Repeat Treatment of Obese Mice With BRL 49653, a New Potent Insulin Sensitizer, Enhances Insulin Action in White Adipocytes: Association With Increased Insulin Binding and Cell-Surface GLUT4 as Measured by Photoaffinity Labeling

Young, Paul; Cawthorne, Michael A.; Coyle, Paul J.; Holder, Julie C.; Holman, Geoffrey D.; Kozka, Izabela J.; Kirkham, David M.; Lister, Carolyn A.; Smith, Stephen A.

doi:10.2337/diab.44.9.1087

Cited by 109 publications

(37 citation statements)

References 21 publications

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“…While free fatty acids and eicosanoids are endogenous ligands that mediate PPAR activity, development of a class of small molecule agonists for PPARγ, termed thiazolidinediones (TZDs), have provided significant clinical benefit for the treatment of type II diabetes. (Oakes, Kennedy et al 1994, Young, Cawthorne et al 1995, Petersen, Krssak et al 2000, Smith, Lister et al 2000) Beyond their use as anti-diabetic therapies, administration of these compounds, in particular troglitazone, has yielded significant cytotoxicity both in vitro and in vivo against various tumor cell types, suggesting that TZDs also possess utility as cancer chemotherapeutic agents. (Kubota, Koshizuka et al 1998, Galli, Ceni et al 2004, Galli, Mello et al 2006, Srivastava, Kollipara et al 2014) Accordingly, a variety of putative mechanisms have been proposed for troglitazone’s anti-proliferative effects, and multiple studies have attributed these effects to both PPARγ-dependent and –independent processes.…”

Section: Introductionmentioning

confidence: 99%

Troglitazone suppresses glutamine metabolism through a PPAR-independent mechanism

Reynolds

Clem

2015

Biological Chemistry

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Enhanced glutamine metabolism is required for tumor cell growth and survival, which suggests that agents targeting glutaminolysis may have utility within anti-cancer therapies. Troglitazone, a PPARγ agonist, exhibits significant anti-tumor activity and can alter glutamine metabolism in multiple cell types. Therefore, we examined whether troglitazone would disrupt glutamine metabolism in tumor cells and whether its action was reliant on PPARγ activity. We found that troglitazone treatment suppressed glutamine uptake and the expression of the glutamine transporter, ASCT2, and glutaminase. In addition, troglitazone reduced 13C-glutamine incorporation into the TCA cycle, decreased [ATP], and resulted in an increase in reactive oxygen species (ROS). Further, troglitazone treatment decreased tumor cell growth, which was partially rescued with the addition of the TCA-intermediate, alpha-ketoglutarate, or the anti-oxidant N-acetylcysteine. Importantly, troglitazone’s effects on glutamine uptake or viable cell number were found to be PPARγ-independent. In contrast, troglitazone caused a decrease in c-Myc levels, while the proteasomal inhibitor, MG132, rescued c-Myc, ASCT2 and GLS1 expression, as well as glutamine uptake and cell number. Lastly, combinatorial treatment of troglitazone and metformin resulted in a synergistic decrease in cell number. Therefore, characterizing new anti-tumor properties of previously approved FDA therapies supports the potential for repurposing of these agents.

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Section: Introductionmentioning

confidence: 99%

Troglitazone suppresses glutamine metabolism through a PPAR-independent mechanism

Reynolds

Clem

2015

Biological Chemistry

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“…Rosiglitazone significantly reduced the three parameters glucose, triglycerides and insulin. Thiazolidinedione antidiabetic agents that act to directly improve insulin sensitivity, increasing glucose uptake by adipose tissue and skeletal muscle (Young et al 1995), are agonists for PPARg, a member of the PPAR family of nuclear receptors that also includes PPARa and PPARd (also known as PPARb). PPARg, highly expressed in adipose tissue, plays an important role in the regulation of adipogenesis lipid metabolism and glucose homeostasis (Auboeuf et al 1997;Lehrke & Lazar et al 2005).…”

Section: Resultsmentioning

confidence: 99%

“…Increasing evidence suggests roles for PPARg in cellular processes outside adipose tissue, including for example in skeletal muscle (Loviscach et al 2000). Activation of PPARg in fat and possibly skeletal muscle is believed to contribute to the antihyperglycaemic activity of the thiazolidinediones, possibly through mechanisms including upregulation of transport proteins for glucose, including GLUT1 and GLUT4 (Young et al 1995;Shimaya et al 1998), and fatty acids (Frohnert et al 1999).…”

Section: Resultsmentioning

confidence: 99%

Metabolic effects of various antidiabetic and hypolipidaemic agents on a high-fat diet and multiple low-dose streptozocin (MLDS) mouse model of diabetes

Arulmozhi

Kurian

Bodhankar

et al. 2008

Journal of Pharmacy and Pharmacology

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Insulin resistance and subsequent insulin secretory defect are two main features of type 2 diabetes and associated metabolic disorders. The animal models of type 2 diabetes are very complex and are as heterogeneous as the disease. We have evaluated the effect of various antidiabetic and lipid lowering agents (fenofibrate, rosiglitazone, glimepiride, metformin and simvastatin) on the metabolic abnormalities induced by combining a high-fat diet and multiple low-dose streptozocin (MLDS) in mice. Male Swiss albino mice were orally treated with the above agents and fed with a diet containing high fat for 28 days. On day 15 the animals were injected intraperitoneally with low-dose streptozocin (40 mg kg(-1)), which was administered for five consecutive days. At the end of the 28-day treatment plasma metabolic parameters (glucose, triglyceride and immunoreactive insulin) were estimated. The antidiabetic and hypolipidaemic agents exhibited differential effects on these metabolic parameters. With the exception of fenofibrate all these agents reduced the plasma glucose levels, and the effects of metformin and rosiglitazone on glucose were found to be statistically significant. Although the effect of the test drugs on cholesterol was modest, a significant decrease in triglyceride levels was observed with sub-chronic treatment with these agents. Interestingly, glimepiride mildly elevated the insulin levels while the other antidiabetics and hypolipidaemics reduced the insulin levels, with metformin and rosiglitazone exhibiting statistically significant effects on insulin. To our knowledge this is the first report on the effect of various peroxisome proliferator-activated receptor modulators and newer antidiabetics on the metabolic effects induced by the combined high-fat diet and MLDS model of type 2 diabetes in Swiss albino mice. The results suggested the complexity of the hyperglycaemia, hyperinsulinaemia and hypertriglyceridaemia induced by the high-fat diet and MLDS mouse model, and their correction by various antidiabetics and antihyperlipidaemics may have involved diverse mechanisms.

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“…The combinations pioglitazone plus melatonin and rosiglitazone plus melatonin, decrease the elevated blood glucose level may be via increase in the glucose uptake though translocation of GLUT-4 by melatonin[17] and thiazolidinediones along with the increased insulin sensitivity[2837]. The decrease in the serum triglyceride level in combination groups, pioglitazone plus melatonin and rosiglitazone plus melatonin might be due to increase in the lipoprotein lipase activity which causes uptake of triglyceride in fat cells[13] by thiazolidinediones and melatonin may decreases Δ-5 desaturase activity in liver microsomes which may help in decrease in hyperlipidemia in the combination treated group[18].…”

Section: Discussionmentioning

confidence: 99%

Effects of combination of thiazolidinediones with melatonin in dexamethasone-induced insulin resistance in mice

et al. 2011

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In type 2 Diabetes, oxidative stress plays an important role in development and aggregation of insulin resistance. In the present study, long term administration of the dexamethasone led to the development of insulin resistance in mice. The effect of thiazolidinediones pioglitazone and rosiglitazone, with melatonin on dexamethasone-induced insulin resistance was evaluated in mice. Insulin resistant mice were treated with combination of pioglitazone (10 mg/kg/day, p.o.) or rosiglitazone (5 mg/kg/day, p.o.) with melatonin 10 mg/kg/day p.o. from day 7 to day 22. In the biochemical parameters, the serum glucose, triglyceride levels were significantly lowered (P<0.05) in the combination groups as compared to dexamethasone treated group as well as with individual groups of pioglitazone, rosiglitazone, and melatonin. There was also, significant increased (P<0.05) in the body weight gain in combination treated groups as compared to dexamethasone as well as individual groups. The combination groups proved to be effective in normalizing the levels of superoxide dismutase, catalase, glutathione reductase and lipid peroxidation in liver homogenates may be due to antioxidant effects of melatonin and decreased hyperglycemia induced insulin resistance by thiazolidinediones. The glucose uptake in the isolated hemidiaphragm of mice was significantly increased in combination treated groups (PM and RM) than dexamethasone alone treated mice as well as individual (pioglitazone, rosiglitazone, melatonin) treated groups probably via increased in expression of GLUT-4 by melatonin and thiazolidinediones as well as increased in insulin sensitivity by thiazolidinediones. Hence, it can be concluded that combination of pioglitazone and rosiglitazone, thiazolidinediones, with melatonin may reduces the insulin resistance via decreased in oxidative stress and control on hyperglycemia.

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Repeat Treatment of Obese Mice With BRL 49653, a New Potent Insulin Sensitizer, Enhances Insulin Action in White Adipocytes: Association With Increased Insulin Binding and Cell-Surface GLUT4 as Measured by Photoaffinity Labeling

Cited by 109 publications

References 21 publications

Troglitazone suppresses glutamine metabolism through a PPAR-independent mechanism

Troglitazone suppresses glutamine metabolism through a PPAR-independent mechanism

Metabolic effects of various antidiabetic and hypolipidaemic agents on a high-fat diet and multiple low-dose streptozocin (MLDS) mouse model of diabetes

Effects of combination of thiazolidinediones with melatonin in dexamethasone-induced insulin resistance in mice

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