Abstract
In a previous study, cilostazol promoted differentiation of 3T3-L1 fibroblasts into adipocytes and improved insulin sensitivity by stimulating peroxisome proliferator-activated receptor (PPAR) γ transcription. This study evaluated the in vivo efficacy of cilostazol to protect a db/db mouse model of type 2 diabetes against altered metabolic abnormalities and proinflammatory markers via activation of PPARγ transcription. Eight-week-old db/db mice were treated with cilostazol or rosiglitazone for 12 days. Cilostazol significantly decreased plasma glucose and triglyceride levels, as did rosiglitazone, a PPARγ agonist. Elevated plasma insulin and resistin levels were significantly decreased by cilostazol, and decreased adiponectin mRNA expression was elevated along with increased plasma adiponectin. Cilostazol significantly increased both adipocyte fatty acid binding protein and fatty acid transport protein-1 mRNA expressions with increased glucose transport 4 in the adipose tissue. Cilostazol and rosiglitazone significantly suppressed proinflammatory markers (superoxide, tumor necrosis factor-α, and vascular cell adhesion molecule-1) in the carotid artery of db/db mice. In an in vitro study with 3T3-L1 fibroblasts, cilostazol significantly increased PPARγ transcription activity, as did rosiglitazone. The transcription activity stimulated by cilostazol was attenuated by KT5720 [(9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9, 12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo [3,4-I][1,6]-benzodiazocine-10-carboxylic acid hexyl ester], a cAMP-dependent protein kinase inhibitor, and GW9662 (2-chloro-5-nitrobenzanilide), an antagonist of PPARγ activity, indicative of implication of the phosphatidylinositol 3-kinase/Akt signal pathway. These results suggest that cilostazol may improve insulin sensitivity along with anti-inflammatory effects in type 2 diabetic patients via activation of both cAMP-dependent protein kinase and PPARγ transcription.
Footnotes
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This work was supported by the Medical Research Center program of Ministry of Science and Technology/Korean Science and Engineering Foundation [Grant R13-2005-009]; and the Pusan National University [postdoctoral program].
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doi:10.1124/jpet.108.146456.
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ABBREVIATIONS: TNF, tumor necrosis factor; PPAR, peroxisome proliferator-activated receptor; cilostazol, OPC-13013, 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy]-3,4-dihydro-2(1H)-quinolinone; VCAM, vascular cell adhesion molecule; GLUT4, glucose transporter 4; PCR, polymerase chain reaction; aP2, adipocyte fatty acid binding protein; FATP, fatty acid transport protein; PPRE, peroxisome proliferator response element; siRNA, small interfering RNA; GW9662, 2-chloro-5-nitrobenzanilide; PD98059, 2′-amino-3′-methoxyflavone; LY294002, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride; PI3K, phosphatidylinositol 3-kinase; MEK, mitogen-activated protein kinase kinase; SP600125, 1,9-pyrazoloanthrone; SB239063 trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxypyridimidin-4-yl)imidazole; KT5720, (9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3′, 2′, 1′-kl]pyrrolo [3,4-I][1,6]benzodiazocine-10-carboxylic acid hexyl ester; SH5, d-3-deoxy-2-O-methyl-myo-inositol 1-[(R)-2-methoxy-3-(octadecyloxy)propyl hydrogen phosphate].
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received September 21, 2008.
- Accepted February 11, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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