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Urocortin 2 Gene Transfer Improves Glycemic Control and Reduces Retinopathy and Mortality in Murine Insulin Deficiency.
Molecular Therapy - Methods & Clinical Development ( IF 4.7 ) Pub Date : 2019-12-14 , DOI: 10.1016/j.omtm.2019.12.002
Mei Hua Gao 1, 2 , Dimosthenis Giamouridis 1, 2, 3 , N Chin Lai 1, 2 , Tracy Guo 1, 2 , Bing Xia 1, 2 , Young Chul Kim 1, 2 , Viet Anh Nguyen Huu 4 , Dorota Skowronska-Krawczyk 4 , Louise Lantier 5 , Raag Bhargava 1, 2 , H Kirk Hammond 1, 2
Affiliation  

Type 1 diabetes affects 20 million patients worldwide. Insulin is the primary and commonly the sole therapy for type 1 diabetes. However, only a minority of patients attain the targeted glucose control and reduced adverse events. We tested urocortin 2 gene transfer as single-agent therapy for insulin deficiency using two mouse models. Urocortin 2 gene transfer reduced blood glucose for months after a single intravenous injection, through increased skeletal muscle insulin sensitivity, increased insulin release in response to glucose stimulation, and increased plasma insulin levels before and during euglycemic clamp. The combined increases in both insulin availability and sensitivity resulted in improved glycemic indices-events that were not anticipated in these insulin-deficient models. In addition, urocortin 2 gene transfer reduced ocular manifestations of long-standing insulin deficiency such as vascular leak and improved retinal function. Finally, mortality was reduced by urocortin 2 gene transfer. The mechanisms for these beneficial effects included increased activities of AMP-activated protein kinase and Akt (protein kinase B) in skeletal muscle, increased skeletal muscle glucose uptake, and increased insulin release. These data suggest that urocortin 2 gene transfer may be a viable therapy for new onset type 1 diabetes and might reduce insulin needs in later stage disease.

中文翻译:

Urocortin 2基因转移可改善血糖控制,并降低鼠胰岛素缺乏症的视网膜病变和死亡率。

1型糖尿病影响全球2千万患者。胰岛素是1型糖尿病的主要治疗方法,也是唯一的治疗方法。但是,只有少数患者达到了目标血糖控制并减少了不良事件。我们使用两种小鼠模型测试了urocortin 2基因转移作为胰岛素缺乏症的单药疗法。通过增加骨骼肌胰岛素敏感性,响应葡萄糖刺激而增加的胰岛素释放以及在正常血糖钳制之前和期间血浆胰岛素水平的提高,单次静脉内注射后Urocortin 2基因转移可降低血糖数月。胰岛素利用率和敏感性的综合提高导致了血糖指数的改善,而这些胰岛素不足的模型并未预料到这些事件。此外,urocortin 2基因转移减少了长期胰岛素缺乏的眼部表现,例如血管渗漏,并改善了视网膜功能。最后,通过尿皮质素2基因转移降低了死亡率。这些有益作用的机制包括增加骨骼肌中AMP激活的蛋白激酶和Akt(蛋白激酶B)的活性,增加骨骼肌的葡萄糖摄取和增加胰岛素释放。这些数据表明,urocortin 2基因转移可能是新发1型糖尿病的可行疗法,并可能减少后期疾病中的胰岛素需求。这些有益作用的机制包括增加骨骼肌中AMP激活的蛋白激酶和Akt(蛋白激酶B)的活性,增加骨骼肌的葡萄糖摄取和增加胰岛素释放。这些数据表明,urocortin 2基因转移可能是新发1型糖尿病的可行疗法,并可能减少后期疾病中的胰岛素需求。这些有益作用的机制包括增加骨骼肌中AMP激活的蛋白激酶和Akt(蛋白激酶B)的活性,增加骨骼肌的葡萄糖摄取和增加胰岛素释放。这些数据表明,urocortin 2基因转移可能是新发1型糖尿病的可行疗法,并可能减少后期疾病中的胰岛素需求。
更新日期:2019-12-14
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