Pleiotropic Effects of Thiazolidinediones: Implications for the Treatment of Patients With Type 2 Diabetes Mellitus

Abstract

Thiazolidinediones (TZDs) are insulin-sensitizing antidiabetes agents that act through the peroxisome proliferator-activated receptor-γ to cause a durable improvement in glycemic control in patients with type 2 diabetes mellitus. Although less well recognized, TZDs also exert a protective effect on β-cell function. In addition to their beneficial effects on glucose homeostasis, TZDs-especially pioglitazone-exert a number of other pleiotropic effects that make them ideal agents as monotherapy or in combination with other oral agents, glucagon-like peptide-1 analogs, or insulin. Pioglitazone improves endothelial dysfunction, reduces blood pressure, corrects diabetic dyslipidemia, and reduces circulating levels of inflammatory cytokines and prothrombotic factors. Pioglitazone also redistributes fat and toxic lipid metabolites in muscle, liver, β cells, and arteries, and deposits the fat in subcutaneous adipocytes where it cannot exert its lipotoxic effects. Consistent with these antiatherogenic effects, pioglitazone reduced major adverse cardiac event endpoints (ie, mortality, myocardial infarction, and stroke) in the Prospective Pioglitazone Clinical Trial in Macrovascular Events and in a meta-analysis of all other published pioglitazone trials. Pioglitazone also mobilizes fat out of the liver, improving liver function and histologic abnormalities in patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Pioglitazone also reduces proteinuria, all-cause mortality, and cardiovascular events in patients with type 2 diabetes mellitus with a reduced glomerular filtration rate. These benefits must be weighed against the side effects of the drug, including weight gain, fluid retention, atypical fractures, and, possibly, bladder cancer. When low doses of pioglitazone are used (eg, 7.5-30 mg/d) with gradual titration, and physician recognition of the potential side effects are applied, the risk-to-benefit ratio is very favorable. Despite having similar effects on glycemic control, pioglitazone and rosiglitazone appear to have different effects on cardiovascular outcomes. Rosiglitazone has been associated with an increased risk of myocardial infarction, and its use in the United States is restricted because of cardiovascular safety concerns.

Insulin Sensitizing and Anti-Inflammatory Effects of Thiazolidinediones Are Heightened in Obese Patients

“…39 On the other hand, pioglitazone has been shown to have particular benefits in certain populations, such as improving liver function in individuals with nonalcoholic fatty liver disease and reducing proteinuria in patients with both T2DM and reduced glomerular filtration rate. 40 The sample size and duration of the current study were not designed to address the safety of pioglitazone, although it was reassuring that none of the subjects in this study experienced any adverse effects.…”

Current and Emerging Treatment Options in Diabetes Care

“…TZDs exert a number of pleiotropic effects, such as reducing circulating levels of pro-inflammatory cytokines and increasing adiponectin levels, which may add to the insulin-sensitizing effects associated with their usage (Defronzo et al 2013;Hauner 2002;Tonelli et al 2004). However, PPARγ is abundantly expressed in fat cells (also in the muscle and liver), and activation by TZDs initiates lipogenic transcriptional signaling and the most common adverse effect associated with TZDs -weight gain (Fonseca 2003;Smith et al 2005).…”

Ethanol Extract of Tithonia diversifolia (Hemsley) A Gray Standardized Ameliorates Hyperglycemia, Polyphagia, and Weight Loss in Diabetic Rats

“…Activation of PPARs γ can increase the expression of a number of genes related to lipid and glucose metabolism and regulate insulin transcription in pancreas β cells (Grygiel-Górniak, 2014;Leonardini, Laviola, Perrini, Natalicchio, & Giorgino, 2009). However, in its development thiazolidinediones have a pleiotropic effect that increases the risk of miocard infarction as reported in previous studies (Defronzo et al, 2015), so that Tithonia diversifolia leaf extract can be a complementary or alternative therapy in the treatment of DM. The ameliorative effect of Tithonia diversifolia leaf also due to its antioxidant effect which can decrease oxidative stress caused by diabetes.…”

“…The use of conventional medicines as anti-hyperglycemia has been reported to have some side effects (Defronzo, Mehta, & Schnure, 2015). Based on this, it needs a breakthrough in the treatment of DM through the discovery of new drugs by exploring the medicinal plants that have traditionally been used to treat anti-diabetes.…”