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Thomas W Gardner, Mandy Losiewicz, Sergey Zolov, Steven F Abcouwer, Patrice E Fort; Insulin-like growth factor 2 is a native ligand of the retinal insulin receptor. Invest. Ophthalmol. Vis. Sci. 2016;57(12):98.
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© ARVO (1962-2015); The Authors (2016-present)
The retinal insulin receptor exhibits a high basal kinase activity and protein synthetic activity relative to that of skeletal muscle and liver and the mechanisms of this activity is important to understand its link to key homeostatic processes. The purpose of this study was to test the hypothesis that insulin-like growth factors-1 and -2 (IGFs) contribute to this high basal activity.
Retinal content of insulin and IGFs were assessed by q-PCR in rats at various postnatal ages, and by immunoblotting in normal and diabetic Sprague-Dawley rat retinas and vitreous. Neutralizing antibodies were injected intravitreally in normal rats followed by insulin receptor kinase assays. Retinal insulin receptor splice forms were compared among retina, brain, liver and kidney by PCR. Normal ex vivo retinas were stimulated with IGF-2 isoforms and specific inhibitors were used to further assess the impact on downstream effectors.
Retinal insulin mRNA was barely detectable by q-PCR in normal rat retina whereas IGF-1 and -2 were expressed within physiologic ranges. Retinal insulin levels were 5 ng/mg protein and did not vary with feeding and fasting. Normal rat vitreous insulin concentrations were below the limits of an ultrasensitive ELISA but vitreous IGF-1 and IGF-2 concentration in the vitreous ranged from 1 to 10 µg/mL protein. Neutralizing antibodies against IGF-1 and IGF-2 but not insulin reduced retinal insulin receptor kinase activity and autophosphorylation by 25% (P < 0.05) below control values, and did not reduce IGF-1 receptor kinase activity. Retina and brain express only the small “A” insulin receptor splice form. Four weeks of diabetes had no effect on retinal IGF-1 mRNA content but reduced retinal IGF-2 mRNA by 20%, and reduced total IGF-2 protein content ≈ 80% in the vitreous. Akt kinase inhibitors significantly impaired Akt Ser473 phosphorylation, but not insulin receptor phosphorylation of ex vivo retinas in response to IGF-2.
IGF-2 is a native ligand of the retinal insulin receptor and provides the high basal activity that influences anabolic processes such as protein synthesis and cell survival, whereas pancreas-derived insulin likely has little role. Diabetes may impair retinal insulin receptor function in part via loss of IGF-2 availability, and this effect may contribute to loss of anabolic activities in diabetes.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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