Dipeptidyl peptidase- IV inhibitor alogliptin improves stress-induced insulin resistance and prothrombotic state in a murine model
Dipeptidyl peptidase- IV inhibitor alogliptin improves stress-induced insulin resistance and prothrombotic state in a murine model
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DOI：
10.1016/j.psyneuen.2016.08.004
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发表时间：
2016-11
影响因子：
3.7
通讯作者：
Maimaiti Yisireyili;Kyosuke Takeshita;M. Hayashi;Hongxian Wu;Y. Uchida;Koji Yamamoto;R. Kikuchi;Chang-ning Hao;T. Nakayama;X. Cheng;T. Matsushita;S. Nakamura;T. Murohara
中科院分区：
文献类型：
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作者：
Maimaiti Yisireyili;Kyosuke Takeshita;M. Hayashi;Hongxian Wu;Y. Uchida;Koji Yamamoto;R. Kikuchi;Chang-ning Hao;T. Nakayama;X. Cheng;T. Matsushita;S. Nakamura;T. Murohara
背景应激可引起内脏脂肪组织中游离脂肪酸（free fatty acid，FFA）的分解释放和轻度炎症反应，并通过增加脂肪因子分泌介导，导致糖代谢紊乱和血栓前状态。我们测试的假设，阿格列汀，二肽基肽酶-4抑制剂，可以改善慢性stressinmice.Method和resultsC 57 BL/6 J小鼠的生物学效应进行2周的间歇性约束应力和口服治疗的车辆或阿格列汀（剂量：15或45 mg/kg/天）。采用酶联免疫吸附试验测定血脂、促炎细胞因子（单核细胞趋化蛋白-1、肿瘤坏死因子-α和白细胞介素-6）和8-羟基脱氧鸟苷的血浆水平。通过CD 11 b阳性细胞计数检测腹股沟白色脂肪组织（WAT）中单核/巨噬细胞的积聚，并分别通过免疫组织化学和RT-PCR检测CD 68和F4/80的mRNA表达。RT-PCR检测上述促炎细胞因子、NADPH氧化酶4、脂联素和凝血因子（纤溶酶原激活抑制剂-1和组织因子）在WAT中的mRNA水平。通过葡萄糖和胰岛素耐量试验、血浆DPP-4活性、胰高血糖素样肽-1水平、WAT和骨骼肌中DPP-4、胰岛素受体底物-1和葡萄糖转运蛋白4的表达来评估葡萄糖代谢。阿格列汀给药抑制应激诱导的FFA释放，氧化应激，脂肪组织炎症，DPP-4激活，和血栓前状态的剂量依赖性的方式，并提高胰岛素敏感性在stressedmice.ConclusionsThe结果表明，阿格列汀改善应激诱导的血栓前状态和胰岛素抵抗，这表明阿格列汀可能有有益的治疗效果，对糖尿病患者的心血管并发症的压力。
BackgroundStress evokes lipolytic release of free fatty acid (FFA) and low-grade inflammation in visceral adipose tissue, mediated by increased adipokine secretion, and contributes to glucose metabolism disorder and prothrombotic state. We tested the hypothesis that alogliptin, a dipeptidyl peptidase-4 inhibitor, can ameliorate the biological effects of chronic stress in mice.Method and resultsC57BL/6J mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle or alogliptin (dose: 15 or 45 mg/kg/day). Plasma levels of lipids, proinflammatory cytokines (monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-6), and 8-hydroxydeoxyguanosine were measured with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT) was examined by CD11b-positive cell count and mRNA expression of CD68 and F4/80 was examined by immunohistochemistry and RT-PCR, respectively. The mRNA levels of the above-mentioned proinflammatory cytokines, NADPH oxidase 4, adiponectin, and coagulation factors (plasminogen activation inhibitor-1 and tissue factor) in WAT were also assessed with RT-PCR. Glucose metabolism was assessed by glucose and insulin tolerance tests, plasma levels of DPP-4 activity, glucagon-like peptide-1, expression of DPP-4, insulin receptor substrate-1 and glucose transporter 4 in WAT and skeletal muscle. Alogliptin administration suppressed stress-induced FFA release, oxidative stress, adipose tissue inflammation, DPP-4 activation, and prothrombotic state in a dose-dependent manner, and improved insulin sensitivity in stressed mice.ConclusionsThe results indicate that alogliptin improves stress-induced prothrombotic state and insulin resistance; suggesting that alogliptin could have beneficial therapeutic effects against cardiovascular complications in diabetic patients under stress.