Cilostazol ameliorates systemic insulin resistance in diabetic db/db mice by suppressing chronic inflammation in adipose tissue via modulation of both adipocyte and macrophage functions

Eur J Pharmacol. 2013 May 5;707(1-3):120-9. doi: 10.1016/j.ejphar.2013.03.016. Epub 2013 Mar 22.


Cilostazol, an inhibitor of phosphodiesterase 3B, is widely used as an anti-platelet drug in diabetic patients. Recently, cilostazol has been shown to promote preadipocyte differentiation to mature adipocyte and affect glucose homeostasis; therefore, we examined the impact of cilostazol on impaired glucose metabolism in adipose tissues of diabetic db/db mice. Administration of cilostazol at 100-300 mg/kg/day significantly improved glucose tolerance and insulin sensitivity in a dose-dependent manner in db/db mice, whereas these effects were not observed in non-diabetic control mice. Cilostazol reduced the adipocyte size and suppressed mRNA expressions of monocyte chemoattractant protein 1, CD11c, and tumor necrosis factor α (TNFα) in the epididymal fat tissue of db/db mice. As for the cellular mechanism, cilostazol attenuated lipopolysaccharide (LPS)-induced TNFα expression by decreasing the mRNA and protein levels of Toll-like receptor 4 in Raw264.3 macrophages. Cilostazol also effectively ameliorated the TNFα-induced decrease of insulin-stimulated Akt phosphorylation and [(3)H]2-deoxyglucose uptake by suppressing c-Jun N terminal kinase-mediated serine phosphorylation of insulin receptor substrate 1 in 3T3-L1 adipocytes. Importantly, the improvement of impaired insulin signaling was blunted by pretreatment with KT5720, a protein kinase A inhibitor, but not with GW9662, a peroxisome proliferator-activated receptor γ. These results indicate that cilostazol suppressed TNFα production from macrophages and attenuated TNFα-induced chronic inflammation in adipose tissue, leading to the improvement of glucose intolerance and insulin resistance in obese diabetic mice. Thus, the present study reveals an additional benefit in the use of cilostazol in the treatment of patients with type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Animals
  • Chronic Disease
  • Cilostazol
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / physiopathology
  • Dose-Response Relationship, Drug
  • Glucose / metabolism
  • Glucose Intolerance / drug therapy
  • Inflammation / drug therapy*
  • Inflammation / pathology
  • Insulin Resistance
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Obesity / drug therapy
  • Obesity / physiopathology
  • Phosphodiesterase 3 Inhibitors / administration & dosage
  • Phosphodiesterase 3 Inhibitors / pharmacology*
  • RNA, Messenger / metabolism
  • Tetrazoles / administration & dosage
  • Tetrazoles / pharmacology*
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / drug effects
  • Tumor Necrosis Factor-alpha / metabolism


  • Phosphodiesterase 3 Inhibitors
  • RNA, Messenger
  • Tetrazoles
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Glucose
  • Cilostazol