Diabetes downregulates GLUT1 expression in the retina and its microvessels but not in the cerebral cortex or its microvessels.

Capillaries in the retina are more susceptible to develop microvascular lesions in diabetes than capillaries in the embryologically similar cerebral cortex. Because available evidence implicates hyperglycemia in the pathogenesis of diabetic retinopathy, differences in glucose transport into the retina and brain might contribute to this observed tissue difference in susceptibility to diabetes-induced microvascular disease. Thus, we compared levels of GLUT1 and GLUT3 expression in the retina, cerebrum, and their respective microvessels by Western blot analysis. In nondiabetic animals, the content of GLUT1 protein in retina and its microvessels was multifold greater than that of cerebral cortex gray matter and its microvessels. Streptozotocin-induced diabetes of a 2-week or 2-month duration reduced GLUT1 expression in the retina and its microvasculature by approximately 50%, but it resulted in no reduction in GLUT1 expression in cerebrum or its microvessels. The density of capillaries in retinas of diabetic animals did not change from normal, and so the observed decrease in GLUT1 expression in the retina and retinal capillaries of diabetic animals cannot be attributed to fewer vessels. Despite the diabetes-induced reduction of GLUT1 expression in retina, neural retina of diabetic rats still possessed more GLUT1 than the cerebrum. Retinal pigment epithelium (RPE) possessed more GLUT1 than neural retina or its microvessels, and expression of the transporter in the RPE was not affected by diabetes. GLUT3 levels were greater in cerebral gray matter than in retina, and they were unaffected by diabetes in either tissue. The effect of diabetes on GLUT1 expression differs between retina and cerebral cortex, suggesting that glucose transport is regulated differently in these embryologically similar tissues. Because diabetes results in downregulation of GLUT1 expression in retinal microvessels, but not in RPE, the fraction of the glucose entering the retina in diabetes is likely to be greater across the RPE than across the retinal vasculature.

Glut1 and glut3 expression, but not capillary density, is increased by cobalt chloride in rat cerebrum and retina.

Treatment of rats with cobalt chloride [Co(II)], an agent that stimulates the expression of a set of hypoxia-responsive genes, for 10-12 days resulted in 1.45- and 1.40-fold increases in the content of Glut1 mRNA and Glut1 in cerebral gray matter, respectively (P<0. 05 for both changes). The increase in Glut1 content was associated with a significant increase in the content of Glut1 staining in microvessels isolated from cerebral gray matter, and in the intensity of Glut1 in microvessels of the frontal lobe and hippocampus assessed by immunohistochemistry. The abundance of Glut3 in cerebrum of Co(II)-treated rats also increased by 1.3-fold (P<0. 05), but the increase was not associated with a change in the content of Glut3 mRNA. In retina, treatment with Co(II) resulted in 2.48- and 1.23-fold increases in the content of Glut1 mRNA and Glut1 protein, respectively (P<0.05 for both changes); similar increases in Glut1 protein expression were observed in isolated retinal microvasculature. The content of Glut3 in retina also increased 1. 5-fold in Co(II)-treated rats (P<0.05). In addition, treatment with Co(II) resulted in a significant 2.2-fold increase in the expression of VEGF in the cerebrum. However, despite the Co(II)-induced increase in Glut1 expression in cerebral and retinal microvasculature and VEGF in cerebrum, there was no increase in the capillary density in either tissue. It is concluded that a 10-12 day exposure to Co(II), presumably acting through the hypoxia-signaling pathway, results in enhanced expression of both major glucose transporters in cerebral cortex and retina, without increasing the capillary density of either tissue.