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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Impaired insulin-mediated vasorelaxation in a nonobese model of type 2 diabetes: role of endothelin-1.
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Impaired insulin-mediated vasorelaxation in a nonobese model of type 2 diabetes: role of endothelin-1.

机译：2型糖尿病非肥胖模型中胰岛素介导的血管舒张受损：内皮素1的作用。

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摘要

Insulin resistance involves decreased phosphorylation of insulin receptor substrate (IRS) proteins and (or) Akt. In the vasculature, modulated Akt phosphorylation may cause impaired vasorelaxation via decreased eNOS activation. Diet-induced insulin resistance enhances endothelin-1(ET-1)-mediated vasoconstriction and prevents vasodilatation to insulin. Presently, we evaluated insulin-mediated vascular relaxation, assessed molecular markers of the insulin signaling pathway, and determined the involvement of ET-1 in response to insulin by using selective ETA- or ETB-receptor blockade in a lean model of type 2 diabetes. Dose-response curves to insulin (0.01-100 ng/mL) were generated with wire myograph using thoracic aorta rings from control Wistar or diabetic Goto-Kakizaki (GK) rats (n=3-11). Maximal relaxation (Rmax) to insulin was significantly impaired and insulin sensitivity was decreased in the GK group. Preincubation with 1 micromol/L BQ-123 or BQ-788 for ETA- and ETB-receptor blockade, respectively,resulted in improved insulin sensitivity. Immunoblotting for native and phosphorylated Akt and IRS-1 revealed a decrease in Akt activation in the GK group. In vivo hyperinsulinemic euglycemic clamp studies showed decreased glucose utilization in GK rats, indicative of insulin resistance. These findings provide evidence that vascular insulin resistance occurs in a nonobese model of diabetes and that both ET receptor subtypes are involved in vascular relaxation to insulin.
机译：胰岛素抵抗涉及胰岛素受体底物（IRS）蛋白和（或）Akt的磷酸化降低。在脉管系统中，调节的Akt磷酸化可能会通过降低eNOS激活而导致血管舒张受损。饮食诱导的胰岛素抵抗增强了内皮素-1（ET-1）介导的血管收缩，并阻止了胰岛素的血管舒张。目前，我们在2型糖尿病瘦模型中使用选择性ETA或ETB受体阻滞剂，评估了胰岛素介导的血管舒张，评估了胰岛素信号通路的分子标记，并确定了ET-1对胰岛素的应答。使用来自对照Wistar或糖尿病Goto-Kakizaki（GK）大鼠（n = 3-11）的胸主动脉环，用钢丝肌电图仪绘制了对胰岛素（0.01-100 ng / mL）的剂量反应曲线。 GK组的胰岛素最大舒张（Rmax）明显受损，胰岛素敏感性降低。分别与1 micromol / L BQ-123或BQ-788进行预孵育分别进行ETA和ETB受体阻滞，可改善胰岛素敏感性。天然和磷酸化的Akt和IRS-1的免疫印迹显示，GK组的Akt激活降低。体内高胰岛素正常血糖钳夹研究显示，GK大鼠的葡萄糖利用率降低，表明胰岛素抵抗。这些发现提供了在非肥胖糖尿病模型中发生血管胰岛素抵抗的证据，并且两种ET受体亚型都参与了血管对胰岛素的舒张。

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