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 ameliorates systemic insulin resistance in diabetic db/db mice by suppressing chronic inflammation in adipose tissue via modulation of both adipocyte and macrophage functions.
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西洛他唑通过调节脂肪细胞和巨噬细胞功能抑制脂肪组织中的慢性炎症，从而改善糖尿病 db/db 小鼠的全身胰岛素抵抗。
DOI：
10.1016/j.ejphar.2013.03.016
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Sasaoka T.
中科院分区：
文献类型：
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作者：
Wada T;Onogi Y;Kimura Y;Nakano T;Fusanobori H;Ishii Y;Sasahara M;Tsuneki H;Sasaoka T.
西洛他唑是一种磷酸二酯酶 3B 抑制剂，广泛用作糖尿病患者的抗血小板药物。最近，西洛他唑被证明可以促进前脂肪细胞分化为成熟脂肪细胞并影响葡萄糖稳态；因此，我们研究了西洛他唑对糖尿病 db/db 小鼠脂肪组织中葡萄糖代谢受损的影响。给予 db/db 小鼠 100–300mg/kg/天的西洛他唑以剂量依赖性方式显着改善葡萄糖耐量和胰岛素敏感性，而在非糖尿病对照小鼠中未观察到这些效果。西洛他唑可减少 db/db 小鼠附睾脂肪组织中的脂肪细胞大小并抑制单核细胞趋化蛋白 1、CD11c 和肿瘤坏死因子 α (TNFα) 的 mRNA 表达。至于细胞机制，西洛他唑通过降低 Raw264.3 巨噬细胞中 Toll 样受体 4 的 mRNA 和蛋白水平来减弱脂多糖 (LPS) 诱导的 TNFα 表达。西洛他唑还通过抑制 3T3-L1 脂肪细胞中胰岛素受体底物 1 的 c-Jun N 末端激酶介导的丝氨酸磷酸化，有效改善 TNFα 诱导的胰岛素刺激的 Akt 磷酸化和 [3H]2-脱氧葡萄糖摄取的减少。重要的是，用 KT5720（一种蛋白激酶 A 抑制剂）预处理会削弱胰岛素信号传导受损的改善效果，但用 GW9662（一种过氧化物酶体增殖物激活受体 γ）预处理则不会。这些结果表明，西洛他唑抑制巨噬细胞产生 TNFα，并减轻 TNFα 诱导的脂肪组织慢性炎症，从而改善肥胖糖尿病小鼠的葡萄糖耐受不良和胰岛素抵抗。因此，本研究揭示了使用西洛他唑治疗 2 型糖尿病患者的额外益处。
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 100–300mg/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 [3H]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.