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Differential roles of hyperglycemia and hypoinsulinemia in diabetes induced
retinal cell death: evidence for retinal insulin resistance.
Fort PE, Losiewicz MK, Reiter CE, Singh RS, Nakamura M, Abcouwer SF, Barber AJ,
Submitted Externally on 3/17/2014
Volume : Pages
6 : e26498
Diabetes pathology derives from the combination of hyperglycemia and
hypoinsulinemia or insulin resistance leading to diabetic complications
including diabetic neuropathy, nephropathy and retinopathy. Diabetic retinopathy
is characterized by numerous retinal defects affecting the vasculature and the
neuro-retina, but the relative contributions of the loss of retinal insulin
signaling and hyperglycemia have never been directly compared. In this study we
tested the hypothesis that increased retinal insulin signaling and glycemic
normalization would exert differential effects on retinal cell survival and
retinal physiology during diabetes. We have demonstrated in this study that both
subconjunctival insulin administration and systemic glycemic reduction using the
sodium-glucose linked transporter inhibitor phloridzin affected the regulation
of retinal cell survival in diabetic rats. Both treatments partially restored
the retinal insulin signaling without increasing plasma insulin levels. Retinal
transcriptomic and histological analysis also clearly demonstrated that local
administration of insulin and systemic glycemia normalization use different
pathways to counteract the effects of diabetes on the retina. While local
insulin primarily affected inflammation-associated pathways, systemic glycemic
control affected pathways involved in the regulation of cell signaling and
metabolism. These results suggest that hyperglycemia induces resistance to
growth factor action in the retina and clearly demonstrate that both restoration
of glycemic control and retinal insulin signaling can act through different
pathways to both normalize diabetes-induced retinal abnormality and prevent
Investigators with authorship
University of Michigan-Ann Arbor
Pennsylvania State University-Penn State College of Medicine
Neuropathy & Neurocognition
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Please acknowledge all posters, manuscripts or scientific materials that were generated in part or whole using funds from the Diabetic Complications Consortium(DiaComp) using the following text:
Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255
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