Haddad Youssef, Couture Réjean
Department of Pharmacology and Physiology, Faculty of Medicine, Université de MontréalMontréal, QC, Canada.
Front Pharmacol. 2017 Aug 2;8:509. doi: 10.3389/fphar.2017.00509. eCollection 2017.
Kinin B1 receptor (B1R) contributes to insulin resistance, an early event in type 2 diabetes, through the upregulation and activation of the inducible form of nitric oxide synthase (iNOS), pro-inflammatory cytokines and the oxidative stress. This study addresses the hypothesis that inhibition of kininase 1 (carboxypeptidase M, CPM), the key enzyme involved in the biosynthesis of B1R agonists, could exert the same beneficial effects to B1R antagonism in insulin resistance. Male Sprague-Dawley rats were made insulin resistant with a drinking solution containing 10% D-glucose for a period of 9 weeks. Control rats received tap water. During the last week, kininase 1 was blocked with Mergetpa (1 mg kg twice daily, s.c.) and the impact was determined on insulin resistance (HOMA index), metabolic hormone levels, oxidative stress and the expression of several markers of inflammation by western blot and qRT-PCR. Glucose-fed rats displayed hyperglycemia, hyperinsulinemia, hyperleptinemia, insulin resistance, hypertension, positive body weight gain, and enhanced expression of B1R, CPM, iNOS, and IL-1β in renal cortex, aorta and liver. Markers of oxidative stress (superoxide anion and nitrotyrosine expression) were also enhanced in aorta and renal cortex. Mergetpa reversed and normalized most of those alterations, but failed to affect leptin levels and hypertension. Pharmacological blockade of kininase 1 (CPM) exerted similar beneficial effects to a 1-week treatment with a B1R antagonist (SSR240612) or an iNOS inhibitor (1,400 W). These data reinforce the detrimental role of B1R in insulin resistance and recommend CPM as a new therapeutic target.
激肽B1受体（B1R）通过上调并激活诱导型一氧化氮合酶（iNOS）、促炎细胞因子和氧化应激，导致胰岛素抵抗，这是2型糖尿病的早期事件。本研究探讨了以下假说：抑制激肽酶1（羧肽酶M，CPM），即参与B1R激动剂生物合成的关键酶，可能对胰岛素抵抗产生与B1R拮抗剂相同的有益作用。雄性Sprague-Dawley大鼠饮用含10% D-葡萄糖的溶液9周，诱导产生胰岛素抵抗。对照大鼠饮用自来水。在最后一周，用Mergetpa（1 mg/kg，每日两次，皮下注射）阻断激肽酶1，并通过蛋白质免疫印迹法和定量逆转录-聚合酶链反应（qRT-PCR）测定其对胰岛素抵抗（稳态模型评估指数）、代谢激素水平、氧化应激以及几种炎症标志物表达的影响。喂食葡萄糖的大鼠出现高血糖、高胰岛素血症、高瘦素血症、胰岛素抵抗、高血压、体重增加，并且肾皮质、主动脉和肝脏中B1R、CPM、iNOS和IL-1β的表达增强。主动脉和肾皮质中氧化应激标志物（超氧阴离子和硝基酪氨酸表达）也增强。Mergetpa逆转并使其中大部分改变恢复正常，但未能影响瘦素水平和高血压。激肽酶1（CPM）的药理学阻断对B1R拮抗剂（SSR240612）或iNOS抑制剂（1,400 W）治疗1周产生的有益作用相似。这些数据强化了B1R在胰岛素抵抗中的有害作用，并推荐CPM作为一个新的治疗靶点。
