Thiazolidinediones: effects on insulin resistance and the cardiovascular system

Quinn, Cathy E.; Hamilton, Paul; Lockhart, Christopher; McVeigh, Gary E.

doi:10.1038/sj.bjp.0707452

Cited by 134 publications

(88 citation statements)

References 123 publications

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“…It has attracted much attention as a regulator of metabolic status and target for the thiazolidinedione drugs that are licensed for use in the treatment of type-2 diabetes and include rosiglitazone and pioglitazone (Quinn et al, 2008). Like TRP channels, PPAR-␥ has promiscuous sensitivity to a range of ligands (Kliewer et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Rapid and Contrasting Effects of Rosiglitazone on Transient Receptor Potential TRPM3 and TRPC5 Channels

Majeed¹,

Bahnasi²,

Seymour³

et al. 2011

Mol Pharmacol

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The aim of this study was to generate new insight into chemical regulation of transient receptor potential (TRP) channels with relevance to glucose homeostasis and the metabolic syndrome. Human TRP melastatin 2 (TRPM2), TRPM3, and TRP canonical 5 (TRPC5) were conditionally overexpressed in human embryonic kidney 293 cells and studied by using calciummeasurement and patch-clamp techniques. Rosiglitazone and other peroxisome proliferator-activated receptor-␥ (PPAR-␥) agonists were investigated. TRPM2 was unaffected by rosiglitazone at concentrations up to 10 M but was inhibited completely at higher concentrations (IC 50 , ϳ22.5 M). TRPM3 was more potently inhibited, with effects occurring in a biphasic concentration-dependent manner such that there was approximately 20% inhibition at low concentrations (0.1-1 M) and full inhibition at higher concentrations (IC 50 , 5-10 M). PPAR-␥ antagonism by 2-chloro-5-nitrobenzanilide (GW9662) did not prevent inhibition of TRPM3 by rosiglitazone. TRPC5 was strongly stimulated by rosiglitazone at concentrations of Ն10 M (EC 50 , ϳ30 M). Effects on TRPM3 and TRPC5 occurred rapidly and reversibly. Troglitazone and pioglitazone inhibited TRPM3 (IC 50 , 12 M) but lacked effect on TRPC5, suggesting no relevance of PPAR-␥ or the thiazolidinedione moiety to rosiglitazone stimulation of TRPC5. A rosiglitazone-related but, was a weak stimulator of TRPM3 and TRPC5. The natural PPAR-␥ agonist 15-deoxy prostaglandin J 2 , had no effect on TRPM3 or TRPC5. The data suggest that rosiglitazone contains chemical moieties that rapidly, strongly, and differentially modulate TRP channels independently of PPAR-␥, potentially contributing to biological consequences of the agent and providing the basis for novel TRP channel pharmacology.

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Section: Introductionmentioning

confidence: 99%

Rapid and Contrasting Effects of Rosiglitazone on Transient Receptor Potential TRPM3 and TRPC5 Channels

Majeed¹,

Bahnasi²,

Seymour³

et al. 2011

Mol Pharmacol

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“…TZDs are selective and potent agonists for the peroxisome proliferatoractivated receptor (PPAR)g, and influence the transcription of genes that regulate lipid and glucose metabolism (8). Recent data suggest that PPARg agonists also may modulate other biological processes that are involved in atherosclerosis, including inflammation (9,10).…”

Section: Introductionmentioning

confidence: 99%

Treatment with the PPARγ agonist rosiglitazone downregulates interleukin-1 receptor antagonist in individuals with metabolic syndrome

Halvorsen¹,

Heggen²,

Ueland³

et al. 2010

European Journal of Endocrinology

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Objectives: Thiazolidinediones (TZDs) reduce insulin resistance, but also have pleiotropic properties including effects on inflammation. The balance between protective and proatherogenic effects may differ in various patient populations. We studied the effect of rosiglitazone on inflammatory markers in patients with metabolic syndrome (MetSyn). Methods: In a cross-over randomized controlled trial, 23 subjects with MetSyn were assigned to treatment with rosiglitazone that was uptitrated from 4 mg/day for 6 weeks followed by 8 mg/day for 6 weeks or matching placebo for 12 weeks, and then to the opposite treatment for 12 weeks. Plasma levels of inflammatory and metabolic markers were measured during follow-up. Results: Our main findings were i) compared to placebo, rosiglitazone significantly decreased the plasma levels of the naturally occurring interleukin (IL)1 inhibitor, IL1 receptor antagonist (IL1Ra; PZ0.001), potentially reflecting inflammatory effects on the IL1 system; ii) parallel to this, rosiglitazone decreased plasma levels of IL10 (PZ0.029) further suggesting inflammatory effects; iii) rosiglitazone decreased uric acid levels (PZ0.001), and monocyte chemoattractant protein-1 (PZ0.05) and C-reactive protein (PZ0.06) tended to be lower after rosiglitazone than placebo, suggesting potential pro-and anti-inflammatory effects simultaneously and iv) in vitro, rosiglitazone enhanced IL1Ra and decreased IL1b in THP-1 monocytes, illustrating the complex effects of these medications, potentially exhibiting anti-inflammatory effects on the IL1 system in certain tissues or cells at least at certain concentrations. Conclusion: Our findings suggest inflammatory effects on the IL1 system during rosiglitazone therapy in MetSyn. However, anti-inflammatory effects were also observed, and the net effect of TZDs in MetSyn should be further investigated.

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“…3 The mechanisms of TZD action are still being investigated but it has been clearly demonstrated that some of their effects are mediated through activation of the peroxisome proliferator-activated receptor-c (PPARc), a member of the nuclear receptor superfamily of ligand-dependent transcription factors predominantly expressed in adipocytes but also in other normal and transformed cells. 4 Beyond the metabolic actions, several studies indicate that TZD may have also anticancer properties in a variety of different epithelial malignancies.…”

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confidence: 99%

Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus–transgenic mice by peroxisome proliferator‐activated receptor γ–independent regulation of nucleophosmin†

et al. 2010

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Antidiabetic thiazolidinediones (TZD) have in vitro antiproliferative effect in epithelial cancers, including hepatocellular carcinoma (HCC). The effective anticancer properties and the underlying molecular mechanisms of these drugs in vivo remain unclear. In addition, the primary biological target of TZD, the ligand-dependent transcription factor peroxisome proliferator-activated receptor c (PPARc), is up-regulated in HCC and seems to provide tumor-promoting responses. The aim of our study was to evaluate whether chronic administration of TZD may affect hepatic carcinogenesis in vivo in relation to PPARc expression and activity. The effect of TZD oral administration for 26 weeks was tested on tumor formation in PPARc-expressing and PPARc-deficient mouse models of hepatic carcinogenesis. Proteomic analysis was performed in freshly isolated hepatocytes by differential in gel electrophoresis and mass spectrometry analysis. Identified TZD targets were confirmed in cultured PPARc-deficient hepatocytes. TZD administration in hepatitis B virus (HBV)-transgenic mice (TgN[Alb1HBV]44Bri) reduced tumor incidence in the liver, inhibiting hepatocyte proliferation and increasing apoptosis. PPARc deletion in hepatocytes of HBV-transgenic mice (Tg[HBV]CreKOc) did not modify hepatic carcinogenesis but increased the TZD antitumorigenic effect. Proteomic analysis identified nucleophosmin (NPM) as a TZD target in PPARc-deficient hepatocytes. TZD inhibited NPM expression at protein and messenger RNA levels and decreased NPM promoter activity. TZD inhibition of NPM was associated with the induction of p53 phosphorylation and p21 expression. Conclusion: These findings suggest that chronic administration of TZD has anticancer activity in the liver via inhibition of NPM expression and indicate that these drugs might be useful for HCC chemoprevention and treatment. (HEPATOLOGY 2010;52:493-505)

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Thiazolidinediones: effects on insulin resistance and the cardiovascular system

Cited by 134 publications

References 123 publications

Rapid and Contrasting Effects of Rosiglitazone on Transient Receptor Potential TRPM3 and TRPC5 Channels

Rapid and Contrasting Effects of Rosiglitazone on Transient Receptor Potential TRPM3 and TRPC5 Channels

Treatment with the PPARγ agonist rosiglitazone downregulates interleukin-1 receptor antagonist in individuals with metabolic syndrome

Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus–transgenic mice by peroxisome proliferator‐activated receptor γ–independent regulation of nucleophosmin†

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