Suppression of GLUT1; A new strategy to prevent diabetic complications
Suppression of GLUT1; A new strategy to prevent diabetic complications
复制标题
DOI：
10.1002/jcp.24133
复制
发表时间：
2013-02-01
影响因子：
5.6
通讯作者：
Campochiaro, Peter A.
中科院分区：
文献类型：
--
作者：
Lu, Lili;Seidel, Christopher P.;Campochiaro, Peter A.
高血糖导致视网膜中的高葡萄糖水平，因为GLUT 1，血液和视网膜之间唯一的葡萄糖转运蛋白，在血糖高时转运更多的葡萄糖。这是糖尿病视网膜病变的最终原因。通过眼内注射针对编码GLUT 1的SLC 2A 1 mRNA的siRNA库来敲低GLUT 1显著降低糖尿病小鼠的平均视网膜葡萄糖水平。用毛喉素或染料木黄酮（它们结合GLUT 1并抑制葡萄糖转运）对糖尿病小鼠进行全身性治疗，可显著降低视网膜葡萄糖至与非糖尿病患者相同的水平。1，9-双脱氧毛喉素结合GLUT 1但不刺激腺苷酸环化酶，在降低糖尿病患者视网膜葡萄糖方面与毛喉素具有相同的效果，表明环AMP无贡献。GLUT 1抑制剂还降低了红细胞中的葡萄糖和糖化血红蛋白水平，为该效应提供了外周生物标志物。相比之下，糖尿病患者的大脑葡萄糖水平没有增加，也没有被毛喉素降低。用毛喉素治疗糖尿病患者可预防糖尿病视网膜病变的早期生物标志物，包括超氧化物自由基升高、伴侣蛋白β 2晶体蛋白表达增加和血管内皮生长因子（VEGF）表达增加。这些数据将GLUT 1确定为预防糖尿病视网膜病变的有前景的治疗靶点。J.细胞。228：251257，2013。(c)2012年威利期刊公司
High blood glucose results in high glucose levels in retina, because GLUT1, the sole glucose transporter between blood and retina, transports more glucose when blood glucose is high. This is the ultimate cause of diabetic retinopathy. Knockdown of GLUT1 by intraocular injections of a pool of siRNAs directed against SLC2A1 mRNA which codes for GLUT1 significantly reduced mean retinal glucose levels in diabetic mice. Systemic treatment of diabetic mice with forskolin or genistein, which bind GLUT1 and inhibit glucose transport, significantly reduced retinal glucose to the same levels seen in non-diabetics. 1,9-Dideoxyforskolin, which binds GLUT1 but does not stimulate adenylate cyclase had an equivalent effect to that of forskolin regarding lowering retinal glucose in diabetics indicating that cyclic AMP is noncontributory. GLUT1 inhibitors also reduced glucose and glycohemoglobin levels in red blood cells providing a peripheral biomarker for the effect. In contrast, brain glucose levels were not increased in diabetics and not reduced by forskolin. Treatment of diabetics with forskolin prevented early biomarkers of diabetic retinopathy, including elevation of superoxide radicals, increased expression of the chaperone protein beta 2 crystallin, and increased expression of vascular endothelial growth factor (VEGF). These data identify GLUT1 as a promising therapeutic target for prevention of diabetic retinopathy. J. Cell. Physiol. 228: 251257, 2013. (c) 2012 Wiley Periodicals, Inc.