natural lipophilic molecules such as fatty acid chains and products originating from arachidonic acid and prostaglandins9.
PPAR-γ full agonist pharmacophore:
-Tertiary amine
-2-6 Carbon linker between tertiary amine and ether
-Glitazone group (thiazolidine-2,4-dione, and benzene ring)
-Adverse Effects of PPAR-γ full agonists:
-Adipogenesis
-Fluid retention
-Increase risk of heart failure
The protein target of Rosiglitazone is peroxisome proliferator-activated receptor gamma (PPAR-γ). The structure of the protein target consists mostly of alpha helices with 2 beta pleated sheets. The alpha helices are colored green in all of the following Jmol images, the beta pleated sheets are color purple. Click on the following two buttons to see the structure of PPAR-γ. One of the natural fatty acids forms two hydrogen bonds with two different histidine residues, 323 and 449. There are also a few hydrophobic pockets created by the fatty acids that will be shown later.
Whole Protein StructureThe ligand binding region of PPAR-γ is modeled after three natural ligands to PPAR-γ. The images below are of the three natural nonanoic acids bound to PPAR-γ in three different arms of the ligand binding site. Each arm has different interactions that give an agonizing effect to PPAR-γ. The binding site forms a 'U' shape as it wraps around one of the helices in PPAR-γ. Click on the first button below to see the binding region, and the second button to see the 'U' shape.
Ligand Binding Region from 3 Nonanoic AcidsRosiglitazone fits into two different arms of the binding site in PPAR-γ, which gives it a full agonist effect. Rosiglitazone forms the same two hydrogen bonds with histidine residues 323 and 449, but it forms two additional hydrogen bonds with a tyrosine and lysine residue. These four hydrogen bonds give the TZD head of rosiglitazone a fixed position in the binding pocket of PPAR-γ.
Hydrogen Bond Interactions with ProteinIf you are having trouble seeing the interactions, click the button below to remove the protein to help see it better.
Hydrogen Bond Interactions without ProteinUnlike the natural fatty acids that bind to PPAR-γ, rosiglitazone is able to reach into another arm of the binding site through the tight pocket between the cysteine and methionine residues. The central benzene ring of rosiglitazone fits right between the pocket into the other arm. The ability of the molecule to fit in this tight pocket is what gives it agonist effect in two different arms.
Rosiglitazone has more interactions besides hydrogen bonding. There are also some areas of hydrophobic interactions within the binding site. The sulfur atom in the TZD ring of rosiglitazone fits within the hydrophobic pocket of two phenylalanines, one glutamine, and one lysine residue. These hydrophobic interactions are seen in the next image.
Hydrophobic InteractionsThe way rosiglitazone interacts with the PPAR-γ binding site results in full agonist action. Since PPARs are nuclear hormone receptors, agonist activity results in enhanced transcription of some genes as well as the reduced transcription of other genes at the cellular level. The most relevant effect of rosiglitazone that involves type II diabetes is the decrease of insulin resistance, especially in adipose tissue. This is mediated by increased transcription of genes that code for glucose transporters.
Mainly, expression of the glucose transporter GLUT4 in adipose tissue is enhanced, which leads to improved use of glucose by the adipose tissue, skeletal muscle, and liver. Other effects, such as lowering of cholesterol levels in the plasma and shifting of the storage of free fatty acids from non-adipose cells to adipocytes, as well as the release of cytokines such as TNF-alpha, resistin, and adiponectin are regulated to enhance insulin sensitivity. Finally, adipogenesis is promoted in such a way that the fat in the body is redistributed from visceral to subcutaneous stores. The subcutaneous adipocytes tend to be less lipophilic and more insulin sensitive. It is important to make the distinction that rosiglitazone does not stimulate the production of insulin; rather it enhances the sensitivity of tissue to the presence of insulin. Therefore, treatment of type I diabetes with drugs in this class is not effective.
The negative effects of rosiglitazone have important ramifications for select patient populations who may otherwise be candidates for treatment with this drug. Rosiglitazone, and other drugs in the same class, increase fluid retention which in turn increases the risk of congestive heart failure, especially with the concomitant use of a sulfonylurea or insulin therapy. The direct mechanism of thiazolidinedione-induced edema is unknown, but some of the potential mechanisms includes expansion of plasma volume and increased vascular endothelial cell permeability related to an increase in vascular permeability factor expression. Due to the previously stated effects, treatment of type II diabetes with rosiglitazone or other drugs in the same class in patients who have a pre-existing diagnosis of heart disease (class III or IV) or heart failure is not recommended, especially since these types of patients were excluded from premarketing clinical trials. Similarly, rosiglitazone therapy should be discontinued if deterioration in cardiac status is noted or suspected.
Referring back to the case synopsis presented at the beginning of this paper, one is now able to understand the mechanism behind why the female patient experienced increased fluid retention and an episode of acute pulmonary edema. The patient had a pre-existing condition of congestive heart failure for almost 10 years, and yet the patient was still prescribed rosiglitazone which has been shown to increase fluid retention and thus increase the chance for an exacerbation event. The patient was noted to have had edema in her legs for 2 weeks prior to her visit to the emergency department, which is a noted consequence or side effect of rosiglitazone. Since the medication was not discontinued and the patient did not seek reversal treatment for the edema, she experienced an acute episode of pulmonary edema due to the accumulation of fluid two weeks later.
1. Nolte RT, Wisely GB, Westin S, et al. Ligand Binding and Co-Activator Assembly of the Peroxisome Proliferator-Activated Receptor-Gamma. Nature. 1998;395(6698):137-143. http://www.ncbi.nlm.nih.gov/pubmed/9744270. Accessed December 3, 2014.
2. Liberato MV, Nascimento AS, Ayers SD, Lin JZ, Cvoro A, et al. (2012) Medium Chain Fatty Acids Are Selective Peroxisome Proliferator Activated Receptor (PPAR) Activators and Pan-PPAR Partial Agonists. PLoS ONE 7(5): e36297. Doi: 10.1371/journal.one.0036297. Accessed December 3, 2014.
3. Rosiglitazone Maleate. IN: Micromedex 2.0 [database online]. Truven Health Analytics Inc. http://0-www.micromedexsolutions.com.topcat.switchinc.org/micromedex2/librarian/PFDefaultActionId/evidencexpert.DoIntegratedSearch Updated periodically. Accessed December 1, 2014.