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

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 alpha (TNF alpha) in the epididymal fat tissue of db/db mice. As for the cellular mechanism, cilostazol attenuated lipopolysaccharide (LPS)-induced TNF alpha expression by decreasing the mRNA and protein levels of Toll-like receptor 4 in Raw264.3 macrophages. Cilostazol also effectively ameliorated the TNF alpha-induced decrease of insulin-stimulated Akt phosphorylation and [H-3]2-deoxyglucose uptake by suppressing c-Jun N terminal kinase-mediated serine phosphorylation of insulin receptor substrate 1 in 3T3-L1 adipocyfes. 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 gamma. These results indicate that cilostazol suppressed TNF alpha production from macrophages and attenuated TNF alpha-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. (C) 2013 Elsevier By. All rights reserved.