Medicamentsen-ligne vous propose les traitements dont vous avez besoin afin de prendre soin de votre santé sexuelle. Avec plus de 6 ans d'expérience et plus de 90.000 clients francophones, nous étions la première clinique fournissant du acheter kamagra original en France à vente en ligne et le premier vendeur en ligne de Viagra dans le monde. Pourquoi prendre des risques si vous pouvez être sûr avec Medicamentsen-ligne - Le service auquel vous pouvez faire confiance.

Bjdvd.com

The British Journal of Diabetes & Vascular Disease The online version of this article can be found at: can be found at:
The British Journal of Diabetes & Vascular Disease
Additional services and information for
Thiazolidinedione-induced effects beyondglycaemic control Abstract
Effects of pioglitazone on selected target genes affecting The thiazolidinediones exert their insulin
sensitising effect by binding to the nuclear
receptors (transcription factors) peroxisome

proliferator activated receptor (PPAR) γ and, to varying
Target gene
degrees, to PPARα. Several different genes are activated
by thiazolidinediones, many of which contribute to the
increase in insulin sensitivity (eg. an increase in glucose
uptake and utilisation, a decrease in gluconeogenesis
and in insulin-antagonistic cytokines, such as tumour
necrosis factor
α). Activation of other genes indirectly
reduces insulin resistance by, for example, increasing
free fatty acid (FFA) uptake and oxidation resulting in
lower circulating FFA levels. The action of
thiazolidinediones at PPARγ is generally responsible for
their insulin sensitising effects while action at PPARα
contributes to their lipid lowering effects. Therefore,
the relative affinities of the different thiazolidinediones

for PPARγ and PPARα will also lead to a different
spectrum of actions for each agent.

Key words: diabetic dyslipidaemia, insulin resistance,
cerides and an increase in high-density lipoprotein (HDL) parti- PPAR receptors, pioglitazone, thiazolidinedione.
cles.2 PPARβ/δ is ubiquitous but its role in insulin resistanceremains unclear.2 The peroxisome proliferator activated receptors
PPARγ exists in two isoforms: PPARγ1 and PPARγ2.2 A wide variety of tissues express PPARγ1, while PPARγ2 is found pre- The peroxisome proliferator activated receptor (PPARs; α, β/δ and dominantly (and at high levels) in adipose tissue where it plays a γ) are part of a subfamily of the nuclear hormone receptor super- key role in adipogenesis.1,2 PPARγ also appears to modulate sev- family. Other members of this family include 9-cis-retinoic acid eral genes regulating energy storage and utilisation, in particular receptor (RXR), thyroid receptor and vitamin D receptor.1 The those affecting insulin sensitivity.1,2 However, the exact mecha- three PPARs are distributed differently in different organs.1 PPARα nisms by which PPARγ activation promotes insulin sensitivity are is highly expressed in liver but is also found in skeletal and car- still unknown. Some possible target genes are shown in table 1.
diac muscle. It regulates genes involved in fatty acid oxidation; The natural ligands for PPARγ are also largely unknown. The fatty acids below 20 carbons in length are oxidised in mitochon- most likely candidates are eicosanoids.2 Nonetheless, several dria while longer fatty acids are oxidised in peroxisomes.2 Insulin high-affinity synthetic ligands have been generated, most impor- reduces the expression of these genes while glucocorticoids increase their expression.2 The fibrate class of lipid-lowering After a PPAR binds with a ligand it becomes activated and agents act via PPARα resulting in a reduction in serum trigly- forms an activated complex with RXR which binds to specificperoxisome proliferator response elements (PPRE).3,4 These aredirect repeats of the nuclear receptor hexameric (AGGTCA)DNA core recognition motif separated by one or two Correspondence to: Professor Ulf SmithThe Lundberg Laboratory for Diabetes Research, Department of Internal nucleotides (DR1 and DR2). Formation of the complex triggers Medicine, The Sahlgrenska Academy, S-413 45 Göteborg, Sweden. recruitment of coactivator proteins. These coactivators are Tel: +46 31 342 1104; Fax: +46 31 82 9138 required for transcriptional activation.1,2,4 This results in increased transcription and protein synthesis, which in turn Br J Diabetes Vasc Dis 2002;2(suppl 1):S24–S27
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE PPARγ polymorphism
Figure 1. Development of the thiazolidinediones
PPARγ appears to be fundamental to the pathophysiology ofinsulin resistance and diabetes. Various polymorphisms inPPARγ are associated with increased or decreased degrees of insulin resistance.1 For example, the Pro12Ala mutation in the Precursors
Prototype
PPARγ2-specific exon B appears to be associated with improved insulin sensitivity, lower body mass index and higher plasma Rosiglitazone, SKB
HDL concentrations.5 By contrast, Barroso et al.6 have described two different mutations in the ligand-binding domain, which AL-294, Takeda
result in severe insulin resistance, dyslipidaemia and hyperten- Ciglitazone, Takeda
Pioglitazone, Takeda
Thiazolidinediones and insulin resistance
AL-321, Takeda
The thiazolidinedione class was first discovered by Takeda Chemical Industries in 1975 and the lead substance for all future Troglitazone, Sankyo
thiazolidinedione derivatives (ciglitazone) was synthesised in1980. Structural modification of this prototype molecule by dif-ferent pharmaceutical companies produced several agents withgreater glucose-lowering potential. In 1982, pioglitazone was tor alpha (TNFα).20 These different effects probably explain the synthesised and shown to be suitable for further development.
insulin sensitising and antihyperglycaemic effects of the thiazo- Other agents in this new group of drugs are rosiglitazone and troglitazone (now withdrawn) (figure 1). The thiazolidinediones bind with varying affinities to PPARγ Antihyperglycaemic effects
and PPARα. For example, pioglitazone has a comparable activity Several studies have indicated that pioglitazone increases expres- at PPARγ to rosiglitazone, but appears to be a stronger activator sion of glucose transporters (GLUT) 1 and 4,9-11 which in turn of PPARα than rosiglitazone (figure 2).7 increases glucose uptake. Studies in people with type 2 diabetes Insulin resistance is the prime defect in type 2 diabetes – in using the euglycaemic-hyperinsulinaemic clamp have, indeed, such individuals insulin production can no longer compensate for shown an increase in insulin-stimulated glucose disposal with the high level of insulin resistance resulting in hyperglycaemia pioglitazone treatment.21,22 In addition, pioglitazone has been and diabetes.8 Pioglitazone opposes insulin resistance in several shown to improve the deficiency in insulin stimulation of PI-3- ways, including increased expression of glucose transporters and kinase and reduce hyperglycaemia and hyperinsulinaemia in a rat uptake,9-11 enhancing insulin signalling,12,13 reducing hepatic glu- model of insulin resistance.12 Further, pioglitazone has been found cose production,14-17 increasing fatty acid uptake and lipogenesis to target insulin receptor substrate 2 (IRS-2), a key molecule for by adipocytes,18,19 decreasing cytokines like tumour necrosis fac- insulin signalling and action.13 Pioglitazone also lowers blood glu- Figure 2. Activation of PPARα and PPARγ1 by pioglitazone or rosiglitazone. Full-length hPPARγ1 and hRXRγ or hPPARα and hRXRα expression plasmids were
co-transfected into COS-1 cells with reporter plasmid contained PPRE, and cells were cultured in the presence of pioglitazone or rosiglitazone for 48 hours. The cell extracts were assayed for luciferase activity. The dotted lines indicate plasma C at corresponding maximal clinical doses of pioglitazone 45 mg and of rosiglitazone 8 mg7 Fold induction (PP
Fold induction (PP
Fold induction (PP
Fold induction (PP
Log (conc. [M])
Log (conc. [M])
Adapted with permission from Sakamoto et al.7 Copyright, Biochem Biophys Res Commun 2000. All rights reserved.
VOLUME 2 SUPPLEMENT 1 . JANUARY/FEBRUARY 2002 Figure 3. Pioglitazone: metabolic control in type 2 diabetes
Key messages
glucose uptake
utilisation
● PPARγ is fundamental to the pathophysiology of fat storage
Improved glucose
Thiazolidinediones
lipolysis
Thiazolidinediones act on PPARγ to increase insulin and lipid levels
free fatty acids
● Pioglitazone opposes insulin resistance by increasing glucose output
glucose uptake, enhancing insulin signalling, reducing VLDL synthesis
gluconeogenesis, increasing fatty acid uptake anddecreasing cytokines ● Pioglitazone lowers plasma triglycerides and increases HDL cholesterol production from the liver ● Pioglitazone appears to decrease visceral fat and may cose by reducing hepatic glucose production via increased activity of phosophoenolpyruvate carboxykinase (PEPCK), a key enzyme inglucose production.14 Lastly, pioglitazone reduces production ofinsulin-antagonistic cytokines like TNFα.20 Pioglitazone also indirectly lowers blood glucose by its effects Pioglitazone also increases lipoprotein lipase in cultured on FFA uptake and oxidation. When plasma-free fatty acids (FFA) adipocytes.31 Decreased activity of this enzyme may be respon- are elevated, insulin-stimulated glucose uptake can be impaired23 sible for the slowed clearance of triglyceride-rich lipoproteins in and hepatic glucose output increased.24 The effects of pioglita- insulin-resistant states. The three different thiazolidinediones zone on metabolic control in type 2 diabetes are summarised in studied so far have shown differences in their effects on plas- ma lipids. Pioglitazone lowers triglycerides and raises HDL cho- However, insulin resistance has consequences beyond hyper- lesterol but does not affect low-density lipoprotein (LDL) cho- glycaemia. Thus, it is likely that the actions of pioglitazone on lesterol.8,27 Rosiglitazone, in contrast, appears to have no effect insulin resistance result in effects beyond glycaemic control.
on triglycerides or on HDL cholesterol while significantlyincreasing LDL cholesterol.1,8,32 Troglitazone decreases trigly- Effects on dyslipidaemia
cerides and FFA and also increases HDL cholesterol.1,8 Insulin resistance is linked, not only with disturbances of glu- These varying effects of the thiazolidinediones on lipid pro- cose metabolism, but also with lipid abnormalities – typically files may also have clinical relevance. As high triglyceride and low increased triglycerides and decreased high-density lipoprotein HDL cholesterol levels typical of insulin resistance are known car- (HDL) cholesterol.25 This occurs in part because insulin resis- diovascular risk factors, an agent which can reverse these tance in adipose tissue results in a reduced anti-lipolytic effect changes, even in part, might bring benefits in terms of cardio- of insulin, causing low glucose uptake and increased FFA and vascular events. This requires further investigation like the ongo- glycerol release. Increased FFAs passing into the liver result in increased triglycerides, apolipoprotein B and very low-density Another effect of pioglitazone that may be relevant to lipid lipoprotein (VLDL) production, which in turn causes a decrease metabolism is that it appears to affect visceral adiposity.27 Visceral in HDL levels by affecting transfer of lipids between VLDL and fat is also linked to insulin resistance25 and is important in lipid HDL particles (described elsewhere in this supplement).26 It is of metabolism because increased lipolysis in this fat depot (as interest, therefore, that pioglitazone also has a beneficial effect occurs in insulin resistance) directly increases the concentration on this dyslipidaemia, lowering plasma triglycerides and raising of FFAs in the portal circulation. This may have immediate effects on VLDL and triglyceride production from the liver.26 The effects of pioglitazone on lipid metabolism appear to occur in several ways. Insulin exerts its antilipolytic effect by Conclusions
activating and phosphorylating the enzyme phosphodiesterase The insulin sensitising effect of pioglitazone and other thiazo- 3B (PDE 3B), which in turn inactivates and dephosphorylates lidinediones is mediated mainly through PPARγ activation, hormone-sensitive lipase.28 Decreased PDE 3B has been found whereas the lipid-lowering effect is in part mediated through in adipocytes from people with type 2 diabetes.29 In a mouse PPARα activation. Differential effects of different TZDs on the model of obesity which shows reduced PDE 3B levels, pioglita- lipid levels may be related to their affinity for PPARα receptors.
zone has been shown to restore PDE 3B mRNA and protein lev- Whether these differences also affect the cardiovascular risk in els and so decrease lipolysis and lower plasma FFA.30 type 2 diabetes patients remains to be established. THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE References
1995;44:384-9.
16. Sugiyama Y, Shimura Y, Ikeda H. Effects of pioglitazone on hepatic and 1. Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from peripheral insulin resistance in Wistar fatty rats. Arzneimittelforschung orphan receptors to drug discovery. J Med Chem 2000;43:527-50.
1990;40:436-40.
2. Rosen ED, Spiegelman BM. PPARγ: a nuclear regulator of metabolism, 17. Nishimura Y, Inoue Y, Takeuchi H, Oka Y. Acute effects of pioglitazone differentiation, and cell growth. J Biol Chem 2001;276:37731-4.
on glucose metabolism in perfused rat liver. Acta Diabetol 1997;34:206-
3. Auwerx J. PPARγ, the ultimate thrifty gene. Diabetologia 1999;42:1033-
18. Hallakou S, Doare L, Foufelle F et al. Pioglitazone induces in vivo 4. Schoonjans K, Staels B, Auwerx J. Role of the peroxisome proliferator- adipocyte differentiation in the obese Zucker fa/fa rat. Diabetes 1997; activated receptor (PPAR) in mediating the effects of fibrates and fatty 46:1393-9.
acids on gene expression. J Lipid Res 1996;37:907-25.
19. Swanson ML, Bleasdale JE. Antidiabetic agent pioglitazone increases 5. Mori H, Ikegami H, Kawaguchi Y et al. The Pro12--->Ala substitution in insulin receptors on 3T3-L1 adipocytes. Drug Dev Res 1995;35:69-82.
PPAR-gamma is associated with resistance to development of diabetes in 20. Murase K, Odaka H, Suzuki N, Tayuki N, Ikeda H. Pioglitazone time- the general population: possible involvement in impairment of insulin dependently reduces tumour necrosis factor-α level in muscle and secretion in individuals with type 2 diabetes. Diabetes 2001;50:891-4.
improves metabolic abnormalities in Wistar fatty rats. Diabetologia 1998; 6. Barroso I, Gurnell M, Crowley VEF et al. Dominant negative mutations in 41:257-64.
human PPARγ associated with severe insulin resistance, diabetes mellitus 21. Miyazaki Y, Mahankali A, Matsuda M et al. Improved glycaemic control and hypertension. Nature 1999;402:880-3.
and enhanced insulin sensitivity in Type 2 diabetic subjects treated with 7. Sakamoto J, Kimura H, Moriyama S et al. Activation of human peroxi- pioglitazone. Diabetes Care 2001;24:710-9.
some proliferator-activated receptor (PPAR) subtypes by pioglitazone.
22. Yamasaki Y, Kawamori R, Wasada T et al. Pioglitazone (AD-4833) ame- Biochem Biophys Res Commun 2000;278:704-11.
liorates insulin resistance in patients with NIDDM. Tohuku J Exp Med 8. Campbell IW. Antidiabetic drugs present and future: will improving 1997;183:173-83.
insulin resistance benefit cardiovascular risk in type 2 diabetes mellitus? 23. Roden M, Price TB, Perseghin G et al. Mechanism of free fatty-acid- Drugs 2000;60:1017-28.
induced insulin resistance in humans. J Clin Invest 1996;97:2859-65.
9. El-Kebbi IM, Roser S, Pollet RJ. Regulation of glucose transport by piogli- 24. Rebrin K, Steil GM, Getty L, Bergman RN. Free fatty acid as a link in the tazone in cultured muscle cells. Metabolism 1994;43:953-9.
regulation of hepatic glucose output by peripheral insulin. Diabetes 10. Sandouk T, Reda D, Hofmann C. The antidiabetic agent pioglitazone 1995;44:1038-45.
increases expression of glucose transporters in 3T3-F442A cells by 25. Groop L, Orho-Melander M. The dysmetabolic syndrome. J Intern Med increasing messenger ribonucleic acid transcript stability. Endocrinology 2001;250:105-20.
1993;133:352-9.
26. Laakso M. Insulin resistance and cardiovascular disease. Br J Diabetes 11. Hofmann C, Lorenz K, Colca JR. Glucose transport deficiency in diabetic Vasc Dis 2002;2(suppl 1):S7-S9.
animals is corrected by treatment with the oral antihyperglycemic agent 27. Brunetti P. Pioglitazone – current profile. Br J Diabetes Vasc Dis 2002;2
pioglitazone. Endocrinology 1991;129:1915-25.
12. Hayakawa T, Shiraki T, Morimoto T et al. Pioglitazone improves insulin 28. Carey GB. Mechanisms regulating adipocyte lipolysis. Adv Exp Med Biol signalling defects in skeletal muscle from Wistar fatty (fa/fa) rats.
1998;441:157-70.
Biochem Biophys Res Commun 1996;223:439-44.
29. Engfeldt P, Arner P, Bolinder J, Ostman J. Phosphodiesterase activity in 13. Smith U, Gogg S, Johansson A, Olausson T, Rotter V, Svalstedt B.
human subcutaneous adipose tissue in insulin- and noninsulin-depen- Thiazolidinediones (PPARγ agonists) but not PPARα agonists increase IRS- dent diabetes mellitus. J Clin Endocrinol Metab 1982;55:983-8.
2 gene expression in 3T3-L1 and human adipocytes. FASEB J 2001;15:
30. Tang Y, Osawa H, Onuma H, Nishimiya T, Ochi M, Makino H.
Improvement in insulin resistance and the restoration of reduced phos- 14. Hofmann CA, Edwards CWI, Hillman RM et al. Treatment of insulin-resis- phodiesterase 3B gene expression by pioglitazone in adipose tissue of tant mice with the oral antidiabetic agent pioglitazone: elevation of liver obese diabetic KKAy mice. Diabetes 1999;48:1830-5.
GLUT 2 and phosphoenolpyruvate carboxykinase expression.
31. Kletzien RF, Clarke SD, Ulrich RG. Enhancement of adipocyte differentia- Endocrinology 1992;130:735-40.
tion by an insulin sensitising agent. Mol Pharmacol 1992;41:393-8.
15. Hofmann C, Lorenz K, Williams D, Palazuk BJ, Colca JR. Insulin sensitisa- 32. King AB. A comparison in a clinical setting of the efficacy and side effects tion in diabetic rat liver by an antihyperglycemic agent. Metabolism of three thiazolidinediones. Diabetes Care 2000;23:557.
VOLUME 2 SUPPLEMENT 1 . JANUARY/FEBRUARY 2002

Source: http://bjdvd.com/content/2/1_suppl/S24.full.pdf

Microsoft word - k-10_pi _2011-03-10_.doc

PRESCRIBING INFORMATION ©2011 GlaxoSmithKline Inc. All Rights Reserved ®K-10 is a registered trademark, used under license by GlaxoSmithKline Inc. PRESCRIBING INFORMATION NAME OF DRUG (Potassium Chloride Solution, 10%) THERAPEUTIC CLASSIFICATION INDICATIONS The prevention and treatment of hypokalemic states which may occur in conjunction with diuretic therapy, di

embavene.fi

BASES COMPLETAS DEL VI CONCURSO LITERARIO INTERNACIONAL “ÁNGEL GANIVET” La Asociación de Países Amigos (A.P.A), con sede en Helsinki, convoca al VI Concurso Literario Internacional “Ángel Ganivet” en las modalidades de cuento y poesía, y éstas son las bases que finalmente lo rigen: 1. Pueden participar todas las personas que lo deseen, cualquiera que sea su nacionalidad

Copyright © 2010-2014 Pharmacy Pills Pdf