The role of PPARs in the microvascular dysfunction in diabetes

There is a major defect in skin blood flow (SkBF) in people with type 2 diabetes (T2DM). This defect is associated with relatively normal nitric oxide (NO) production in the skin. The abnormal blood flow cosegregates with hypertension, dyslipidemia, abnormal fatty acid composition, a proinflammatory state, and insulin resistance. Since these covariates are an integral part of the insulin resistance syndrome, we examined the effects of the thiazoledindiones (TZDs) as insulin sensitizers for their ability to correct the abnormal blood flow. The PPARgamma rosiglitazone improved NO production to normal levels, but had a small effect on SKBF. In contrast, pioglitazone had a small effect on skin neurovascular function but a dramatic effect on reducing nitrosative stress. These effects do not appear to be due to the insulin sensitizing properties of these compounds but are associated with a reduction in indices of inflammation, hemodilution, and are likely to be due to one of the many "vascular" effects of TZDs. The role of inflammation in the disordered neurovascular function in diabetes cannot be underplayed and the possible contribution of PPARalpha agonists to alter the inflammatory state needs to be explored further. Since blood flow regulation is mediated by mechanisms other than NO, such as prostaglandins and endothelial derived hyperpolarizing factor, which, in turn, are compromised by the inflammatory state, we anticipate that activation of both the PPARgamma as well as PPARalpha should ameliorate the disordered blood flow in type 2 diabetes. While it now appears that the PPARs may have a major role to play in protection from macrovascular disease, their contribution to amelioration of the microvascular defects in type 2 diabetes has fallen short of spectacular success. In this respect, the combinations of PPARalpha, PPARbeta and PPARgamma may better serve the unique requirements for improving the microvascular defect in diabetes.     

Role of PPAR- gamma agonist thiazolidinediones in treatment of pre-diabetic and diabetic individuals: a cardiovascular perspective

The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors, which contain a type II zinc finger DNA binding motif and a hydrophobic ligand binding pocket. These receptors are thought to play an important role in metabolic diseases such as obesity, insulin resistance, and coronary artery disease. Three subtypes of PPAR receptors have been described: PPARalpha, PPARdelta/beta, and PPARgamma. PPARalpha is found in the liver, muscle, kidney, and heart. In the liver, its role is to up-regulate genes involved in fatty acid uptake (beta-oxidation and omega-oxidation). PPARdelta/beta is involved in fatty acid oxidation in muscle. PPARgamma has high expression in fat, low expression in the liver, and very low expression in the muscle. The thiazolidinediones (TZD) are synthetic ligands of PPARgamma. By activating a number of genes in tissues, PPARgamma increases glucose and lipid uptake, increases glucose oxidation, decreases free fatty acid concentration, and decreases insulin resistance. There is a sound rationale for the use of TZDs in patients with type 2 diabetes mellitus and promising preliminary data in patients with patients with pre-diabetes. In patients with type 2 diabetes, thiazolidinediones had been shown to decrease mean HbA(1c)by 1.5% and lower HbA(1c) to less than 7% in 30% of patients. Decreased muscle insulin resistance primarily mediates the glucose lowering effect. In addition, there are several nonhypoglycemic effects of TZDs which may be beneficial to both diabetics and patients with pre-diabetes. These include effects on lipid metabolism, blood pressure, endothelial function, atherosclerotic plaque, coagulation, and albuminuria. In a pilot study, we recently demonstrated that insulin sensitizers such as thiazolidinediones appear to be associated with better clinical outcomes compared to insulin providers in diabetic patients presenting with acute coronary syndromes. In another study, we showed that the prediabetic state is a marker for worse prognosis in patients with acute coronary syndromes. In this article, we review the existing literature on the effectiveness of PPAR-gamma agonists in patients with either overt diabetes or a prediabetic state.     

Ertiprotafib improves glycemic control and lowers lipids via multiple mechanisms

Ertiprotafib belongs to a novel class of insulin sensitizers developed for treatment of type 2 diabetes. In insulin-resistant rodent models, ertiprotafib and a close analog lowered both fasting blood glucose and insulin levels and improved glycemic excursion during an oral glucose tolerance test. In addition, treatment of rodents improved lipid profiles, with significantly lowered triglyceride and free fatty acid levels. These results suggested that this therapeutic activity might involve mechanisms in addition to PTP1b inhibition. In this study, we demonstrate that ertiprotafib activates peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma at concentrations comparable with those of known agonists of these regulators. Furthermore, it is able to drive adipocyte differentiation of C3H10T(1/2) cells, a hallmark of PPARgamma activation. Livers from ertiprotafib-treated animals showed significant induction of acyl-CoA oxidase activity, probably caused by PPARalpha engagement in these animals. We also show that ertiprotafib inhibits PTP1b in vitro with nonclassic kinetics at concentrations above its EC(50) for PPAR agonism. Thus, the complete mechanism of action for ertiprotafib and related compounds in vivo may involve multiple independent mechanisms, including (but not necessarily limited to) PTP1b inhibition and dual PPARalpha/PPARgamma agonism. Ertiprotafib pharmacology and interpretation of clinical results must be seen in light of this complexity.     

Tesaglitazar: a promising approach in type 2 diabetes

While glycemic control remains the cornerstone of clinical management for patients with type 2 diabetes, the importance of a more comprehensive approach that addresses the multiple metabolic abnormalities seen in this population is now widely recognized. Abnormal lipid metabolism resulting in dyslipidemia contributes greatly to the markedly increased risks of cardiovascular disease observed in diabetic patients and in prediabetic patients with signs of insulin resistance. The peroxisome proliferator-activated receptors (PPARs) play a key role in the regulation of energy homeostasis and the coordination of inflammatory responses. As such, they are interesting targets for addressing both the glucose and lipid abnormalities associated with insulin resistance. The thiazolidinediones (TZDs), which activate PPARgamma, appear to improve glycemic control primarily by increasing peripheral insulin sensitivity and reducing hepatic glucose production, thereby helping to preserve beta-cell function. They have also demonstrated modest beneficial effects on some lipid parameters. The fibrate drugs, which activate PPARalpha, produce robust improvements in dyslipidemia, decrease atherosclerotic lesions and may have an effect on cardiovascular events, but do not affect glycemia. Theoretically, a compound targeting both the alpha and gamma PPARs simultaneously might combine the benefits of TZDs and fibrates. Tesaglitazar is a dual-acting PPARalpha/gamma agonist currently being investigated in phase III clinical trials as an alternative treatment for insulin resistance and the characteristic dyslypidemia of type 2 diabetes. This article reviews the available data on the clinical efficacy and safety of tesaglitazar in patients with type 2 diabetes and in individuals without diabetes but with insulin resistance.     

Thiazolidinediones: effects on insulin resistance and the cardiovascular system

Thiazolidinediones (TZDs) have been used for the treatment of hyperglycaemia in type 2 diabetes for the past 10 years. They may delay the development of type 2 diabetes in individuals at high risk of developing the condition, and have been shown to have potentially beneficial effects on cardiovascular risk factors. TZDs act as agonists of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) primarily in adipose tissue. PPAR-gamma receptor activation by TZDs improves insulin sensitivity by promoting fatty acid uptake into adipose tissue, increasing production of adiponectin and reducing levels of inflammatory mediators such as tumour necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor-1(PAI-1) and interleukin-6 (IL-6). Clinically, TZDs have been shown to reduce measures of atherosclerosis such as carotid intima-media thickness (CIMT). However, in spite of beneficial effects on markers of cardiovascular risk, TZDs have not been definitively shown to reduce cardiovascular events in patients, and the safety of rosiglitazone in this respect has recently been called into question. Dual PPAR-alpha/gamma agonists may offer superior treatment of insulin resistance and cardioprotection, but their safety has not yet been assured.     

噻唑烷二酮类不良反应研究进展

噻唑烷二酮类胰岛素增敏剂通过增加外周组织对胰岛素的敏感性而改善胰岛素抵抗,降低血胰岛素水平、减少胰岛素用量,降低血糖和HbAlc,提高HDL-C水平,保护胰岛β细胞功能;还能对抗多种心血管疾病危险因子的损害,有益于糖尿病大血管和微血管并发症的防治.然而近年来有关噻唑烷二酮类药物不良反应的报道越来越多,部分病人甚至因此而停药.笔者综述噻唑烷二酮类药物不良反应.     

Muraglitazar: an agent for the treatment of type 2 diabetes and associated dyslipidemia

Many studies indicate that postprandial metabolic abnormalities, such as hyperglycemia and dyslipidemia, which are exaggerated and prolonged in type 2 diabetes, are important risk factors for cardiovascular disease. Different pharmacotherapies have been developed to specifically target these risk factors associated with type 2 diabetes. The peroxisome proliferator-activated receptor (PPAR) agonists, which are potent insulin sensitizers, have been the focus of much research during the past decade. Since their development, PPAR agonists have emerged as an important target for the treatment of insulin resistance and dyslipidemia. The more recent development of agonists that selectively target both the alpha and gamma PPARs has provided a potential treatment of global risk in patients with the metabolic syndrome or type 2 diabetes. Muraglitazar is a non-thiazolidinedione, oxybenzylglycine dual PPARalpha/gamma agonist that is in advanced clinical development for the treatment of type 2 diabetes and its associated dyslipidemia. This article summarizes the available clinical data on the efficacy and safety of muraglitazar in patients with type 2 diabetes.     

The potential insulin sensitizing and glucose lowering effects of a novel indole derivative in vitro and in vivo.

Thiazolidinediones (TZDs) such as rosiglitazone are antidiabetic peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. PPARgamma agents improve diabetes by increasing insulin sensitivity and enhancing the differentiation of preadipocytes into adipocytes. The present study aimed to identify if 1-(4-chlorobenzoyl)-5-hydroxy-2-methyl-3-indoleacetitic acid (GY3), a newly synthesized indole compound, could enhance adipocytes differentiation and insulin sensitivity. The results showed that both GY3 and rosiglitazone significantly increased the lipid accumulating of 3T3-L1 adipocytes induced by isobutylmethylxanthine, dexamethasone and insulin mixture, but GY3 (not rosiglitazone) failed to increase the lipid accumulation when induced by insulin alone. In addition, GY3- or rosiglitaozne-induced protein expression of GLUT4 and adiponectin was determined by Western blot analysis. GY3 activated PPARalpha weakly but did not affect PPARgamma, while rosiglitazone activated PPARgamma significantly, suggesting different mechanisms between GY3 and rosiglitazone on adipocyte differentiation. Furthermore, both GY3 and rosiglitazone enhanced the adiponectin and insulin pathway proteins expression and adiponectin secretion in mature adipocytes, but only GY3 not rosiglitazone elevated gene expression of leptin and resistin. Both GY3 and rosiglitazone enhanced glucose consumption in HepG2 cells especially in the presence of insulin. In the in vivo study, GY3 decreased serum glucose and insulin in db/db mice, indicating the insulin sensitizing effect might contribute to its antidiabetic mechanism. Altogether, these results suggest that GY3 could improve insulin resistance and lower glucose level, GY3 and its derivatives might be developed as a substitution therapy for diseases with insulin resistance.     

Design, synthesis, and structure-activity relationship study of peroxisome proliferator-activated receptor (PPAR) delta-selective ligands

Improvements in our understanding of the functions of peroxisome proliferator-activated receptor (PPAR) subtypes as master regulators of many biological functions have made it possible to develop novel PPAR ligands with characteristic subtype selectivity as biochemical tools and/or candidate drugs for the treatment of PPAR-dependent diseases such as metabolic syndrome, which includes type II diabetes, dyslipidemia, obesity, hypertension, and inflammation. Based on the findings that the glitazone-class antidiabetic agents, and fibrate-class antidyslipidemic agents are ligands of PPARgamma and PPARalpha respectively, much research interest has been focused on these two subtypes as therapeutic targets for the treatment of type II diabetes and dyslipidemia. In contrast, research interest in PPARdelta has been limited. However, since 2001, the availability of PPARdelta knockout animals and selective ligands has led to the uncovering of possible roles of PPARdelta in fatty acid metabolism, insulin resistance, reverse cholesterol transport, inflammation, and so on. It has become clear that ligands able to modulate PPARdelta-mediated pathways are candidates for the treatment of altered metabolic function. This review focuses on recent medicinal chemical studies to identify PPARdelta-selective agonists.     

PPARalpha and PPARgamma dual agonists for the treatment of type 2 diabetes and the metabolic syndrome

The discovery of the crucial role of peroxisome proliferator-activated receptors (PPARs) as regulators of lipid and glucose metabolism has raised interest in the development of synthetic ligands as potential tools for therapeutic intervention in type 2 diabetes and the metabolic syndrome. PPARalpha activators primarily improve dyslipidemia, whereas thiazolidinediones are potent PPARgamma activators that improve insulin resistance. Important research programs to develop agonists that combine the therapeutic effects of both PPARalpha- and PPARgamma-selective agonists, creating the expectation of greater efficacy and other advantages in the treatment of type 2 diabetes and the metabolic syndrome, have therefore been undertaken. Among these dual PPARalpha/gamma agonists, compounds that belong to the glitazar class are in the most advanced stage of development. However, although they demonstrated beneficial impact over selective PPAR agonists by improving both lipid and glucose homeostasis, safety has been a critical issue and has led to the discontinuation of their development because of adverse toxicity profiles. However, the target-related mechanism responsible for the identified safety issues and the relevance of rodent toxicities to the human situation are unclear. Therefore, future development of dual PPARalpha/gamma agonists with selective PPAR modulator activity appears appropriate and should be feasible.     

Peroxisome proliferator-activated receptor-gamma: therapeutic target for diseases beyond diabetes: quo vadis?

The discovery that the insulin-sensitising thiazolidinediones (TZDs), specific peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, have antiproliferative, anti-inflammatory and immunomodulatory effects has led to the evaluation of their potential use in the treatment of diabetic complications and inflammatory, proliferative diseases in non-insulin-resistant, euglycaemic individuals. Apart from improving insulin resistance, plasma lipids and systemic inflammatory markers, ameliorating atherosclerosis and preventing coronary artery restenosis in diabetic subjects, currently approved TZDs have been shown to improve psoriasis and ulcerative colitis in euglycaemic human subjects. These data imply that the activation of PPAR-gamma may improve cardiovascular risk factors and cardiovascular outcomes in both insulin-resistant diabetic and non-diabetic individuals. Through their immunomodulatory and anti-inflammatory actions, TZDs and other PPAR-gamma agonists may prove to be effective in treating diseases unrelated to insulin resistance, such as autoimmune (e.g., multiple sclerosis), atopic (e.g., asthma, atopic dermatitis) and other inflammatory diseases (e.g., psoriasis, ulcerative colitis). Newer and safer selective PPAR-gamma agonists are presently under development. Furthermore, of considerable interest is the recent discovery that a unique subset of currently prescribed antihypertensive angiotensin II Type 1 receptor antagonists has selective PPAR-gamma-modulating activity. These discoveries pave the way for the development of drugs for treating chronic multigenic cardiovascular and metabolic diseases, for which therapy is presently insufficient or non-existent. The potential utility of the currently available TZDs rosiglitazone and pioglitazone and PPAR-gamma-modulating angiotensin II Type 1 receptor antagonists in treating cardiovascular, metabolic and inflammatory diseases in insulin resistant and euglycaemic states is of immense clinical potential and should be investigated.     

Fine tuning of PPAR ligands for type 2 diabetes and metabolic syndrome

Type 2 diabetes mellitus (T2DM) is highly prevalent chronic disease. Recently, many biological targets are discovered for treatment of this disease. The identification of the nuclear hormone receptor peroxisome proliferator activated receptors (PPAR) and their subtypes alpha, gamma and delta or beta as targets for controlling lipid, glucose and energy homeostasis has proved to be exciting. As hyperlipidaemia, obesity and insulin resistance are independent risk factors for coronary heart disease and macrovascular complications of diabetes; new agents that increase insulin sensitivity as well as decrease hyperlipidaemia by distinct yet complementary mechanism are being studied as they may provide improved therapy for T2DM and related disorders. In this article, we review highly potent PPARgamma agonists, PPARalpha/gamma dual agonists, PPAR pan agonists, alternative PPAR ligands like partial agonists or selective PPAR modulators (SPPARMs) and antagonists from a chemist point of view.     

Cardioprotective effects of thiazolidinediones, peroxisome proliferator-activated receptor-gamma agonists

Greater myocardial injury in response to ischemia/ reperfusion (I/R) and increased incidence of congestive heart failure and death in noninsulin-dependent diabetes mellitus, or type 2 diabetes, patients has been clearly identified. Thiazolidinediones (TZDs), peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, act as insulin sensitizers and are a novel class of oral antidiabetic drugs. An emerging body of evidence, mainly from preclinical studies, suggest that TZDs protect the heart from acute I/R injury and also might attenuate cardiac remodeling and heart failure. The mechanisms involved in this cardioprotection by TZDs are multi-factorial and not completely understood. These novel activities of TZDs could benefit type 2 diabetes patients and offer benefits beyond glycemic control. This new knowledge about the cardioprotective effects of TZDs is still limited, and more investigations, especially clinical studies, are required.     

Recent findings concerning thiazolidinediones in the treatment of diabetes

Thiazolidinediones (TZDs) are peroxisomal proliferator-activated receptor (PPAR)-gamma agonists. They increase insulin action through several mechanisms including: stimulation of the expression of genes that increase fat oxidation and lower plasma free fatty acid levels; increased expression, synthesis and release of adiponectin; and stimulation of adipocyte differentiation resulting in more and smaller fat cells. TZDs lower blood sugar comparably to sulfonylureas and metformin. The clinical use of TZDs is limited due to the long duration of time required before they reach their full blood sugar-lowering action (3-4 months) and adverse effects such as fluid retention, resulting in excessive weight gain and occasionally in peripheral and/or pulmonary oedema and congestive heart failure. Troglitazone, a TZD that has since been removed from the market because of hepatoxicity, has been demonstrated to decrease the progression from normal or impaired glucose tolerance to overt Type 2 diabetes mellitus. Pioglitazone, another TZD, marginally decreased the incidence of cardiovascular complications in patients with Type 2 diabetes mellitus (PROactive trial). Other, as yet, unapproved uses of TZDs include: non-alcoholic fatty liver disease, in which TZDs reduced hepatic fat accumulation and improved liver function tests; polycystic ovary syndrome, where TZDs improved ovulation, hirsutism and endothelial dysfunction; and lipodystrophies, where TZDs increased body fat (marginally) and decrease liver size. Lastly, because PPAR-alpha and -gamma agonists improve atherosclerotic vascular disease and insulin sensitivity, respectively, dual PPAR-alpha/gamma agonists, which are currently undergoing clinical trials, may be useful in treating patients with the metabolic syndrome.