RSS-Feed abonnieren
DOI: 10.1055/s-0030-1261952
© Georg Thieme Verlag KG Stuttgart · New York
Indomethacin Activates Peroxisome Proliferator-activated Receptor γ to Improve Insulin Resistance in Cotton Pellet Granuloma Model
Publikationsverlauf
received 26.05.2010
accepted 24.06.2010
Publikationsdatum:
27. Juli 2010 (online)
![](https://www.thieme-connect.de/media/hmr/201011/lookinside/thumbnails/10.1055-s-0030-1261952-1.jpg)
Abstract
Inflammation is involved in the development of insulin resistance and diabetes. However, the effectiveness of anti-inflammatory drugs in diabetic therapy remains obscure. In the present study, the possible mechanisms of indomethacin, one of the nonsteroidal anti-inflammatory drugs, in the improvement of insulin resistance were investigated. Indomethacin treatment significantly decreased cotton pellet implantation induced white blood cell count elevation and immune cells infiltration in epididymal white adipose tissue. Also, cotton pellet implantation induced impaired glucose utilization and insulin resistance were improved by indomethacin. The decrement in phosphoinsulin receptor and phospho-Akt levels induced by cotton pellet implantation was improved by indomethacin as well. Moreover, indomethacin decreased cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression in epididymal white adipose tissue with a marked reduction of prostaglandin 2 (PGE2) and nitrite/nitrate (NOx) levels in cotton pellet-implanted mice. Furthermore, pretreatment of peroxisome proliferator-activated receptor γ (PPARγ) antagonist, GW9662 not only reversed indomethacin-modified COX-2 and iNOS levels but also reversed indomethacin-improved insulin sensitivity determined by homeostasis model assessment-insulin resistance (HOMA-IR). Taken together, indomethacin might elevate the expression of PPARγ to decrease serum NOx and PGE2 to result in the improvement of insulin resistance.
Key words
cotton pellet granuloma - diabetes - indomethacin - insulin resistance - nitric oxide - peroxisome proliferator-activated receptor γ - prostaglandin E2
References
- 1 Schmidt MI, Duncan BB. Diabesity: an inflammatory metabolic condition. Clin Chem Lab Med. 2003; 41 1120-1130
- 2 Karalis KP, Giannogonas P, Kodela E, Koutmani Y, Zoumakis M, Teli T. Mechanisms of obesity and related pathology: linking immune responses to metabolic stress. FEBS J. 2009; 276 5747-5754
- 3 Andersen K, Pedersen BK. The role of inflammation in vascular insulin resistance with focus on IL-6. Horm Metab Res. 2008; 40 635-639
- 4 Mercader J, Granados N, Caimari A, Oliver P, Bonet ML, Palou A. Retinol-binding protein 4 and nicotinamide phosphoribosyltransferase/visfatin in rat obesity models. Horm Metab Res. 2008; 40 467-472
- 5 Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006; 116 1793-1801
- 6 Nieto-Vazquez I, Fernandez-Veledo S, Kramer DK, Vila-Bedmar R, Garcia-Guerra L, Lorenzo M. Insulin resistance associated to obesity: the link TNF-alpha. Arch Physiol Biochem. 2008; 114 183-194
- 7 Tremblay F, Jacques H, Marette A. Modulation of insulin action by dietary proteins and amino acids: role of the mammalian target of rapamycin nutrient sensing pathway. Curr Opin Clin Nutr Metab Care. 2005; 8 457-462
- 8 Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest. 2003; 112 1785-1788
- 9 Wu HT, Chang CK, Tsao CW, Wen YJ, Ling SM, Cheng KC, Chang CJ, Cheng JT. Insulin resistance without obesity induced by cotton pellet granuloma in mice. Lab Invest. 2009; 89 362-369
- 10 Bolduc C, Larose M, Lafond N, Yoshioka M, Rodrigue MA, Morissette J, Labrie C, Raymond V, St-Amand J. Adipose tissue transcriptome by serial analysis of gene expression. Obes Res. 2004; 12 750-757
- 11 Konheim YL, Wolford JK. Association of a promoter variant in the inducible cyclooxygenase-2 gene (PTGS2) with type 2 diabetes mellitus in Pima Indians. Hum Genet. 2003; 113 377-381
- 12 Helmersson J, Vessby B, Larsson A, Basu S. Association of type 2 diabetes with cyclooxygenase-mediated inflammation and oxidative stress in an elderly population. Circulation. 2004; 109 1729-1734
- 13 Hsieh PS, Jin JS, Chiang CF, Chan PC, Chen CH, Shih KC. COX-2-mediated inflammation in fat is crucial for obesity-linked insulin resistance and fatty liver. Obesity (Silver Spring). 2009; 17 1150-1157
- 14 Nagareddy PR, Xia Z, McNeill JH, MacLeod KM. Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes. Am J Physiol Heart Circ Physiol. 2005; 289 H2144-H2152
- 15 Nunes SF, Figueiredo IV, Soares PJ, Costa NE, Lopes MC, Caramona MM. Semicarbazide-sensitive amine oxidase activity and total nitrite and nitrate concentrations in serum: novel biochemical markers for type 2 diabetes?. Acta Diabetol. 2009; 46 135-140
- 16 FitzGerald GA, Loll P. COX in a crystal ball: current status and future promise of prostaglandin research. J Clin Invest. 2001; 107 1335-1337
- 17 Ribeiro M, Cella M, Farina M, Franchi A. Effects of aminoguanidine and cyclooxygenase inhibitors on nitric oxide and prostaglandin production, and nitric oxide synthase and cyclooxygenase expression induced by lipopolysaccharide in the estrogenized rat uterus. Neuroimmunomodulation. 2004; 11 191-198
- 18 Maeda T, Kiguchi N, Kobayashi Y, Ozaki M, Kishioka S. Pioglitazone attenuates tactile allodynia and thermal hyperalgesia in mice subjected to peripheral nerve injury. J Pharmacol Sci. 2008; 108 341-347
- 19 Plomgaard P, Nielsen AR, Fischer CP, Mortensen OH, Broholm C, Penkowa M, Krogh-Madsen R, Erikstrup C, Lindegaard B, Petersen AM, Taudorf S, Pedersen BK. Associations between insulin resistance and TNF-alpha in plasma, skeletal muscle and adipose tissue in humans with and without type 2 diabetes. Diabetologia. 2007; 50 2562-2571
- 20 Hundal RS, Petersen KF, Mayerson AB, Randhawa PS, Inzucchi S, Shoelson SE, Shulman GI. Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest. 2002; 109 1321-1326
- 21 El Midaoui A, Wu R, de Champlain J. Prevention of hypertension, hyperglycemia and vascular oxidative stress by aspirin treatment in chronically glucose-fed rats. J Hypertens. 2002; 20 1407-1412
- 22 Perucca E. Drug interactions with nimesulide. Drugs. 1993; 46 (S 01) 79-82
- 23 Kaneki M, Shimizu N, Yamada D, Chang K. Nitrosative stress and pathogenesis of insulin resistance. Antioxid Redox Signal. 2007; 9 319-329
- 24 Carvalho-Filho MA, Ropelle ER, Pauli RJ, Cintra DE, Tsukumo DM, Silveira LR, Curi R, Carvalheira JB, Velloso LA, Saad MJ. Aspirin attenuates insulin resistance in muscle of diet-induced obese rats by inhibiting inducible nitric oxide synthase production and S-nitrosylation of IRbeta/IRS-1 and Akt. Diabetologia. 2009; 52 2425-2434
- 25 Straus DS, Glass CK. Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol. 2007; 28 551-558
- 26 Vasudevan AR, Balasubramanyam A. Thiazolidinediones: a review of their mechanisms of insulin sensitization, therapeutic potential, clinical efficacy, and tolerability. Diabetes Technol Ther. 2004; 6 850-863
- 27 Hazra S, Dubinett SM. Ciglitazone mediates COX-2 dependent suppression of PGE2 in human non-small cell lung cancer cells. Prostaglandins Leukot Essent Fatty Acids. 2007; 77 51-58
- 28 Xing B, Xin T, Hunter RL, Bing G. Pioglitazone inhibition of lipopolysaccharide-induced nitric oxide synthase is associated with altered activity of p38 MAP kinase and PI3K/Akt. J Neuroinflammation. 2008; 5 4
- 29 Zhang F, Liu F, Yan M, Ji H, Hu L, Li X, Qian J, He X, Zhang L, Shen A, Cheng C. Peroxisome proliferator-activated receptor-gamma agonists suppress iNOS expression induced by LPS in rat primary Schwann cells. J Neuroimmunol. 2010; 218 36-47
- 30 Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA. Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1997; 272 3406-3410
- 31 Bjorkman DJ. Nonsteroidal anti-inflammatory drug-induced gastrointestinal injury. Am J Med. 1996; 101 25S-32S
- 32 Zhang J, Wang J, Wu H, He Y, Zhu G, Cui X, Tang L. Design, synthesis and insulin-sensitizing activity of indomethacin and diclofenac derivatives. Bioorg Med Chem Lett. 2009; 19 3324-3327
Correspondence
J.-T. Cheng
Departmnt of Medical Research
Chi-Mei Medical Center
Yong Kang City
Tainan County
73101 Taiwan
Telefon: +886/6/331 8516
Fax: +886/6/238 6548
eMail: m980103@mail.chimei.org.tw