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

Abstract

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 bỹ 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. Diabetes 49:1016-1021, 2000 H yperglycemia is sufficient to initiate the development of diabetic retinopathy. This fact has been made especially clear by the development of diabetic-like retinopathy in normal nondiabetic dogs and rodents that were experimentally made hyperglycemic by feeding them a diet enriched with galactose (1-5). Studies demonstrating that intensive therapy sufficient to minimize hyperglycemia inhibits the development of retinopathy (6-8) are consistent with the evidence that hyperglycemia plays a critical role in the pathogenesis of retinal disease. However, the mechanism by which hyperglycemia causes diabetic retinopathy remains unclear. Excessive transport or concentration of glucose within cells of the retina is a common thread underlying most of the biochemical mechanisms that have been postulated to play a role in the pathogenesis of diabetic retinopathy.Retina and cerebral cortex are embryologically similar, yet, we and others (9-11) have found them to differ in their sus...

Apoptotic death of photoreceptors in the streptozotocin-induced diabetic rat retina

“…Apoptotic cell death is initiated in a very few photoreceptors about one month after the onset of diabetes, and accelerates from three months onwards. Thus, the main causal factor for the apoptosis in the ONL is not likely to be directly associated with altered glucose metabolism and consequent altered vascular conditions, as supported by another report [15,29]. They describe that the main glucose transporter in the retina, GLT-1, is much more strongly expressed in the pigment epithelium than in the neural retina or its microvessels.…”

“…GLT-1 in the epithelium is less affected or completely unaffected by diabetes. However, whether the regulatory mode of the GLT-1 in the neural retina in response to diabetes is upregulation [29] or downregulation [18,30], is still controversial.…”

VEGF Expression in Hypoxia and Hyperglycemia

“…Potential changes in the expression of glucose transporters, although not studied by our group, have been examined previously (35). It has been demonstrated that endothelial cells (except retinal endothelium) are unable to downregulate the expression of glucose transporters in hyperglycemia and therefore remain continuously exposed to the elevated glucose influx and oxidant stress (36,37,38). These data collectively indicate that preexisting endothelial dysfunction may modify cell responsiveness to VEGF and that VEGF under these circumstances becomes insufficient for angiogenesis.…”

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

“…The accumulation of AGEs and glucose in the retina has been associated with other conditions of hyperglycemia, notably diabetic retinopathy, and some of the phenotypes noted in this work, such as RPE thinning, RPE vacuolation, photoreceptor degeneration, and thinning of the inner retinal layer, were also observed in humans and experimental models of diabetic retinopathy (33,(53)(54)(55)(56)(57)(58)(59). Glycation results in the dysfunction of structural proteins and impaired protein-editing machineries, including autophagy and the ubiquitin proteolytic systems, functions that are required for the degradation of phagosomes and AGEs (11,29,60).…”