Pharmacogenomics and Pharmacogenetics of Thiazolidinediones: Role in Diabetes and Cardiovascular Risk Factors

Abstract

The most important goal in the treatment of patients with diabetes is to prevent the risk of cardiovascular disease (CVD), the first cause of mortality in these subjects. Thiazolidinediones (TZDs), a class of antidiabetic drugs, act as insulin sensitizers increasing insulin-dependent glucose disposal and reducing hepatic glucose output. TZDs including pioglitazone, rosiglitazone and troglitazone, by activating PPAR-γ have shown pleiotropic effects in reducing vascular risk factors and atherosclerosis. However, troglitazone was removed from the market due to its hepatoxicity, and rosiglitazone and pioglitazone both have particular warnings due to being associated with heart diseases. Specific genetic variations in genes involved in the pathways regulated by TDZs have demonstrated to modify the variability in treatment with these drugs, especially in their side effects. Therefore, pharmacogenomics and pharmacogenetics are an important tool in further understand intersubject variability per se but also to assess the therapeutic potential of such variability in drug individualization and therapeutic optimization.

The effect of abscisic acid chronic treatment on neuroinflammatory markers and memory in a rat model of high-fat diet induced neuroinflammation

“…Insulin sensitizers have been proposed as a promising tool for the reduction of obesity-induced insulin resistance and inflammation processes. The thiazolidinediones (TDZ) are a family of synthetic insulin sensitizer molecules; however, some of them have undesirable side effects [2–4]. Thus, alternative compounds with analogous properties but fewer side effects are needed.…”

Using Personalized Medicine in the Management of Diabetes Mellitus

“…In addition, these genes were demonstrated to reduce insulin resistance. 69 As seen with the other OGLTs, there is pronounced interindividual variability in response to TZD treatment. Clinical studies of pioglitazone and rosiglitazone show that between 12% and 45% of T2DM patients failed to achieve sufficient reduction in either fasting plasma glucose and/or HbA1 c concentrations.…”

“…PPAR‐γ activation in mature adipose cells induces expression of genes involved in the insulin signaling cascade and as a result improves insulin sensitivity in diabetic patients. In addition, these genes were demonstrated to reduce insulin resistance …”

The contribution of bone marrow-derived cells to the human adipocyte pool

“…7 Unfortunately, side effects mediated via actions in non-adipose tissues (primarily fluid retention and osteoporosis), have limited their clinical use in recent years. 8 A fundamental question in understanding fat cell formation relates to the origin of adipocytes. While it is clear that they differentiate from progenitor cells present in the perivascular stroma, [9][10][11][12] it is not yet known from where, when or how these cells migrate into the tissue.…”