Differential roles of hyperglycemia and hypoinsulinemia in diabetes induced retinal cell death: Evidence for retinal insulin resistance

Patrice E. Fort, Mandy K. Losiewicz, Chad E.N. Reiter, Ravi S.J. Singh, Makoto Nakamura, Steven F. Abcouwer, Alistair J. Barber, Thomas W. Gardner

Research output: Contribution to journalArticle

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Abstract

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 vision loss.

Original languageEnglish (US)
Article numbere26498
JournalPloS one
Volume6
Issue number10
DOIs
StatePublished - Nov 2 2011

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Cell death
hyperglycemia
Medical problems
insulin resistance
Hyperglycemia
diabetes
Insulin Resistance
cell death
Cell Death
insulin
Insulin
retina
Retina
glycemic control
Diabetic Retinopathy
cell viability
Cell Survival
Sodium-Glucose Transport Proteins
diabetic neuropathy
diabetic retinopathy

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Fort, P. E., Losiewicz, M. K., Reiter, C. E. N., Singh, R. S. J., Nakamura, M., Abcouwer, S. F., ... Gardner, T. W. (2011). Differential roles of hyperglycemia and hypoinsulinemia in diabetes induced retinal cell death: Evidence for retinal insulin resistance. PloS one, 6(10), [e26498]. https://doi.org/10.1371/journal.pone.0026498
Fort, Patrice E. ; Losiewicz, Mandy K. ; Reiter, Chad E.N. ; Singh, Ravi S.J. ; Nakamura, Makoto ; Abcouwer, Steven F. ; Barber, Alistair J. ; Gardner, Thomas W. / Differential roles of hyperglycemia and hypoinsulinemia in diabetes induced retinal cell death : Evidence for retinal insulin resistance. In: PloS one. 2011 ; Vol. 6, No. 10.
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Differential roles of hyperglycemia and hypoinsulinemia in diabetes induced retinal cell death : Evidence for retinal insulin resistance. / Fort, Patrice E.; Losiewicz, Mandy K.; Reiter, Chad E.N.; Singh, Ravi S.J.; Nakamura, Makoto; Abcouwer, Steven F.; Barber, Alistair J.; Gardner, Thomas W.

In: PloS one, Vol. 6, No. 10, e26498, 02.11.2011.

Research output: Contribution to journalArticle

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