Tesaglitazar, a novel dual peroxisome proliferator-activated receptor α/γ agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population

Fagerberg, Björn; Edwards, S.; Halmos, T; Lopatyński, J; Schuster, Herbert; Stender, Steen; Støa-Birketvedt, Grethe; Tonstad, Serena; Halldorsdottir, S.; Gause‐Nilsson, Ingrid

doi:10.1007/s00125-005-1846-8

Cited by 103 publications

(98 citation statements)

References 33 publications

(39 reference statements)

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“…16,17) In recent years, several structurally diverse PPAR dual agonists or PPAR pan agonists have been discovered. [17][18][19][20][21][22] Although several of them have been discontinued because of various side effects such as carcinogenesis in preclinical murine models, the effects of some new class of dual and pan PPAR agonists on the regulation of glucose and lipid metabolism with improved safety patterns have been demonstrated in experimental animal models.…”

Section: Discussionmentioning

confidence: 99%

Two Thiophenes Compounds Are Partial Peroxisome Proliferator-Activated Receptor .ALPHA./.GAMMA. Dual Agonists

Zheng

Yang

Shao

et al. 2011

Biological & Pharmaceutical Bulletin

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Section: Discussionmentioning

confidence: 99%

Two Thiophenes Compounds Are Partial Peroxisome Proliferator-Activated Receptor .ALPHA./.GAMMA. Dual Agonists

Zheng

Yang

Shao

et al. 2011

Biological & Pharmaceutical Bulletin

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“…A number of research groups have conducted extensive investigations in an effort to develop efficacious dual PPAR ␣/␥ agonists and develop potential agents such as ragaglitazar, tesaglitazar, muraglitazar, and chromane-2-carboxylic acids derivatives (15)(16)(17)(18). However, the use of these agents has been discontinued because of serious side effects, including carcinogenesis (19).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of Peroxisome Proliferators–Activated Receptor-α/γ Dual Agonist With Alleviation of Endoplasmic Reticulum Stress for the Treatment of Diabetes

et al. 2008

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OBJECTIVE-Peroxisome proliferator-activated receptor (PPAR)␣/␥ dual agonists have the potential to be used as therapeutic agents for the treatment of type 2 diabetes. This study evaluated the function of macelignan, a natural compound isolated from Myristica fragrans, as a dual agonist for PPAR␣/␥ and investigated its antidiabetes effects in animal models.RESEARCH DESIGN AND METHODS-GAL4/PPAR chimera transactivation was performed and the expression of PPAR␣/␥ target genes was monitored to examine the ability of macelignan to activate PPAR␣/␥. Additionally, macelignan was administrated to obese diabetic (db/db) mice to investigate antidiabetes effects and elucidate its molecular mechanisms.RESULTS-Macelignan reduced serum glucose, insulin, triglycerides, free fatty acid levels, and triglycerides levels in the skeletal muscle and liver of db/db mice. Furthermore, macelignan significantly improved glucose and insulin tolerance in these mice, and without altering food intake, their body weights were slightly reduced while weights of troglitazone-treated mice increased. Macelignan increased adiponectin expression in adipose tissue and serum, whereas the expression and serum levels of tumor necrosis factor-␣ and interleukin-6 decreased. Macelignan downregulated inflammatory gene expression in the liver and increased AMP-activated protein kinase activation in the skeletal muscle of db/db mice. Strikingly, macelignan reduced endoplasmic reticulum (ER) stress and c-Jun NH 2 -terminal kinase activation in the liver and adipose tissue of db/db mice and subsequently increased insulin signaling. T he worldwide prevalence of type 2 diabetes is steadily rising; therefore, in addition to a more aggressive approach in managing diabetes through diet and exercise, antidiabetes agents that ameliorate insulin resistance and hyperlipidemia are also needed. CONCLUSIONS-MacelignanAs members of the nuclear hormone receptor superfamily, peroxisome proliferator-activated receptors (PPARs) bind to specific DNA response elements as heterodimers with the retinoid-X receptor to control glucose and lipid metabolism, which offers a promising therapeutic approach for treating the metabolic syndrome (1). There are several PPAR isoforms, including PPAR ␣, ␥, and ␦ that share 60 -80% homology in the ligand-and DNA-binding domains (2). Widely expressed in the liver, PPAR␣ functions in the catabolism of fatty acids responsible for decreasing serum triglyceride levels and increasing HDL cholesterol levels in dyslipidemia (3). Therefore, PPAR␣ agonists have the potential to be used to ameliorate insulin resistance and hyperlipidemia. Moreover, PPAR␥ is highly expressed in adipocytes and is involved in adipocyte differentiation, lipid storage, glucose homeostasis, and adipocytokine regulation, which can improve insulin sensitivity and glucose tolerance (4). The primary issue with the utility of classic full PPAR␥ agonists is that they exert a variety of side effects, chiefly weight gain due to edema and increased fat mass (5). However, the side effects ...

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“…For example, muraglitazar-treated patients exhibited increased cardiovascular risk (37), and tesaglitazar has been recently reported to increase serum creatinine levels in insulin-resistant patients (14). Several mechanisms by which tesaglitazar raises serum creatinine levels have been proposed including the following: 1) PPAR␣ activation mediates skeletal myopathy such as acute rhabdomyolysis (40), 2) direct vascular action of PPAR␥ might decrease the glomerular perfusion and ultimately elevate creatinine levels through hemodynamic mechanism (41), and 3) PPAR␥ may have a direct effect on efferent arteriolar tone via downregulation of the AT1 receptor, as described previously (42).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a number of PPAR␣/␥ dual agonists have been or remain under evaluation for their efficacy in animal models of insulin resistance and in type 2 diabetic patients (13)(14)(15)(16)(17)(18). However, most studies have focused on the lipid-lowering effect and metabolic alterations, and little is known about the renal protective effect of PPAR ␣/␥ dual agonists in diabetic nephropathy.…”

mentioning

confidence: 99%

Peroxisome Proliferator–Activated Receptor α/γ Dual Agonist Tesaglitazar Attenuates Diabetic Nephropathy in db/db Mice

Ryong

Zhang

et al. 2007

Diabetes

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Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors and play a central role in insulin sensitivity, lipid metabolism, and inflammation. Both PPAR␣ and -␥ are expressed in the kidney, and their agonists exhibit renoprotective effects in type 2 diabetes. In the present studies, we investigated the effect of the PPAR␣/␥ dual agonist tesaglitazar on diabetic nephropathy in type 2 diabetic db/db mice. Treatment of db/db mice with tesaglitazar for 3 months significantly lowered fasting plasma glucose and homeostasis model assessment of insulin resistance levels but had little effect on body weight, adiposity, or cardiac function. Treatment with tesaglitazar was associated with reduced plasma insulin and total triglyceride levels and increased plasma adiponectin levels. Notably, tesaglitazar markedly attenuated albuminuria and significantly lowered glomerulofibrosis, collagen deposition, and transforming growth factor-␤1 expression in renal tissues of db/db mice. In cultured mesangial cells and proximal tubule cells, where both PPAR␣ and -␥ were expressed, tesaglitazar treatment abolished high glucoseinduced total collagen protein production and type I and IV collagen gene expression. Collectively, tesaglitazar treatment not only improved insulin resistance, glycemic control, and lipid profile but also markedly attenuated albuminuria and renal glomerular fibrosis in db/db mice. These findings support the utility of dual PPAR␣/␥ agonists in treating type 2 diabetes and diabetic nephropathy.

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Tesaglitazar, a novel dual peroxisome proliferator-activated receptor α/γ agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population

Cited by 103 publications

References 33 publications

Two Thiophenes Compounds Are Partial Peroxisome Proliferator-Activated Receptor .ALPHA./.GAMMA. Dual Agonists

Two Thiophenes Compounds Are Partial Peroxisome Proliferator-Activated Receptor .ALPHA./.GAMMA. Dual Agonists

Therapeutic Potential of Peroxisome Proliferators–Activated Receptor-α/γ Dual Agonist With Alleviation of Endoplasmic Reticulum Stress for the Treatment of Diabetes

Peroxisome Proliferator–Activated Receptor α/γ Dual Agonist Tesaglitazar Attenuates Diabetic Nephropathy in db/db Mice

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