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.
Highlights
Deletion of the insulin receptor (IR) causes morphologic defects in the eye and brain of zebrafish [3] and Drosophila [4], and deletion of the mouse insulin responsive substrate gene, Irs-2, impairs retinal ganglion cell and photoreceptor maturation [5]
Retinal IGFs and insulin receptor expression during ontogeny and diabetes Lofqvist et al [16] reported the high relative expression of retinal Igf-1/2 mRNA’s compared with insulin mRNA in normal mouse retina, but little is known about their expression and potential role in the adult mammalian retina
Igf1 content in P7 liver is 30-fold higher than in retina, and in adult rats, this difference further increases by a factor of 10 times. These results reveal that the adult retina expresses abundant insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2), which likely function in an autocrine or paracrine manner [15]
Summary
Deletion of the insulin receptor (IR) causes morphologic defects in the eye and brain of zebrafish [3] and Drosophila [4], and deletion of the mouse insulin responsive substrate gene, Irs-2, impairs retinal ganglion cell and photoreceptor maturation [5]. Intravitreal, and subconjunctival administration of insulin restores prosurvival IR and Akt kinase activities and reduces retinal cell death associated with diabetes [9, 11] It is unknown how the basal IR activity in normal adult animals is determined and how diabetes impacts this regulation. IGF-2 regulates retinal insulin receptor activity note, the growth-promoting effects of IGF-2 during development are mediated largely via the IR [18], and the retinal IR is highly sensitive to IGF-2 (reviewed in [19]) Taken together, these data led us to hypothesize that IGF-1 and/or IGF-2 may be important endogenous ligands of the retinal IR and play a critical prosurvival role in retinal neurons, a function disrupted by diabetes. These findings provide novel insights into the regulation of prosurvival signaling pathways in the retina and how they are compromised by diabetes
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