Current Advances in the Biochemical and Physiological Aspects of the Treatment of Type 2 Diabetes Mellitus with Thiazolidinediones

Abstract

The present review summarizes the current advances in the biochemical and physiological aspects in the treatment of type 2 diabetes mellitus (DM2) with thiazolidinediones (TZDs). DM2 is a metabolic disorder characterized by hyperglycemia, triggering the abnormal activation of physiological pathways such as glucose autooxidation, polyol's pathway, formation of advance glycation end (AGE) products, and glycolysis, leading to the overproduction of reactive oxygen species (ROS) and proinflammatory cytokines, which are responsible for the micro- and macrovascular complications of the disease. The treatment of DM2 has been directed toward the reduction of hyperglycemia using different drugs such as insulin sensitizers, as the case of TZDs, which are able to lower blood glucose levels and circulating triglycerides by binding to the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) as full agonists. When TZDs interact with PPARγ, the receptor regulates the transcription of different genes involved in glucose homeostasis, insulin resistance, and adipogenesis. However, TZDs exhibit some adverse effects such as fluid retention, weight gain, hepatotoxicity, plasma-volume expansion, hemodilution, edema, bone fractures, and congestive heart failure, which limits their use in DM2 patients.

Figure 1

The main pathways triggered by hyperglycemia include glucose autooxidation and constant activation of polyols' pathway and formation of advance glycation end products (AGEs) and excessive glycolysis. With the constant activation of these pathways, living cells and tissues are damaged, mainly by impairment of target protein function, increase in oxidative stress, and activation of signal transduction pathways, leading to the imbalance of normal physiological functions and therefore the development of diabetic complications.

Figure 2

Main functional domains of nuclear PPARs. All three isotypes of PPAR have 4 main functional domains: A/B, which is the activation function 1 (AF-1); C, or DNA binding domain; D, which serves as a hinge between C and E/F; and E/F, which includes AF-2, a ligand binding dimerization transactivation domain.

Figure 3

Crystal structure of PPARγ (PDB: 2PRG entry), cocrystalized with rosiglitazone (ligand) and steroid receptor coactivator 1 (SRC-1, coactivator). Figure constructed using Visual Molecular Dynamics (VMD) software.

Figure 4

Mechanism of action of PPARγ when it is activated by its exogenous ligands thiazolidinediones (TZDs).