Retinal Adaptation to Changing Glycemic Levels in a Rat Model of Type 2 Diabetes

Abstract

PurposeGlucose concentrations are elevated in retinal cells in undiagnosed and in undertreated diabetes. Studies of diabetic patients suggest that retinal function adapts, to some extent, to this increased supply of glucose. The aim of the present study was to examine such adaptation in a model of type 2 diabetes and assess how the retina responds to the subsequent institution of glycemic control.MethodsElectroretinography (ERG) was conducted on untreated Zucker diabetic fatty (ZDF) rats and congenic controls from 8–22 weeks of age and on ZDFs treated with daily insulin from 16–22 weeks of age. Retinal sections from various ages were prepared and compared histologically and by immunocytochemistry.Principal Findings/ConclusionsAcute hyperglycemia did not have an effect on control rats while chronic hyperglycemia in the ZDF was associated with scotopic ERG amplitudes which were up to 20% higher than those of age-matched controls. This change followed the onset of hyperglycemia with a delay of over one month, supporting that habituation to hyperglycemia is a slow process. When glycemia was lowered, an immediate decrease in ZDF photoreceptoral activity was induced as seen by a reduction in a-wave amplitudes and maximum slopes of about 30%. A direct effect of insulin on the ERG was unlikely since the expression of phosphorylated Akt kinase was not affected by treatment. The electrophysiological differences between untreated ZDFs and controls preceded an activation of Müller cells in the ZDFs (up-regulation of glial fibrillary acidic protein), which was attenuated by insulin treatment. There were otherwise no signs of cell death or morphological alterations in any of the experimental groups. These data show that under chronic hyperglycemia, the ZDF retina became abnormally sensitive to variations in substrate supply. In diabetes, a similar inability to cope with intensive glucose lowering could render the retina susceptible to damage.

Histologic Characterization of Retina Neuroglia Modifications in Diabetic Zucker Diabetic Fatty Rats

“…The reduction in the number of nuclei found in our study may be linked with an increased number of TUNELpositive ectopic nuclei in ZDF rats. Although increased apoptosis in the retina of ZDF animals, particularly in the ONL, INL, and GCL, was described at 26 weeks of age, 20 Johnson et al only found occasional TUNEL-positive cells in retinas both of lean and ZDF rats at 16 and 23 weeks of age, 11 which is consistent with our results. Significant differences in photoreceptor cell death patterns among rodent strains were described.…”

“…10 Retinal functional analysis of ZDF rats was recently described. 11 However, profound cellular and molecular studies of the retina have not yet been performed in those animals. In this study, we characterized retinal degenerative morphologic modifications in ZDF rats by histologic and immunohistochemical evaluation.…”

“…Johnson et al did not report abnormal changes in retinal thickness at 16, 23, and 31 weeks old nor in the number of nuclei per row at the ONL and INL at 23 weeks. 11 However, no detailed measurement data were described, and the number of samples evaluated per group was limited (n ¼ 2 to 4 rats per group). Retinal thickening is a common finding in diabetic patients, 18 and transient thickening of the retina could happen before late onset atrophy, as observed in streptozotocin-induced rats after 7.5 months of diabetes.…”

Neuropeptides, Trophic Factors, and Other Substances Providing Morphofunctional and Metabolic Protection in Experimental Models of Diabetic Retinopathy

“…The electrophysiological differences between untreated ZDF rats and controls preceded an activation of Müller cells in the ZDF rats (upregulation of GFAP), which was attenuated by insulin treatment. There were otherwise no signs of cell death or morphological alterations in ZDF groups ( Johnson et al, 2013). These data show that under chronic hyperglycemia, the ZDF rat retina became abnormally sensitive to variations in B978-0-12-800179-0.00001-5, 00001 IRCMB, 978-0-12-800179-0…”

“…The electrophysiological differences between untreated ZDF rats and controls preceded an activation of Müller cells in the ZDF rats (upregulation of GFAP), which was attenuated by insulin treatment. There were otherwise no signs of cell death or morphological alterations in ZDF groups ( Johnson et al, 2013). These data show that under chronic hyperglycemia, the ZDF rat retina became abnormally sensitive to variations in To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier and typesetter SPi.…”