Suppression of GLUT1; a new strategy to prevent diabetic complications.
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 β2 crystallin, and increased expression of vascular endothelial growth factor (VEGF). These data identify GLUT1 as a promising therapeutic target for prevention of diabetic retinopathy.
Departments of Ophthalmology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Lili
L
Lu
Christopher P
CP
Seidel
Takeshi
T
Iwase
Rebecca K
RK
Stevens
Yuan-Yuan
YY
Gong
Xinyi
X
Wang
Sean F
SF
Hackett
Peter A
PA
Campochiaro
D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry; D005576:Colforsin / Q000031:analogs & derivatives / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D003930:Diabetic Retinopathy / Q000517:prevention & control*; D004912:Erythrocytes / Q000737:chemistry / Q000378:metabolism; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D019833:Genistein / Q000627:therapeutic use; D005947:Glucose / Q000032:analysis; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D012160:Retina / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D013481:Superoxides / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D038206:beta-Crystallin B Chain / Q000096:biosynthesis
D001786:Blood Glucose; D051272:Glucose Transporter Type 1; D047428:Protein Kinase Inhibitors; C495678:Slc2a1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D038206:beta-Crystallin B Chain; C113634:beta-crystallin B2; C467480:vascular endothelial growth factor A, mouse; D013481:Superoxides; D005576:Colforsin; D019833:Genistein; D005947:Glucose; C047983:1,9-dideoxyforskolin