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.

New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N-Substituted Thiazolidinedione

“…Based on the crucial role of thiazolidinediones in the treatment of diabetes, and given the risk associated with the use of the available drugs of this class (AlSalman et al, 2000;Maeda, 2001;Scheen, 2001;Scheen, 2003;Marcy et al, 2004;Alemán-González-Duhart et al, 2016), the development of new safer thiazolidinediones is of current interest (Cesar et al, 2015;Rudnicki et al, 2016;Silva et al, 2016;Naim et al, 2017;Thangavel et al, 2017). Since glitazones do not cause liver damage in laboratory animals, comparing these to new thiazolidinediones in order to research the mechanism of toxicity can be misleading (Patel et al, 2012).…”

“…Troglitazone was the first launched thiazolidinedione, but it was withdrawn from the market due to severe and sometimes fatal hepatotoxicity (Scheen, 2003). Rosiglitazone is available in the United States, whilst in Europe, its approval was withdrawn due to a significant increase in myocardial infarction (Alemán-González-Duhart et al, 2016); hepatotoxicity was also reported (Al-Salman et al, 2000;Forman et al, 2000). Pioglitazone ( Figure 1A) use in the United States is restricted as it may cause urinary bladder cancer (Alemán- González-Duhart et al, 2016).…”

“…Rosiglitazone is available in the United States, whilst in Europe, its approval was withdrawn due to a significant increase in myocardial infarction (Alemán-González-Duhart et al, 2016); hepatotoxicity was also reported (Al-Salman et al, 2000;Forman et al, 2000). Pioglitazone ( Figure 1A) use in the United States is restricted as it may cause urinary bladder cancer (Alemán- González-Duhart et al, 2016). In addition, hepatotoxicity cases have occurred (Maeda, 2001;Marcy et al, 2004), including one fulminant hepatic failure (Chase and Yarze, 2002).…”

Effect of PPAR-γ agonists on macrophage activation in type2 diabetes mellitus

“…Treatment strategies have focused on increasing the insulin receptor sensitivity. It has been clearly shown that Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists such as Rosiglitazone might improve glycemic control by enhancing insulin sensitivity [1] and ameliorate the impaired coronary arteriolar dilation by reducing oxidative stress. In spite of this positive effect on insulin sensitivity of Rosiglitazone, some authors indicated its adverse effects including fluid retention, weight gain, hepatotoxicity, plasma-volume expansion, hemodilution, edema, bone fractures [1].…”

“…It has been clearly shown that Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists such as Rosiglitazone might improve glycemic control by enhancing insulin sensitivity [1] and ameliorate the impaired coronary arteriolar dilation by reducing oxidative stress. In spite of this positive effect on insulin sensitivity of Rosiglitazone, some authors indicated its adverse effects including fluid retention, weight gain, hepatotoxicity, plasma-volume expansion, hemodilution, edema, bone fractures [1]. From 2007 in which was noticed the adverse effect of Rosiglitazone in development of atherosclerosis [2] till today, many conflicting meta-analyses have reported on the cardiovascular effect of thiazolidinediones [3][4][5].…”