Cilostazol ameliorates metabolic abnormalities with suppression of proinflammatory markers in a db/db mouse model of type 2 diabetes via activation of peroxisome proliferator-activated receptor gamma transcription.
In a previous study, cilostazol promoted differentiation of 3T3-L1 fibroblasts into adipocytes and improved insulin sensitivity by stimulating peroxisome proliferator-activated receptor (PPAR) gamma 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 PPARgamma 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 PPARgamma 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-alpha, 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 PPARgamma 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 PPARgamma 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 PPARgamma transcription.
Park
So Youn
SY
Department of Pharmacology, College of Medicine, Pusan National University, Seo-Gu, Busan, Korea.
Shin
Hwa Kyoung
HK
Lee
Jeong Hyun
JH
Kim
Chi Dae
CD
Lee
Won Suk
WS
Rhim
Byung Yong
BY
Hong
Ki Whan
KW
D041721:3T3-L1 Cells; D052242:Adiponectin / Q000097:blood / Q000235:genetics; D000273:Adipose Tissue / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D000077407:Cilostazol; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000096:biosynthesis; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000096:biosynthesis*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D054411:Receptors, Leptin / Q000172:deficiency; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015533:Transcriptional Activation / Q000187:drug effects; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000276:immunology
D052242:Adiponectin; D015415:Biomarkers; D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D047495:PPAR gamma; D010726:Phosphodiesterase Inhibitors; D054411:Receptors, Leptin; C495693:Slc2a4 protein, mouse; D013777:Tetrazoles; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D000077407:Cilostazol