scholarly journals Pioglitazone in the Treatment of Type 2 Diabetes: Safety and Efficacy Review

2010 ◽  
Vol 3 ◽  
pp. CMED.S5372 ◽  
Author(s):  
Cyrus V. Desouza ◽  
Vijay Shivaswamy
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Ppar Gamma ◽  
New Drugs ◽  
Peroxisome Proliferator ◽  
Cardiovascular Safety ◽  
Peroxisome Proliferator Activated Receptor ◽  
Safety And Efficacy ◽  
Beneficial Effects

The increase in obesity and the aging of the population has lead to an increase in the incidence of type 2 diabetes. This has led to the development of new drugs such as thiazolidinediones (TZDs) which are Peroxisome Proliferator-Activated Receptor (PPAR-gamma) agonists, to treat type 2 diabetes. TZDs have recently been at the center of a controversy with regards to their cardiovascular safety. Pioglitazone is a TZD which has been shown to be effective in glycemic control by lowering insulin resistance. Pioglitazone also has beneficial effects on lipid metabolism and cardiovascular risk. The safety and efficacy of pioglitazone including its pleotropic effects are discussed at length in this article.

scholarly journals Peroxisome Proliferator-Activated Receptor γ and Adipose Tissue—Understanding Obesity-Related Changes in Regulation of Lipid and Glucose Metabolism

2006 ◽  
Vol 92 (2) ◽  
pp. 386-395 ◽  
Author(s):  
Arya M. Sharma ◽  
Bart Staels
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Endocrine Function ◽  
Low Grade ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Abstract Context: Adipose tissue is a metabolically dynamic organ, serving as a buffer to control fatty acid flux and a regulator of endocrine function. In obese subjects, and those with type 2 diabetes or the metabolic syndrome, adipose tissue function is altered (i.e. adipocytes display morphological differences alongside aberrant endocrine and metabolic function and low-grade inflammation). Evidence Acquisition: Articles on the role of peroxisome proliferator-activated receptor γ (PPARγ) in adipose tissue of healthy individuals and those with obesity, metabolic syndrome, or type 2 diabetes were sourced using MEDLINE (1990–2006). Evidence Synthesis: Articles were assessed to provide a comprehensive overview of how PPARγ-activating ligands improve adipose tissue function, and how this links to improvements in insulin resistance and the progression to type 2 diabetes and atherosclerosis. Conclusions: PPARγ is highly expressed in adipose tissue, where its activation with thiazolidinediones alters fat topography and adipocyte phenotype and up-regulates genes involved in fatty acid metabolism and triglyceride storage. Furthermore, PPARγ activation is associated with potentially beneficial effects on the expression and secretion of a range of factors, including adiponectin, resistin, IL-6, TNFα, plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, and angiotensinogen, as well as a reduction in plasma nonesterified fatty acid supply. The effects of PPARγ also extend to macrophages, where they suppress production of inflammatory mediators. As such, PPARγ activation appears to have a beneficial effect on the relationship between the macrophage and adipocyte that is distorted in obesity. Thus, PPARγ-activating ligands improve adipose tissue function and may have a role in preventing progression of insulin resistance to diabetes and endothelial dysfunction to atherosclerosis.

scholarly journals Peroxisome proliferator-activated receptor gamma agonists in renal disease

2006 ◽  
Vol 154 (5) ◽  
pp. 613-621 ◽  
Author(s):  
Pedro Iglesias ◽  
Juan J Díez
Keyword(s):  
Type 2 Diabetes ◽  
Renal Function ◽  
Experimental Studies ◽  
Metabolic Effects ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
Patients With Diabetes ◽  
Pparγ Agonists

Type 2 diabetes is a well recognised cause of chronic renal failure (CRF). Only few oral antidiabetic drugs can be used for treating type 2 diabetes in patients with CRF. Among them are repaglinide, a rapid-acting prandial insulin releaser, and peroxisome proliferator-activated receptor gamma (PPARγ) agonists, such as rosiglitazone and pioglitazone. These compounds are metabolised in the liver, therefore accumulation of the drug and the risk of severe and prolonged hypoglycaemia are minimised. PPARγ receptors are expressed in many tissues including the kidney. Recently, numerous healthful effects of PPARγ agonists on several aspects related to renal function have been increasingly reported. These drugs have shown to possess many advantageous anti-inflammatory, haemodynamic, vascular and metabolic effects. In the present paper we have reviewed the more recent experimental studies that evaluated these potential beneficial effects of PPARγ agonists on renal function and revised the results of their utilisation in patients with different degrees of renal impairment, in dialysis patients, and in patients with diabetes mellitus after kidney transplantation. Finally, tolerability and safety profile of PPARγ agonists in patients with reduced glomerular filtration rate are also analysed.

scholarly journals Chiglitazar Preferentially Regulates Gene Expression via Configuration-Restricted Binding and Phosphorylation Inhibition of PPARγ

PPAR Research ◽  
2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
De-Si Pan ◽  
Wei Wang ◽  
Nan-Song Liu ◽  
Qian-Jiao Yang ◽  
Kun Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose And Lipid Metabolism ◽  
Effective Part

Type 2 diabetes mellitus is often treated with insulin-sensitizing drugs called thiazolidinediones (TZD), which improve insulin resistance and glycemic control. Despite their effectiveness in treating diabetes, these drugs provide little protection from eminent cardiovascular disease associated with diabetes. Here we demonstrate how chiglitazar, a configuration-restricted non-TZD peroxisome proliferator-activated receptor (PPAR) pan agonist with moderate transcription activity, preferentially regulates ANGPTL4 and PDK4, which are involved in glucose and lipid metabolism. CDK5-mediated phosphorylation at serine 273 (S273) is a unique regulatory mechanism reserved for PPARγ, and this event is linked to insulin resistance in type 2 diabetes mellitus. Our data demonstrates that chiglitazar modulates gene expression differently from two TZDs, rosiglitazone and pioglitazone, via its configuration-restricted binding and phosphorylation inhibition of PPARγ. Chiglitazar induced significantly greater expression of ANGPTL4 and PDK4 than rosiglitazone and pioglitazone in different cell models. These increased expressions were dependent on the phosphorylation status of PPARγ at S273. Furthermore, ChIP and AlphaScreen assays showed that phosphorylation at S273 inhibited promoter binding and cofactor recruitment by PPARγ. Based on these results, activities from pan agonist chiglitazar can be an effective part of a long-term therapeutic strategy for treating type 2 diabetes in a more balanced action among its targeted organs.

scholarly journals Targeting Peroxisome Proliferator-Activated Receptors Using Thiazolidinediones: Strategy for Design of Novel Antidiabetic Drugs

2017 ◽  
Vol 2017 ◽  
pp. 1-20 ◽  
Author(s):  
Neelaveni Thangavel ◽  
Mohammed Al Bratty ◽  
Sadique Akhtar Javed ◽  
Waquar Ahsan ◽  
Hassan A. Alhazmi
Keyword(s):  
Type 2 Diabetes ◽  
Therapeutic Potential ◽  
Antidiabetic Drugs ◽  
New Drugs ◽  
Antidiabetic Activity ◽  
Future Research ◽  
Structural Domain ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Thiazolidinediones are a class of well-established antidiabetic drugs, also named as glitazones. Thiazolidinedione structure has been an important structural domain of research, involving design and development of new drugs for the treatment of type 2 diabetes. Extensive research on the mechanism of action and the structural requirements has revealed that the intended antidiabetic activity in type 2 diabetes is due to their agonistic effect on peroxisome proliferator-activated receptor (PPAR) belonging to the nuclear receptor super family. Glitazones have specific affinity to PPARγ, one of the subtypes of PPARs. Certain compounds under development have dual PPARα/γ agonistic activity which might be beneficial in obesity and diabetic cardiomyopathy. Interesting array of hybrid compounds of thiazolidinedione PPARγ agonists exhibited therapeutic potential beyond antidiabetic activity. Pharmacology and chemistry of thiazolidinediones as PPARγ agonists and the potential of newer analogues as dual agonists of PPARs and other emerging targets for the therapy of type 2 diabetes are presented. This review highlights the possible modifications of the structural components in the general frame work of thiazolidinediones with respect to their binding efficacy, potency, and selectivity which would guide the future research in design of novel thiazolidinedione derivatives for the management of type 2 diabetes.

scholarly journals The PPARβ/δ-AMPK Connection in the Treatment of Insulin Resistance

2021 ◽  
Vol 22 (16) ◽  
pp. 8555
Author(s):  
David Aguilar-Recarte ◽  
Xavier Palomer ◽  
Walter Wahli ◽  
Manuel Vázquez-Carrera
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
New Drugs ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Ampk Pathway ◽  
Antidiabetic Effects

The current treatment options for type 2 diabetes mellitus do not adequately control the disease in many patients. Consequently, there is a need for new drugs to prevent and treat type 2 diabetes mellitus. Among the new potential pharmacological strategies, activators of peroxisome proliferator-activated receptor (PPAR)β/δ show promise. Remarkably, most of the antidiabetic effects of PPARβ/δ agonists involve AMP-activated protein kinase (AMPK) activation. This review summarizes the recent mechanistic insights into the antidiabetic effects of the PPARβ/δ-AMPK pathway, including the upregulation of glucose uptake, muscle remodeling, enhanced fatty acid oxidation, and autophagy, as well as the inhibition of endoplasmic reticulum stress and inflammation. A better understanding of the mechanisms underlying the effects resulting from the PPARβ/δ-AMPK pathway may provide the basis for the development of new therapies in the prevention and treatment of insulin resistance and type 2 diabetes mellitus.

scholarly journals Effect of sitagliptin on expression of skeletal muscle peroxisome proliferator-activated receptor γ coactivator-1α and irisin in a rat model of type 2 diabetes mellitus

2020 ◽  
Vol 48 (5) ◽  
pp. 030006051988556
Author(s):  
Yuntao Liu ◽  
Feng Xu ◽  
Pan Jiang
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Type 2 Diabetes Mellitus ◽  
Rat Model ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Tnf Α

Objective To evaluate the effect of sitagliptin on skeletal muscle expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), irisin, and phosphoadenylated adenylate activated protein kinase (p-AMPK) in a rat model of type 2 diabetes mellitus (T2DM). Methods A high-fat diet/streptozotocin T2DM rat model was established. Rats were divided into T2DM, low-dose sitagliptin (ST1), high-dose sitagliptin (ST2), and normal control groups (NC). PGC-1α, irisin, and p-AMPK protein levels in skeletal muscle were measured by western blot, and PCG-1α and Fndc5 mRNA levels were assessed by reverse transcription-polymerase chain reaction. Results Fasting plasma glucose (FPG), fasting insulin (FIns), homeostatic model assessment-insulin resistance (HOMA-IR), and tumor necrosis factor-α (TNF-α) were significantly up-regulated in the T2DM compared with the other groups, and FPG, FIns, total cholesterol, triglycerides, TNF-α, and HOMA-IR were significantly down-regulated in the ST2 compared with the ST1 group. PGC-1α, irisin, and p-AMPK expression levels decreased successively in the ST2, ST1, and DM groups compared with the NC, and were all significantly up-regulated in the ST2 compared with the ST1 group. Conclusion Down-regulation of PGC-1α and irisin in skeletal muscle may be involved in T2DM. Sitagliptin can dose-dependently up-regulate PCG-1α and irisin, potentially improving insulin resistance and glycolipid metabolism and inhibiting inflammation.

Efficacy and cardiovascular safety of Thiazolidinediones

2020 ◽  
Vol 15 ◽  
Author(s):  
Raveendran Arkiath Veettil ◽  
Cornelius James Fernandez ◽  
Koshy Jacob
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Glucose Transporter ◽  
Cell Function ◽  
Cardiovascular Safety ◽  
Cardiovascular Outcome Trials ◽  
Glucose Transporter 2 ◽  
Insulin Sensitizers

: Type 2 diabetes mellitus (T2DM) is characterized by a progressive beta cell dysfunction in the setting of peripheral insulin resistance. Insulin resistance in subjects with type 2 diabetes and metabolic syndrome is primarily caused by an ectopic fat accumulation in liver and skeletal muscle. Insulin sensitizers are particularly important in the management of T2DM. Though, thiazolidinediones (TZDs) are principally insulin sensitizers, they possess an ability to preserve pancreatic β-cell function and thereby exhibit durable glycemic control. Cardiovascular outcome trials (CVOTs) have shown that Glucagon-like-peptide 1 receptor agonists (GLP-1 RAs) and sodium glucose transporter-2 inhibitors (SGLT2i) have proven cardiovascular safety. In this era of CVOTs, drugs with proven cardiovascular (CV) safety are often preferred in patients with preexisting cardiovascular disease or at risk of cardiovascular disease. In this review, we will describe the three available drugs belonging to the TZD family, with special emphasis on their efficacy and CV safety.

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