Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus.
Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus.
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DOI：
10.1161/jaha.118.009379
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发表时间：
2018-09-18
影响因子：
5.4
通讯作者：
Hamburg NM
中科院分区：
文献类型：
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作者：
Bretón-Romero R;Weisbrod RM;Feng B;Holbrook M;Ko D;Stathos MM;Zhang JY;Fetterman JL;Hamburg NM
先前的研究表明，营养过剩会引起糖尿病（DM）患者非血管组织的内质网（ER）应激。内质网应激和随后的未折叠蛋白反应可能具有保护作用，但持续激活可能会导致血管损伤。内质网应激是否会导致糖尿病患者的内皮功能障碍仍不清楚。为了表征血管 ER 应激，我们从 42 名 DM 患者和 37 名非 DM 受试者中分离了内皮细胞。与非糖尿病对照组相比，糖尿病患者的内皮细胞显示出更高水平的 ER 应激标记物。早期适应性反应（以较高磷酸化蛋白激酶样 ER 真核起始因子 2a 激酶和需要肌醇的 ER 核信号蛋白 1（分别为 P=0.02、P=0.007）为证）和慢性 ER 应激反应（以较高 C/EBPα 同源蛋白（P=0.02）为证）在 DM 患者中均被激活。较高的肌醇需要的 ER 至核信号蛋白 1 激活与较低的血流介导的扩张相关，与内皮功能障碍一致 (r=0.53，P=0.02)。使用利拉鲁肽（一种胰高血糖素样肽 1 受体激动剂）进行急性治疗，可减少 DM 患者内皮细胞中需要 p 肌醇的 ER 至核信号蛋白 1（P=0.01），并激活其下游靶标 c-jun N 末端激酶（P=0.025）。此外，利拉鲁肽恢复了糖尿病患者胰岛素刺激的内皮一氧化氮合酶活化（P=0.019）。总之，我们的数据表明 ER 应激会导致 DM 患者的血管胰岛素抵抗和内皮功能障碍。此外，我们还证明利拉鲁肽可改善 DM 患者内皮细胞中的 ER 应激、减少 c-jun N 末端激酶激活并恢复胰岛素介导的内皮一氧化氮合酶激活。
Prior studies have shown that nutrient excess induces endoplasmic reticulum (ER) stress in nonvascular tissues from patients with diabetes mellitus (DM). ER stress and the subsequent unfolded protein response may be protective, but sustained activation may drive vascular injury. Whether ER stress contributes to endothelial dysfunction in patients with DM remains unknown. To characterize vascular ER stress, we isolated endothelial cells from 42 patients with DM and 37 subjects without DM. Endothelial cells from patients with DM displayed higher levels of ER stress markers compared with controls without DM. Both the early adaptive response, evidenced by higher phosphorylated protein kinase–like ER eukaryotic initiation factor‐2a kinase and inositol‐requiring ER‐to‐nucleus signaling protein 1 (P=0.02, P=0.007, respectively), and the chronic ER stress response evidenced by higher C/EBPα‐homologous protein (P=0.02), were activated in patients with DM. Higher inositol‐requiring ER‐to‐nucleus signaling protein 1 activation was associated with lower flow–mediated dilation, consistent with endothelial dysfunction (r=0.53, P=0.02). Acute treatment with liraglutide, a glucagon‐like peptide 1 receptor agonist, reduced p‐inositol‐requiring ER‐to‐nucleus signaling protein 1 (P=0.01), and the activation of its downstream target c‐jun N‐terminal kinase (P=0.025) in endothelial cells from patients with DM. Furthermore, liraglutide restored insulin‐stimulated endothelial nitric oxide synthase activation in patients with DM (P=0.019). In summary, our data suggest that ER stress contributes to vascular insulin resistance and endothelial dysfunction in patients with DM. Further, we have demonstrated that liraglutide ameliorates ER stress, decreases c‐jun N‐terminal kinase activation and restores insulin‐mediated endothelial nitric oxide synthase activation in endothelial cells from patients with DM.