Fine Tuning of PPAR Ligands for Type 2 Diabetes and Metabolic Syndrome

Ramachandran, Uma; Kumar, Rakesh; Mittal, Amit

doi:10.2174/138955706776876140

Cited by 38 publications

(17 citation statements)

References 56 publications

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“…Selective PPAR modulators, PPAR␦ agonists, and PPAR␥ antagonists are all being considered as possible approaches to limit the weight gain and/or edema seen with current TZDs. 177 The particularly large size of the PPAR LBD and the fact that distinct biological responses derive from specific ligand-receptor physical interaction provide a scientific basis for such efforts. Certainly, clinical experience establishes that agonists for the same PPAR isotype can have unique effects.…”

Section: Brown and Plutzky Ppars As Therapeutic Targets 525mentioning

confidence: 99%

Peroxisome Proliferator–Activated Receptors as Transcriptional Nodal Points and Therapeutic Targets

2007

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Abstract-Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in the transcriptional regulation of key metabolic pathways such as lipid metabolism, adipogenesis, and insulin sensitivity. More recent work implicates all 3 PPAR isotypes (␣, ␥, and ␦, also known as ␤ or ␤/␦) in inflammatory and atherosclerotic pathways. Because these nuclear receptors are activated by extracellular signals and control multiple gene targets, PPARs can be seen as nodes that control multiple inputs and outputs involved in energy balance, providing insight into how metabolism and the vasculature may be integrated. The ongoing clinical use of fibrates, which activate PPAR␣, and thiazolidinediones, which activate PPAR␥, establishes these receptors as viable drug targets, whereas considerable in vitro animal model and human surrogate marker studies suggest that PPAR activation may limit inflammation and atherosclerosis. Together, these various observations have stimulated intense interest in PPARs as therapeutic targets and led to large-scale cardiovascular end-point trials with PPAR agonists. The first of these studies has generated mixed results that require careful review, especially in anticipation of additional clinical trial data and ongoing attempts to develop novel PPAR modulators. Such analysis of the existing PPAR data, the appropriate use of currently approved PPAR agonists, and continued progress in PPAR therapeutics will be predicated on a better understanding of PPAR biology. what mechanisms synchronize these systems to regulate vascular tone and hemostasis and adaptive responses in the circulation? Pathologically, how do cardiovascular risk factors perturb this balance and foster a chronic inflammatory state? Therapeutically, does this orchestrated view of the vasculature suggest targets that might address underlying "syndromes" rather than individual risk parameters? Peroxisome proliferator-activated receptors (PPARs) have been implicated in the answers to all of these questions, thus explaining the attention focused on these steroid hormone nuclear receptors. [2][3][4] The ongoing clinical use of synthetic PPAR agonists, eg, insulin-sensitizing thiazolidinediones (TZDs) and lipid-lowering fibrates, and the evidence that PPAR activation also may limit inflammation and atherosclerosis have only heightened this interest and the pursuit of novel PPAR agonists. At the same time, the untoward effects and recent mixed clinical cardiovascular trial results seen with synthetic PPAR agonists have prompted questions about PPARs, their mechanisms of action, and the future of PPAR therapeutics. Together, these issues make the science of PPARs and PPAR agonists of obvious importance to the clinician. Here, we overview the clinically relevant aspects of PPAR biology before considering each PPAR isoform and the existing data for PPAR involvement in vascular responses in relevant cell types. This information provides a basis for considering the existing and emerging clinical data in this ...

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Section: Brown and Plutzky Ppars As Therapeutic Targets 525mentioning

confidence: 99%

Peroxisome Proliferator–Activated Receptors as Transcriptional Nodal Points and Therapeutic Targets

2007

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“…Currently, GW-677954, PLX-204, GW625019, LY-465608, DRF-11605, CS-204, and DRL-11605 are under investigation [85].…”

Section: Clinical Applicationmentioning

confidence: 99%

Nuclear Receptors of the Peroxisome Proliferator-Activated Receptor (PPAR) Family in Gestational Diabetes: From Animal Models to Clinical Trials1

Arck

Tóth

Pestka

et al. 2010

Biology of Reproduction

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Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance and affects 2%-8% of all pregnancies. Among other complications, GDM can lead to the development of type 2 diabetes mellitus (DM 2) in both mother and child. Peroxisome proliferator-activated receptors (PPARs) are major regulators of glucose and lipid metabolism. Furthermore, PPARs are mediators of inflammation and angiogenesis and are involved in the maternal adaptational dynamics during pregnancy to serve the requirements of the growing fetus. PPARs were originally named for their ability to induce hepatic peroxisome proliferation in mice in response to xenobiotic stimuli. The expression of three PPAR isoforms, alpha, beta/delta, and gamma, have been described. Each of them is encoded by different genes; however, they share 60%-80% homology in their ligand-binding and DNA-binding domains. PPARs are involved in trophoblast differentiation, invasion, metabolism, and parturition and are expressed in invasive extravillous trophoblast and villous trophoblast cells. Nuclear receptors, to which PPARs belong, are promising targets for disease-specific treatment strategies because they act as transcription factors controlling cellular processes at the level of gene expression and may produce selective alterations in downstream gene expression. To date, PPAR agonists are therapeutically used in patients with DM 2 and in patients with reproductive disorders such as polycystic ovary syndrome. Because of safety concerns and limited data, PPAR agonists are not yet included in GDM-related treatment strategies. Our objective herein is to review newly emerging generations of selective PPAR modulators and panagonists, which may have potent therapeutic implications in the context of GDM.

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“…Bezafibrate, a PPAR-α agonist, has been found to activate all three PPAR isoforms [15,16], but its glucose-lowering effect is not significant in clinical studies [17]. Most pan-PPAR agonists, including GW677954, DRL-11605, PLX-204, GW625019 and netoglitazone, have been discontinued because of safety problems [18][19][20]. Additionally, preclinical studies on pan-PPAR agonists LY465608 and BPR1H036 are not progressing smoothly [21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice

Luo

et al. 2016

Diabetologia

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Fine Tuning of PPAR Ligands for Type 2 Diabetes and Metabolic Syndrome

Cited by 38 publications

References 56 publications

Peroxisome Proliferator–Activated Receptors as Transcriptional Nodal Points and Therapeutic Targets

Peroxisome Proliferator–Activated Receptors as Transcriptional Nodal Points and Therapeutic Targets

Nuclear Receptors of the Peroxisome Proliferator-Activated Receptor (PPAR) Family in Gestational Diabetes: From Animal Models to Clinical Trials1

Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice

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