Table 3.

Summary of data linking IRS proteins to diabetic retinopathy

IRS involved	Rodent genotype/phenotype	Organ affected	Main findings	Reference
IRS2	Irs2 −/− mice	Eye (retina)	Irs2 gene deletion triggered photoreceptor apoptosis with a 50% reduction in cells by day 14, with almost complete photoreceptor loss by 16 months of age. In contrast, normal retinal morphology was maintained in Irs1 −/− mice at up to 2 years of age. Retinas from Irs2 −/− mice displayed higher caspase-3 cleavage and activation, and lower Akt phosphorylation, consistent with apoptotic cell death. Expression of rhodopsin (the light-sensing G-protein-coupled receptor in the retina) was reduced in Irs2 −/− retinas and retinal electrical function showed that Irs2 −/− mice had reduced dark- and light-adapted responses, suggesting lower rod and cone activity, respectively	Yi et al (2005) [45]
IRS2	9- and 12-week-old Irs2 −/− mice	Eye (retina)	At 9 weeks, activation of Müller glial cells was apparent, as demonstrated by outer retinal layers that were considerably thinner than their wild-type counterparts. Thinning extended to each retinal layer in 12-week-old Irs2 −/− mice. Changes in microglia were also detected at 9 weeks with swelling/retraction of microglial processes observed. In both age groups, shortened rod segments were apparent, and rhodopsin distribution in the rod photoreceptors of the outer nuclear layer was abnormal. Photoreceptor atrophy, as well as synaptic changes at the outer plexiform layer were also observed. Retinal ganglion cell degeneration was present in 12-week-old Irs2 −/− mice with the progressive loss of these cells observed	Albert-Fort et al (2014) [83]; Kern and Barber (2008) [84]
IRS1, IRS2	STZ-induced model of type 1 diabetes in Sprague–Dawley rats	Eye (retina)	At 1 month post STZ-induced diabetes, retinal IRS1/2-associated PI3K activity, Akt1 and Akt3 kinase activity, and p70S6K/pGSK3β were decreased with no change in retinal IRS1/2 expression or tyrosine phosphorylation. Such rapid signalling changes and alterations in p70S6K and GSK3β as a result of hyperglycaemia provide further evidence of a role for insulin signalling in retinal cell survival. After 3 months, IR-β expression, autophosphorylation and kinase activity was decreased in diabetic retina. Moreover, IRS2 protein expression was decreased whereas IRS1 was unchanged. These data suggest that IR signalling is compromised relatively early in the diabetic retina, and suggests a critical role for reduced insulin in IRS2 signalling in progressive retinal degeneration	Reiter et al (2006) [85]

P706K, phospho-p70 S6 kinase