Diabetic retinopathy: loss of neuroretinal adaptation to the diabetic metabolic environment

Abstract

Diabetic retinopathy (DR) impairs vision of patients with type 1 and type 2 diabetes, associated with vascular dysfunction and occlusion, retinal edema, hemorrhage, and inappropriate growth of new blood vessels. The recent success of biologic treatments targeting vascular endothelial growth factor (VEGF) demonstrates that treating the vascular aspects in the later stages of the disease can preserve vision in many patients. It would also be highly desirable to prevent the onset of the disease or arrest its progression at a stage preceding the appearance of overt microvascular pathologies. The progression of DR is not necessarily linear but may follow a series of steps that evolve over the course of multiple years. Abundant data suggest that diabetes affects the entire neurovascular unit of the retina, with an early loss of neurovascular coupling, gradual neurodegeneration, gliosis, and neuroinflammation occurring before observable vascular pathologies. In this article, we consider the pathology of DR from the point of view that diabetes causes measurable dysfunctions in the complex integral network of cell types that produce and maintain human vision.

Keywords: diabetic retinopathy; maladaption; metabolism; neurodegeneration; neurovascular unit.

Figure 1

DR changes to the neural retina. Over time, neurons in the inner retinal layers lose adaptation to systemic metabolic alterations caused by diabetes and succumb to cell stress, as evidenced by reduced axonal and dendritic process branching, axonal beading, apoptotic cell death, accumulative cell loss, and retinal layer thinning.

Figure 2

Axonal swellings of Thy1-YFP–positive retinal ganglion cells in a mouse model of diabetic retinopathy. An example of axonal swellings on retinal ganglion cells of Thy1-YFP transgenic mice crossed with Ins2^Akita diabetic mice after 3 months of diabetes. (A) shows an entire dendritic arbor of a retinal ganglion cell in a diabetic retina; (B) shows an enlarged image of the boxed region in A, with axon swelling (arrowhead) at approximately 60 μm from the soma and preceded by a prominent thinning of the axon (arrow). Scale bars: 50 μm in A and 20 μmin B. Taken from Gastinger et al., with permission.

Figure 3

Early evidence of degenerating ganglion cells in human diabetic retinopathy. Ganglion cell bodies and neurites are fragmented and the dendrites are swollen. Hortega stain of frozen sections. Reprinted from Wolter, with permission.

Figure 3

Early evidence of degenerating ganglion cells in human diabetic retinopathy. Ganglion cell bodies and neurites are fragmented and the dendrites are swollen. Hortega stain of frozen sections. Reprinted from Wolter, with permission.

Figure 4

Enlarged axonal beading of parasol cells in human diabetic retinopathy. (a) Axons within a control retina exhibiting low-caliber beading consistent with transportation beads (arrows). (b) Axons within a diabetic retina showing abnormally large and irregular beads along the axons (arrows). Taken from Meyer-Rüsenberg et al., with permission.

Figure 5

Summary of known Akt and mTOR regulation pathways. The mTOR kinase within rictor-containing mTORC2 complex located at ribosomes catalyzes the co-translational phosphorylation of Akt Thr450, thus stabilizing the newly formed Akt protein. Neurotrophins (NT) (e.g., NGF, IGFs, BDNF) bind their respective receptors (NTR), thus activating phosphoinositide 3-kinase (PI3K), resulting in formation of phosphoinositide(3,4,5)-trisphosphate (PIP3). PIP3 recruits phosphoinositide-dependent kinase 1 (PDK1), Akt, and mTORC2 complex to the membrane by association with pleckstrin homology (PH) domains. PDK1 phosphorylates Thr308 of Akt and mTOR within mTORC2 phosphorylates Akt Ser473, thus fully activating Akt. TSC2 inhibits mTORC1 through GTPase activation of the small G-protein Rheb (not shown). Akt-induced phosphorylation of TSC2 at several sites relieves inhibition of mTORC1. In addition, Akt increases the phosphorylation of PRAS40 in mTORC1 and Sin1 in mTORC2. mTORC1 primarily stimulates protein synthesis via its effects on mRNA translation and regulates autophagy, whereas mTORC2 controls dendritic morphology and actin polymerization (see text). Phosphorylations are shown in red and nitrations and nitrosylations are shown in green. Protein nitration occurs when peroxynitrite (ONOO⁻), formed from nitric oxide (NO) and superoxide (O₂⁻), reacts with tyrosine residues (Tyr) forming nitrotyrosine. Nitration has been implicated in inhibition of PI3K and Akt activities. Protein nitrosylation occurs when NO reacts with the thiol group of cysteine residues. Nitrosylation of Cys298 and Cys224 have been implicated in the inhibition of Akt activity.