Diabetes-Driven Retinal Neurodegeneration: Its Role in the Pathogenesis of Diabetic Retinopathy

Abstract

Diabetic retinopathy is a complication of diabetes characterized by an extremely low rate of progression. It takes several years to move from the onset of diabetes, both type 1 and type 2, to the development of retinal microaneurysms, then leading to proliferative diabetic retinopathy and vision loss. The recent demonstration that retinal microaneurysms are preceded and, possibly, caused by a subclinical neurodegeneration mainly affecting the neurovascular unit has suggested, on one hand, the possible existence of a previously unknown early neurodegenerative stage of diabetic retinopathy and, on the other, that an early "neuroprotective" treatment could end up preventing the development of the microvascular stages. This review summarizes the present situation in the field and focuses on the prevention of diabetic retinopathy, which seems, for the first time, to be within reach.

Keywords: diabetic retinopathy; neurodegeneration; prevention.

Figure 1

Progression of DR. DR may develop in patients affected by both Type 1 and Type 2 diabetes. After an initial silent phase, the four stages of DR develop in sequence. (1) Mild non-proliferative (NP) DR (characterized by the development of microaneurysms), (2) moderate NPDR (abnormal structure and caliber of blood vessels), (3) severe NPDR (reduced perfusion, diffuse ischemia), (4) proliferative DR (proliferation of new fragile blood vessels). The rate of progression of DR described here is approximative, as the natural history of the complication differs in different individuals.

Figure 2

The blood vessels that do not form a neurovascular unit have a more permeable endothelium. (a) The endothelial cells of all vessels have tight junctions. The non-neurovascular unit blood vessels’ endothelial cells do have numerous inter-endothelial cell gaps (permeable pores), making them more permeable to certain molecules. In the neurovascular unit (b), the endothelial cells are connected to each other by tight junctions and lack permeable pores. Endothelial cells are surrounded by pericytes, neurons and astrocytes that reinforce and stabilize the neurovascular unit.

Figure 3

Retinal segmentation performed by the Micron IV OCT System and InSight software, Version 1. (Phoenix Technology Group, Pleasanton, CA, USA) in a C57BL6J mouse. RNFL-GCL: retinal nerve fiber layer—ganglion cell layer complex (containing axons and bodies of retinal ganglion cells); IPL: inner plexiform layer (synaptic connections between amacrine, bipolar, and retinal ganglion cells); INL: inner nuclear layer (cell bodies of amacrine, bipolar, and horizontal cells); OPL: outer plexiform layer (synaptic connections between photoreceptors, bipolar and horizontal cells); ONL: outer nuclear layer (cell bodies of photoreceptors, rods and cones); ILS: photoreceptor inner segments; OLS: photoreceptor outer segments.