Pathological upregulation of inner blood-retinal barrier Glut1 glucose transporter expression in diabetes mellitus.
The pathological changes in the retinal microvasculature characteristic of diabetic retinopathy (DR) are the result of chronic exposure to elevated blood glucose. Since glucose entry into the microvascular endothelial cells comprising the inner blood-retinal barrier (BRB) is mediated by the GLUT1 glucose transporter, changes in GLUT1 expression on the inner BRB in long-standing diabetes mellitus may have a direct impact on the subsequent development of retinopathic changes. In the present study, quantitative immunogold electron microscopy for GLUT1 was employed on ultrathin cross-sections of postmortem retina specimens from 3 individuals with long-standing diabetes and minimal or no clinical retinopathy and from 2 non-diabetic individuals without ocular disorders. In the non-diabetic retinal capillaries, GLUT1 immunogold was distributed asymmetrically between the lumenal and ablumenal membranes with a lumenal-to-ablumenal ratio of 1 to 1.7. In the diabetic microvessels, a bimodal distribution pattern of GLUT1 immunoreactivity was observed. In 17 of 40 of the diabetic microvessels examined, the density and distribution of GLUT1 was no different from that of the non-diabetic vessels; however, in a subpopulation of the diabetic microvessels (23 of 40), a dramatic increase in GLUT1 immunoreactivity on the lumenal and albumenal membrane and in the cytoplasm was noted. On the lumenal membrane, the increased expression of immunoreactive GLUT1 was more than 18 times that of the non-diabetic microvessels. These findings demonstrate that localized upregulation of GLUT1 expression at the inner BRB occurs in long-standing diabetes mellitus with minimal or no clinical retinopathy and suggest that this upregulation may serve to amplify the deleterious effects of chronic hyperglycemia on the retinal microvasculature.
Kumagai
A K
AK
Department of Medicine, UCLA School of Medicine 90095-1682, USA.
Vinores
S A
SA
Pardridge
W M
WM
D000368:Aged; D000369:Aged, 80 and over; D001813:Blood-Retinal Barrier / Q000502:physiology*; D016022:Case-Control Studies; D003920:Diabetes Mellitus / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D015854:Up-Regulation