Troglitazone and related compounds: Therapeutic potential beyond diabetes

doi:10.1016/S0024-3205(00)00829-8

Life Sciences

Volume 67, Issue 20, 6 October 2000, Pages 2405-2416

https://doi.org/10.1016/S0024-3205(00)00829-8 Get rights and content

Abstract

Troglitazone and structurally related compounds (pioglitazone, rosiglitazone etc.) containing thiazolidinediones (TZD) are a novel class of antidiabetic agents which decrease blood glucose in diabetic animal models and in patients with Non-Insulin-Dependent Diabetes Mellitus (NIDDM) through alleviating insulin resistance. A large body of evidence is now accumulating indicating that insulin resistance and/or resulting hyperinsulinemia underlie the pathogenesis of not only diabetes but also of the clustering syndrome called “syndrome X” or “insulin resistance syndrome” which includes hypertension, dislipidemia and hypercoagulation. Therefore, TZD class of insulin sensitizers seem to have therapeutic potential to improve this clustering syndrome in addition to diabetes. Moreover, it was demonstrated that the TZD class of insulin sensitizers including troglitazone bind and activate the peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear hormone receptor. Although PPARγ is predominantly expressed in adipose tissue, one of the target tissues for insulin, it have been subsequently found to be expressed in macrophages, vascular smooth muscle cells (VSMC), endothelial cells and several cancer cell lines. PPARγ activation by PPARγ agonists such as TZD class of insulin sensitizers in these cells modulates these cell functions such as the production of inflammatory cytokine by macrophages, proliferation and migration of VSMC, and growth or differentiation in cancer cells. In addition, troglitazone has potent antioxidant effect, and suppresses both L-type and receptor operated Ca²+ channel and protein kinase C. Thus since TZD class of insulin sensitizers has many kind of therapeutic effect in addition to lowering blood glucose, these agents expect to have therapeutic potential beyond diabetes.

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Cited by (67)

A population-based cohort study in Taiwan-use of insulin sensitizers can decrease cancer risk in diabetic patients?
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Citation Excerpt :
Thiazolidinediones (TZDs) are insulin sensitizers that bind and activate peroxisome proliferator-activated receptors gamma (PPARγ), a nuclear hormone receptor [1, 2] Conflicting results have been reported regarding the relationship between TZDs' use and subsequent cancer risk.
The purpose of the study was to explore the possible association between the use of insulin sensitizers (thiazolidinediones, TZDs) and the risk of cancer in Taiwanese diabetic patients.
From the National Health Insurance Research Database (NHIRD) of Taiwan, we identified 22 910 diabetic patients newly diagnosed from 2001 to 2009 and 91 636 non-diabetic comparisons frequency matched with age, sex, and calendar year, excluding those with cancer at the baseline. Among the diabetics, 4159 patients were treated with TZDs and the rest of 18 752 patients were on other anti-diabetic medications (non-TZDs).
In comparison to the non-diabetes group, the non-TZDs group had an increased risk of developing cancer [the adjusted hazard ratio (HR): 1.20 and 95% confidence interval (CI) = 1.11–1.30]. The TZDs group had a HR of 1.18 (95% CI = 0.98–1.42). Analysis of site-specific cancer risks showed that both TZDs and non-TZDs groups with elevated risks of colorectal and pancreatic cancer. However, the non-TZDs group had an increased risk of liver cancer when comparing with TZD and non-diabetes groups.
This study suggests that patients with diabetes are at an elevated risk of cancer (especially in colorectal and pancreatic cancers), and the use of TZDs might decrease the liver cancer risk in diabetic patients. Further investigation using large samples and rigorous methodology is warranted.
Citrus unshiu peel extract ameliorates hyperglycemia and hepatic steatosis by altering inflammation and hepatic glucose- and lipid-regulating enzymes in db/db mice
2013, Journal of Nutritional Biochemistry
Citation Excerpt :
Although it remains unclear whether hepatic steatosis is a consequence of insulin resistance or causes hepatic insulin resistance, patients with NAFLD are more prone to have insulin resistance and Type 2 diabetes [3], and the prevalence of the severe stage of NAFLD is high in Type 2 diabetes [4]. Most notably, insulin sensitizers such as thiazolidinediones and antioxidants improve Type 2 diabetes [5,6]. However, thiazolidinediones like rosiglitazone (RGZ) have some unfavorable complications including weight gain [7], hepatotoxicity [8] and congestive heart failure [9].
Insulin resistance in Type 2 diabetes leads to hepatic steatosis that can accompanied by progressive inflammation of the liver. Citrus unshiu peel is a rich source of citrus flavonoids that possess anti-inflammatory, anti-diabetic and lipid-lowering effects. However, the ability of citrus unshiu peel ethanol extract (CPE) to improve hyperglycemia, adiposity and hepatic steatosis in Type 2 diabetes is unknown. Thus, we evaluated the effects of CPE on markers for glucose, lipid metabolism and inflammation in Type 2 diabetic mice. Male C57BL/KsJ-db/db mice were fed a normal diet with CPE (2 g/100 g diet) or rosiglitazone (0.001 g/100 g diet) for 6 weeks. Mice supplemented with the CPE showed a significant decrease in body weight gain, body fat mass and blood glucose level. The antihyperglycemic effect of CPE appeared to be partially mediated through the inhibition of hepatic gluconeogenic phosphoenolpyruvate carboxykinase mRNA expression and its activity and through the induction of insulin/glucagon secretion. CPE also ameliorated hepatic steatosis and hypertriglyceridemia via the inhibition of gene expression and activities of the lipogenic enzymes and the activation of fatty acid oxidation in the liver. These beneficial effects of CPE may be related to increased levels of anti-inflammatory adiponectin and interleukin (IL)-10, and decreased levels of pro-inflammatory markers (IL-6, monocyte chemotactic protein-1, interferon-γ and tumor necrosis factor-α) in the plasma or liver. Taken together, we suggest that CPE has the potential to improve both hyperglycemia and hepatic steatosis in Type 2 diabetes.
Role of mitogen-activated protein kinase (MAPK) in troglitazone-induced osteoblastic cell death
2007, Toxicology
Troglitazone, a PPARγ agonist, has been reported to induce cell death on different cell types. However, its mechanism of action remains unclear. The present study was undertaken to investigate the effect of troglitazone on cell death and to determine its underlying mechanism in MC3T3-E1 cells, an established osteoblast cell line. Troglitazone induced loss of cell viability in a dose- and time-dependent manner, which was accompanied by apoptosis. Troglitazone increased reactive oxygen species (ROS), but troglitazone-induced cell death was not affected by the antioxidant N-acetylcysteine, suggesting that the ROS generation is not involved in the cytotoxicity of troglitazone. Troglitazone-induced cell death was prevented by the PPARγ antagonist GW9662. Troglitazone treatment inhibited activation of extracellular signal-regulated protein kinase (ERK) and stimulated p38 activation. Troglitazone-induced cell death was increased by the ERK inhibitor U0126 and prevented by transfection with constitutively active MEK1 and the p38 inhibitor SB203580. Troglitazone induced depolarization of mitochondrial membrane potential and its effect was blocked by SB203580 and GW9662. Caspase-3 was activated by troglitazone treatment and pharmacological inhibition of caspase blocked troglitazone-induced cell death. Taken together, these data suggest that troglitazone induces apoptosis via a caspase-dependent mechanism associated with down-regulation of ERK and up-regulation of p38.
Role of PPAR-γ on the pathogenesis and vascular changes in glycerol-induced acute renal failure
2006, Pharmacological Research
Peroxisome proliferator activated receptor-γ (PPAR-γ), a nuclear transcription factor, modulates angiotensin II (AII) or thromboxane A₂ (TxA₂) response in the vasculature via transcriptional regulation of their gene or receptor expression. Increased AII or TxA₂ vasoconstriction and deteriorating renal function observed in glycerol-induced acute renal failure (ARF) may be attributed to a down-regulated PPAR-γ expression/activity probably via an increased free radical generation. In this study, we investigated the effect of PPAR-γ induction in glycerol-induced ARF by examining renal vascular reactivity to AII and TxA₂ and by renal expression/activity of PPAR-γ. Vascular responses to AII or U46619, a TxA₂ mimetic were determined in rat isolated perfused kidney following induction of ARF with glycerol (50%, v/v, i.m.). Extent of renal damage and function were assessed with or without pre-treatment with ciglitazone (9 nmol kg⁻¹ × 21 days), a PPAR-γ inducer. In ARF, vasoconstriction was enhanced to AII (three-fold; p < 0.05) and U46619 (82%; p < 0.05). Ciglitazone reduced AII and U46619 vasoconstriction by 59 ± 1% (p < 0.05) and 56 ± 1% (p < 0.05), respectively. Ciglitazone reduced proteinuria (38 ± 3%) which was two-fold higher in ARF. Similarly, ciglitazone enhanced Na⁺ excretion by 1.5 times while reducing BUN by 49 ± 6%. On the contrary, ciglitazone did not change plasma creatinine which was significantly higher in ARF rats. Ciglitazone reduced free radical generation by 30 ± 3% while elevating nitrite excretion ∼2-fold. PPAR-γ expression and activity were significantly lower in ARF rats and ciglitazone enhanced PPAR-γ protein expression and activity by 45 ± 3% and 52 ± 4%, respectively. Data from this study suggest that reduced PPAR-γ expression and activity may be involved in the pathology of glycerol-induced ARF and induction of PPAR-γ by ciglitazone confers protection through reduced AII and TxA₂ vasoconstriction and/or enhanced renal function via reducing free radical generation.
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MinireviewTroglitazone and related compounds: Therapeutic potential beyond diabetes

Abstract

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Troglitazone and related compounds: Therapeutic potential beyond diabetes