Pioglitazone Ameliorates Tumor Necrosis Factor-α–Induced Insulin Resistance by a Mechanism Independent of Adipogenic Activity of Peroxisome Proliferator–Activated Receptor-γ

Iwata, Minoru; Haruta, Tetsuro; Usui, Isao; Takata, Yasumitsu; Takano, Atsuko; Uno, Tatsuhito; Kawahara, Junko; Ueno, Eiichi; Sasaoka, Toshiyasu; Ishibashi, Osamu; Kobayashi, Masashi

doi:10.2337/diabetes.50.5.1083

Cited by 103 publications

(81 citation statements)

References 54 publications

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“…Further investigation is required to determine the intracellular signalling events regulating the effects of rosiglitazone in the present study. Although the effects of rosiglitazone on insulin target tissues have been largely attributed to selective activation of PPARγ, recent studies have begun to reveal that members of the thiazolidinedione family of drugs can also have marked effects on cell function through PPARγ-independent mechanisms [34,35]. In the present study, addition of GW9662 had no effect on rosiglitazone stimulation of the Ipf1 gene promoter, indicating that these events are not dependent on the activity of PPARγ.…”

Section: Discussioncontrasting

confidence: 45%

Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

et al. 2006

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Aims/hypothesis: Rosiglitazone and metformin are two oral antihyperglycaemic drugs used to treat type 2 diabetes. While both drugs have been shown to improve insulin-sensitive glucose uptake, the direct effects of these drugs on pancreatic beta cells is only now beginning to be clarified. The aim of the present study was to determine the direct effects of these agents on beta cell gene expression. Methods: We used reporter gene analysis to examine the effects of rosiglitazone and metformin on the activity of the proinsulin and insulin promoter factor 1 (IPF1) gene promoters in the glucose-responsive mouse beta cell line Min6. Western blot and gel retardation analyses were used to examine the effects of both drugs on the regulation of IPF1 protein production, nuclear accumulation and DNA binding activity in both Min6 cells and isolated rat islets of Langerhans. Results: Over 24 h, rosiglitazone promoted the nuclear accumulation of IPF1 and forkhead homeobox A2 (FOXA2), independently of glucose concentration, and stimulated a two-fold increase in the activity of the Ipf1 gene promoter (p<0.01). Stimulation of the Ipf1 promoter by rosiglitazone was unaffected by the presence of the peroxisome proliferator activated receptor γ antagonist GW9662. No effect of either rosiglitazone or metformin was observed on proinsulin promoter activity. Metformin stimulated IPF1 nuclear accumulation and DNA binding activity in a time-dependent manner, with maximal effects observed after 2 h. Conclusions/interpretation: Metformin and rosiglitazone have direct effects on beta cell gene expression, suggesting that these agents may play a previously unrecognised role in the direct regulation of pancreatic beta cell function.

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Section: Discussioncontrasting

confidence: 45%

Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

et al. 2006

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“…Interestingly, the protective effect of metformin in this study did not correlate to AMP kinase activation, but via prevention of plasminogen activator inhibitor (PAI)-I upregulation by alcohol [145]. Rosiglitazone and pioglitazone, thiazolidinedione peroxisomal proliferator-activated receptor (PPAR)-γ agonists, decrease insulin resistance and have been shown to decrease TNF-α levels and inflammation in rodent models of NASH [146][147][148][149][150]. Similarly, the PPAR-γ agonist pioglitazone prevents alcohol induced liver injury through interactions with the c-Met signaling pathway resulting in decreased triglyceride synthesis [151].…”

Section: Are Antioxidants Feasible Treatments For Fatty Liver Disease?mentioning

confidence: 70%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

388

302

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Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical "first-hit" in the pathogenesis of liver disease. It is proposed that steatosis "primes" the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or "second-hits". Genetic risk factors can also influence the susceptibility and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunctional are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: 1) the "two-hit" or "multi-hit" hypothesis; 2) the role of mitochondrial bioenergetic defects and oxidant stress; 3) interplay between NO and mitochondria in fatty liver disease; 4) genetic risk factors and oxidative stress responsive genes; and 5) the feasibility of antioxidants for treatment.

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“…Pioglitazone has also been reported to reduce TNF-α-induced insulin resistance in 3T3-L1 cells by a mechanism independent of the adipogenic activity of PPARγ [44]. In that model restoration of insulin response was mostly produced at the level of IRS-1/PI 3-kinase.…”

Section: Discussionmentioning

confidence: 95%

Rosiglitazone ameliorates insulin resistance in brown adipocytes of Wistar rats by impairing TNF-α induction of p38 and p42/p44 mitogen-activated protein kinases

et al. 2004

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Aims/hypothesis. TNF-α caused insulin resistance on glucose uptake and on insulin signalling in fetal brown adipocytes. Since treatment with TNF-α activates stress kinases, including c-jun NH2 terminal kinase (JNK), and p42/p44 and p38 mitogen-activated protein kinases (MAPK), we explored the contribution of these pathways to insulin resistance by TNF-α. Rosiglitazone is used to treat Type 2 diabetes as it improves insulin sensitivity in vivo. However, its ability to ameliorate TNF-α-induced insulin resistance in brown adipocytes remains to be explored. Methods. We used fetal rat primary brown adipocytes cultured with TNF-α, with or without stress kinase inhibitors or rosiglitazone, and further stimulated with insulin. Then, we measured glucose uptake and GLUT4 translocation. To determine the insulin signalling cascade, we submitted cells to lysis, immunoprecipitation and immunoblotting.

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Pioglitazone Ameliorates Tumor Necrosis Factor-α–Induced Insulin Resistance by a Mechanism Independent of Adipogenic Activity of Peroxisome Proliferator–Activated Receptor-γ

Cited by 103 publications

References 54 publications

Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Rosiglitazone ameliorates insulin resistance in brown adipocytes of Wistar rats by impairing TNF-α induction of p38 and p42/p44 mitogen-activated protein kinases

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