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Possible mechanisms through which PPARγ agonist thiazolidinediones reduce hyperglycaemia
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The thiazolidinediones (TZDs) rosiglitazone and pioglitazone are new oral antidiabetic agents with `insulin sensitising' activity for the treatment of type 2 diabetes. Rosiglitazone and pioglitazone produce a slowly generated antihyperglycaemic effect which is often accompanied by decreases in circulating insulin and free fatty acids. Circulating t...
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... The unchanged pioglitazone is excreted in urine, bile and feces [4]. Post the oral dose of 45 mg pioglitazone mean plasma concentration was reported to be around 1482 ± 499.7 ng/mL, 168 ± 50.7 ng/mL, 639 ± 188.9 ng/mL at t max of 3 (2)(3)(4)(5), 16 , 16 (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) h was for pioglitazone, keto pioglitazone (M-III) and hydroxy pioglitazone (M-IV) [5]. ...
High performance liquid chromatographic tandem mass spectrometric method for the determination of pioglitazone, keto pioglitazone (M-III) and hydroxy pioglitazone (M-IV) in human plasma has been developed and validated using pioglitazone-D4, keto pioglitazone-D4 and hydroxy pioglitazone-D5 as internal standards. Solid phase extraction was carried out for sample preparation to extract analyte and internal standard from human plasma. The extracted sample was injected through autosampler in HPLC connected with Hypersil Gold, 100 mm × 4.6 mm, 5 μm using mobile phase consisting of methanol:solution A:solution B - 80:10:10 v/v/v). Pioglitazone, keto pioglitazone (M-III) and hydroxy pioglitazone (M-IV) were chromatographically separated and detected using the MS detector. The best-fit lines using weighting factor (1/concentration2) linear least square regression analysis were obtained by peak area ratio of pioglitazone, keto pioglitazone (M-III) and hydroxy pioglitazone (M-IV) with their internal standards pioglitazone-D4, keto pioglitazone-D4 and hydroxy pioglitazone-D5, respectively. This report provides the results of various validation parameters including stability studies and extended precision and accuracy which is required for long study samples batch analysis. This analytical method is valid for the determination of pioglitazone in the range of 18.9 ng/mL to 2994.4 ng/mL), keto pioglitazone (M-III) (3.23 ng/mL to 512.60 ng/mL), hydroxy pioglitazone (M-IV) 10.1 ng/mL to 1603.8 ng/mL) and using pioglitazone-D4, keto pioglitazone-D4, hydroxy pioglitazone-D5, respectively as internal standards in human plasma using a Hypersil Gold, 100 mm × 4.6 mm, 5 μm column.
... TZDs were high-affinity ligands for agonists of PPARγ and this phenomena was first reported by Lehman et al. (Lehmann, Moore, © 2012Prague Development Center Smith-Oliver, Wilkison et al., 1995. TZDs perform through PPARγ that facilitates the transcription of certain genes that are also responsive to insulin, enabling these agents to improve insulin action (Bailey and Day, 2001). However, this medicine gives side effect that may arise during treatment; TZDs also have side effects that increase the risk of heart attack and angina, fluid retention, weigh gain, cardiac failure, thus TZDs use should be selective in diabetic patients who are not impaired liver and heart failure. ...
In general, a type two diabetes mellitus (T2DM) patient suffers for hyperglycaemia and insulin resistance. Nowadays, there is an anti diabetes drug working as a PPARγ/α agonist and has a significant effect to improve the hyperglycemia and insulin resistance condition. However, this drug gives a negative effect on lipid circulation parameters. In this investigation, nutmeg (Myristica fragrans) extracts (NuSE) was tested against PPARγ using cell-based GAL4/PPAR chimera transactivation and trancient transvection assay with three PPAR response element (PPREs) containing reporters. The results demonstrate that the NuSE has significant PPARγ agonist activity, although their potency was less than the standard PPARγ full agonist. An investigation of antidiabetic activity of the NuSE has been carried out on rats. Rats were treated orally every day for six days with the ethanol of NuSE in several doses. The result of the experiment showed that each dose of NuSE gave hypoglycemic activity (p= 0.01 and p=0.05). The experiment also showed that an increase in dosage caused an increased in the hypoglycemic activity. Therefore, nutmeg (Myristica fragrans) seeds might be potential against antidiabetic agent for the treatment of type two diabetes with a PPAR γ/α. agonistic mechanism.
... In the UK the TZD troglitazone had been both introduced and withdrawn in 1997, due to idiosyncratic liver failure; pioglitazone and rosiglitazone were introduced in 2000 (and the latter was withdrawn in 2010 due to possibly increasing cardiovascular risk, but not death). 2,3 It is noteworthy that in Europe in 2006 the use of insulin in combination with a TZD was off-label, as was and is the use of TZDs in patients with cardiac failure or a history thereof. 2 Not all of the pharmacological agents in the diabetes armamentarium were included in the algorithm although the USA additionally had the amylin analogue pramlintide and the GLP-1 agonist exenatide, both of which were introduced in 2005. ...
... 2,3 It is noteworthy that in Europe in 2006 the use of insulin in combination with a TZD was off-label, as was and is the use of TZDs in patients with cardiac failure or a history thereof. 2 Not all of the pharmacological agents in the diabetes armamentarium were included in the algorithm although the USA additionally had the amylin analogue pramlintide and the GLP-1 agonist exenatide, both of which were introduced in 2005. ...
... The TZDs, of which only pioglitazone is now licensed in Europe, are PPARγ agonists which enhance insulin sensitivitynotably to increase glucose uptake into muscle and fat. 2 Unlike the other antihyperglycaemic agents TZDs are associated with weight gain, but this may be partly due to an increase in fluid retention. ...
Hyperglycaemia is a significant contributor to the morbidity and premature mortality of type 2 diabetes. There are several glucose lowering agents, with each class having a different mechanisms of action, but their utilisation has to be considered within the context of disease pathogenesis; appropriateness of the agent for the patient, patient lifestyle and personal circumstance, and to some extent treatment costs. The most recent joint policy statement from the American Diabetes Association and the European Association for the Study of Diabetes addresses these issues and provides guidance on strategies for a patient centred approach to the implementation of evidence based medicine. Glycaemic targets are flexible, but early intervention, and therapy as intensive as individual circumstance dictates are recommended.
... Lastly, although the best results are typically seen within the first 6 months of treatment with medications indicated for the treatment of AD, the thiazolidinediones can take months to produce maximum results, and it is therefore difficult to interpret these findings. 20 In a second trial, 518 patients with mild-to-moderate AD (MMSE score [16][17][18][19][20][21][22][23][24][25][26] were randomized to receive 1 of 3 doses of rosiglitazone or an identical placebo once daily. 17 Concomitant use of cholinesterase inhibitors, selegiline, memantine, thiazolidinediones, or insulin, or treatment for congestive heart failure currently or within 3 months of enrollment was prohibited, and medications known to affect cognition and/or behavior were not allowed. ...
... Lastly, although the best results are typically seen within the first 6 months of treatment with medications indicated for the treatment of AD, the thiazolidinediones can take months to produce maximum results, and it is therefore difficult to interpret these findings. 20 In a second trial, 518 patients with mild-to-moderate AD (MMSE score [16][17][18][19][20][21][22][23][24][25][26] were randomized to receive 1 of 3 doses of rosiglitazone or an identical placebo once daily. 17 Concomitant use of cholinesterase inhibitors, selegiline, memantine, thiazolidinediones, or insulin, or treatment for congestive heart failure currently or within 3 months of enrollment was prohibited, and medications known to affect cognition and/or behavior were not allowed. ...
... The effect of thiazolidinediones first requires gene transcription and protein synthesis to occur, and maximal glucose lowering has been found to take months. 20 With the exception of the 18-month pioglitazone study assessing safety as the primary outcome, all other trials determined primary outcome at 6 months. However, despite the longer duration of treatment, there continued to be no observed benefit in the pioglitazone group compared to placebo. ...
To review the literature on the efficacy and safety of rosiglitazone and pioglitazone for the treatment of Alzheimer's disease (AD).
Literature was accessed through MEDLINE (1948-August 2011 week 2) and EMBASE (1980-2011 week 32) using the search terms rosiglita-zone, pioglitazone, and Alzheimer's disease. Results were limited to studies conducted in humans and published in English.
Clinical trials evaluating the efficacy and safety of rosiglitazone or pioglitazone in patients with AD were critically evaluated.
The mechanism for development of AD has been linked to both inflammation and decreased insulin sensitivity. Because of this, rosiglitazone and pioglitazone have been evaluated as potential treatments for AD because of their insulin-sensitizing and antiinflammatory effects. Five clinical trials were evaluated (3 assessing rosiglitazone, 2 assessing pioglitazone); 1 trial evaluating rosiglitazone demonstrated a beneficial effect on cognition in patients with probable AD. However, the largest randomized, double-blind, placebo-controlled trials conducted to date failed to demonstrate a difference between rosiglitazone and placebo when assessing primary endpoints. Two small trials evaluating pioglitazone produced conflicting results regarding efficacy in AD; numerous limitations make results difficult to interpret. The safety of these agents was also evaluated in these trials; edema was seen more commonly in patients receiving rosiglitazone or pioglitazone than in those receiving placebo; however, each drug was generally well tolerated.
Results from clinical trials and current safety data suggest that rosiglitazone should not be used for the treatment of AD. Application of results from trials evaluating pioglitazone in the treatment of AD is limited because of major trial limitations; therefore, it should not be recommended at this time. Although these drugs are not commonly used in the treatment of AD, further pharmacoepidemiologic studies are warranted before their use can be recommended.
... As PPAR-γ is expressed by β-cells [20] as well as by endothelium [21], stimulation of PPAR-γ by a TZD provides a potential route to increase VEGF-mediated vascularization of islets and β-cells. Additional potential advantages to this approach are that TZDs have been reported to increase islet β-cell granulation [22] and benefit islet viability in non-insulin dependent diabetic states [23]. ...
Delayed graft revascularization impedes the success of human islet transplantation. This study utilized rotational co-culture of insulin secreting β-cells with human umbilical vein endothelial cells (HUVECs) and a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist to promote insulin and vascular endothelial growth factor (VEGF) secretory function.
Clonal BRIN-BD11 (D11) cells were maintained in static culture (SC) and rotational culture (RC) ± HUVEC and ± the TZD (thiazolidinedione) rosiglitazone (10 mmol/l) as a specific PPAR-γ agonist. HUVECs were cultured in SC and RC ± D11 and ± TZD. D11 insulin secretion was induced by static incubation with low glucose (1.67 mmol/l), high glucose (16.7 mmol/l) and high glucose with 10 mmol/l theophylline (G+T) and assessed by enzyme-linked immunosorbent assay (ELISA). HUVEC proliferation was determined by ATP luminescence, whereas VEGF secretion was quantified by ELISA. Co-cultured cells were characterized by immunostaining for insulin and CD31.
D11 SC and RC showed enhanced insulin secretion in response to 16.7 mmol/l and G+T (p < 0.01); without significant alteration by the TZD. Co-culture with HUVEC in SC and RC also increased D11 insulin secretion when challenged with 16.7 mmol/l and G+T (p < 0.01), and this was slightly enhanced by the TZD. The presence of HUVEC increased D11 SC and RC insulin secretion in response to high glucose and G+T, respectively (p < 0.01). Addition of the TZD increased SC and RC HUVEC ATP content (p < 0.01) and VEGF production (p < 0.01) in the presence and absence of D11 cells.
Rotational co-culture of insulin secreting cells with endothelial cells, and exposure to a PPAR-γ agonist may improve the prospects for graft revascularization and function after implantation.
... La plupart des études ou revues générales [13,[39][40][41] s'accordent sur l'absence de conséquences cliniques de cette rétention hydrosodée, même chez des patients DT2 ayant une néphropathie et une insuffisance rénale légère ou modérée [42,43], du moins dans le cadre du respect des indications, contre-indications et précautions d'emploi des glitazones, telles que définies par les agences de santé dans le cadre des Autorisations de Mise sur le Marché (pour la France, cf. Dictionnaire Vidal ® 2004). ...
PPARgamma nuclear receptors are mainly expressed in adipose tissue. However, they are also expressed in renal glomerular tissue and in vascular walls, thus participating through various and complex mechanisms, to glomerular and vascular sclerosis and to nephropathy development and progression. Studies carried out with glitazones, pharmacological agonists of nuclear receptor PPARgamma, in experimental models, either in vitro, or in vivo in animal models, have demonstrated their favourable effects on arterial blood pressure and on prevention and/or progression of diabetic nephropathy. The few clinical studies conducted in type 2 diabetic patients to assess these effects, are also in favor of a beneficial effect of glitazones on blood pressure and nephropathy in these patients. Thus, it appears extremely important and fully justified to conduct specific studies in patients with type 2 diabetes, with the aim to establish and to better characterize these effects in various clinical conditions (antihypertensive effect in treated hypertensive patients according to the class of antihypertensive agents used, prevention of diabetic nephropathy and/or effect on its progression, renal protection, etc.). Some adverse events, although with a low incidence, may be associated with glitazone use (weight gain, peripheral oedema, fluid retention, etc.), and may limit their use in some patients. It is clearly important to better understand the pathophysiological mechanisms of these effects and their possible long term consequences. Finally, it is important to emphasize the easiness to use glitazones in patients with renal insufficiency, without the need to adjust the drug regimen.
... La plupart des études ou revues générales [13,394041 s'accordent sur l'absence de conséquences cliniques de cette rétention hydrosodée, même chez des patients DT2 ayant une néphropathie et une insuffisance rénale légère ou modérée [42, 43], du moins dans le cadre du respect des indications, contre-indications et précautions d'emploi des glitazones, telles que définies par les agences de santé dans le cadre des Autorisations de Mise sur le Marché (pour la France, cf. Dictionnaire Vidal ® 2004). ...
Le récepteur nucléaire PPARγ est exprimé majoritairement dans le tissu adipeux. Néanmoins, il est également exprimé dans le glomérule rénal et les parois vasculaires, contribuant par des mécanismes multiples et complexes, à la sclérose vasculaire et glomérulaire, et ainsi, au développement de la néphropathie. Des études réalisées avec les glitazones, agonistes pharmacologiques du récepteur nucléaire PPARγ, dans des modèles expérimentaux in vitro, ou in vivo dans des modèles animaux, ont montré que les glitazones avaient des effets favorables sur la pression artérielle et sur la prévention et/ou la progression de la néphropathie diabétique. Les études cliniques réalisées chez des patients diabétiques de type 2, bien que peu nombreuses, sont également en faveur d’un effet bénéfique des glitazones, sur la pression artérielle et la néphropathie chez ces patients. Il est donc important et justifié de réaliser des études spécifiques chez les patients diabétiques de type 2, visant à établir et à mieux caractériser ces effets dans différentes situations cliniques (effet antihypertenseur chez des patients hypertendus selon les classes d’antihypertenseurs associés, prévention et/ou effet sur la progression de la néphropathie diabétique, protection rénale, etc.). Les glitazones ont également des effets indésirables associés (prise de poids, œdèmes périphériques, rétention hydrosodée), qui bien que peu fréquents, peuvent en limiter l’emploi chez certains patients. Il est important de mieux étudier ces effets, d’en préciser les mécanismes physiopathologiques et leurs éventuelles conséquences à long terme. Il faut enfin souligner la possibilité de manier aisément ces médicaments chez le patient insuffisant rénal, sans en modifier la posologie, du fait de leurs propriétés pharmacocinétiques.PPARγ nuclear receptors are mainly expressed in adipose tissue. However, they are also expressed in renal glomerular tissue and in vascular walls, thus participating through various and complex mechanisms, to glomerular and vascular sclerosis and to nephropathy development and progression. Studies carried out with glitazones, pharmacological agonists of nuclear receptor PPARγ, in experimental models, either in vitro, or in vivo in animal models, have demonstrated their favourable effects on arterial blood pressure and on prevention and/or progression of diabetic nephropathy. The few clinical studies conducted in type 2 diabetic patients to assess these effects, are also in favor of a beneficial effect of glitazones on blood pressure and nephropathy in these patients. Thus, it appears extremely important and fully justified to conduct specific studies in patients with type 2 diabetes, with the aim to establish and to better characterize these effects in various clinical conditions (antihypertensive effect in treated hypertensive patients according to the class of antihypertensive agents used, prevention of diabetic nephropathy and/or effect on its progression, renal protection, etc.). Some adverse events, although with a low incidence, may be associated with glitazone use (weight gain, peripheral oedema, fluid retention, etc.), and may limit their use in some patients. It is clearly important to better understand the pathophysiological mechanisms of these effects and their possible long term consequences. Finally, it is important to emphasize the easiness to use glitazones in patients with renal insufficiency, without the need to adjust the drug regimen.
... Two thiazolidinediones (TZDs) are available in the UK, rosiglitazone (Avandia) and pioglitazone (Actos). 1 They facilitate glycaemic control mainly by improved insulin sensitivity, mediated via peroxisome proliferator-activated receptor-gamma (PPARγ). 2 The positioning of TZDs as oral antidiabetic therapies has been the subject of considerable controversy as prescribers attempt to follow the European Agency for the Evaluation of Medicinal Products (EMEA) licence and National Institute for Clinical Excellence (NICE) guidelines (table 1). 3 ...
The National Institute for Clinical Excellence (NICE) recently revised its guidance on the use of thiazolidinediones (TZDs). Days later, the European Agency for the Evaluation of Medicinal Products (EMEA) announced licence changes for TZDs that supersede the NICE guidance. The EMEA has approved TZDs for monotherapy if metformin is contraindicated or not tolerated. This article summarises the latest changes surrounding the use of TZDs in the UK.
... Treatment of patients with TZDs, by their action on the PPARs therefore improves insulin signal-ling, alters the metabolism of FFA and affects glucose uptake, production and utilization (Fig. 3). They also decrease proinflammatory cytokines and could potentially, via the stimulation of PPARa, provide a beneficial lipid profile for patients with diabetes (40). ...
... The oedema however resolves spontaneously. Weight gain is a class effect of the TZDs (40). The weight seems to increase most rapidly in the first few months and stabilizes at about 5% above baseline body weight. ...
Diabetes mellitus is a well-recognized risk-factor for coronary artery disease (CAD). Epidemiological studies have shown that the risk of CAD increases two to sixfold in patients with type 2 diabetes compared with those without the disease. Furthermore the prevalence of diabetes in the UK has increased by 30% since 1991 and the world population of people with diabetes in 2010 is expected to be twice that of 1990. In addition whilst the mortality from CAD in patients without diabetes has declined over the past 20 years the mortality in men with type 2 diabetes has not changed and in women may have increased. UKPDS and other studies have shown a significant improvement in the onset and course of microvascular complications with good diabetic control. However the same is not true for macrovascular complications for which there is no good evidence of improvement with better diabetic control. This apparent lack of benefit from improved care of diabetic patients has led to many different approaches. These include attempts to achieve even better glycaemic control, greater emphasis on other risk factors particularly hypertension and interestingly attention to the prediabetic state characterized by insulin resistance (IR). The latter is associated with a number of abnormalities which could play a causative role in the development of cardiovascular disease. This article will review the concept of IR and the possible interventions available to tackle it.
Given the relationship between glycemia and the complications of diabetes, a number of recommendations have been put forward regarding the goals of glycemic control for patients with diabetes. The most commonly cited are those of the American Diabetes Association, which has given three ascending sets of levels, those to be considered “normal,” those to be used as the “goal” for patients with diabetes, and those above which additional measures are clearly thought to be recommended (Table 1).
