Insulin-like growth factor-2 regulates basal retinal insulin receptor activity.

Content Provider	Europe PMC
Author	Zolov, Sergey N. Imai, Hisanori Losiewicz, Mandy K. Singh, Ravi S.J. Fort, Patrice E. Gardner, Thomas W.
Copyright Year	2021
Abstract	The retinal insulin receptor (IR) exhibits basal kinase activity equivalent to that of the liver of fed animals, but unlike the liver, does not fluctuate with feeding and fasting; it also declines rapidly after the onset of insulin-deficient diabetes. The ligand(s) that determine basal IR activity in the retina has not been identified. Using a highly sensitive insulin assay, we found that retinal insulin concentrations remain constant in fed versus fasted rats and in diabetic versus control rats; vitreous fluid insulin levels were undetectable. Neutralizing antibodies against insulin-like growth factor 2 (IGF-2), but not insulin-like growth factor 1 (IGF-1) or insulin, decreased IR kinase activity in normal rat retinas, and depletion of IGF-2 from serum specifically reduced IR phosphorylation in retinal cells. Immunoprecipitation studies demonstrated that IGF-2 induced greater phosphorylation of the retinal IR than the IGF-1 receptor. Retinal IGF-2 mRNA content was 10-fold higher in adults than pups and orders of magnitude higher than in liver. Diabetes reduced retinal IGF-2, but not IGF-1 or IR, mRNA levels, and reduced IGF-2 and IGF-1 content in vitreous fluid. Finally, intravitreal administration of IGF-2 (mature and pro-forms) increased retinal IR and Akt kinase activity in diabetic rats. Collectively, these data reveal that IGF-2 is the primary ligand that defines basal retinal IR activity and suggest that reduced ocular IGF-2 may contribute to reduced IR activity in response to diabetes. These findings may have importance for understanding the regulation of metabolic and prosurvival signaling in the retina.
ISSN	00219258
Volume Number	296
PubMed Central reference number	PMC8138762
PubMed reference number	33915127
Journal	The Journal of Biological Chemistry [J. Biol. Chem]
e-ISSN	1083351X
DOI	10.1016/j.jbc.2021.100712
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2021-01-01
Access Restriction	Open
Rights License	This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). © 2021 The Authors
Subject Keyword	insulin-like growth factor-2 insulin receptor insulin retina diabetes HRP, horseradish peroxidase IGF-1, Insulin-like growth factor-1 IGF-2, Insulin-like growth factor-2 IGF1R, Insulin-like growth factor-1 receptor IGFBP, Insulin-like growth factor binding protein IR, Insulin receptor PY, phosphorylation
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology Biochemistry