Insulin-like growth factor-2 regulates basal retinal insulin receptor activity
| Autor: | Patrice Fort, Thomas W. Gardner, Ravi S.J. Singh, Hisanori Imai, Sergey N. Zolov, Mandy K. Losiewicz |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
insulin retina medicine.medical_specialty medicine.medical_treatment IGF-1 Insulin-like growth factor-1 IR Insulin receptor Biochemistry 03 medical and health sciences chemistry.chemical_compound Insulin-Like Growth Factor II Internal medicine Diabetes mellitus medicine Animals Phosphorylation insulin receptor Kinase activity Molecular Biology PY phosphorylation Insulin-like growth factor 1 receptor IGF-2 Insulin-like growth factor-2 Retina IGFBP Insulin-like growth factor binding protein diabetes 030102 biochemistry & molecular biology biology Insulin IGF1R Insulin-like growth factor-1 receptor HRP horseradish peroxidase Retinal Cell Biology medicine.disease Receptor Insulin insulin-like growth factor-2 Rats Insulin receptor 030104 developmental biology Endocrinology medicine.anatomical_structure chemistry Insulin-like growth factor 2 biology.protein Proto-Oncogene Proteins c-akt Signal Transduction Research Article |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1016/j.jbc.2021.100712 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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