Emerging Insights into Pathogenesis

Abstract

Diabetic retinopathy (DR) is a frequent complication of diabetes mellitus (DM). Persistent hyperglycemia leads to the activation of multiple cellular pathways involved in the pathogenesis of DR, resulting in increased inflammation, oxidative stress, and vascular dysfunction. DR has been considered a "chronic, low-grade inflammatory disease of the retina". However, an increasing body of evidence suggests that inflammation and neurodegeneration both occur in human diabetes even before the development of clinical signs of DR. One of the first signs of inflammation in DM is the activation of retinal glia cells (RGC). RGC include microglia and macroglial cells (Müller cells and astrocytes). Activated RGC release cytotoxic substances responsible for the recruitment of leukocytes, blood-retinal barrier breakdown, direct glial dysfunction, and neuronal cell death. Recently, many inflammatory mediators, growth factors, and other molecules have been investigated in human vitreous and aqueous humor samples to better understand, in vivo, the multiple pathways and mechanisms leading to the pathogenesis of DR and its complications, such as diabetic macular edema, with potential for more tailored treatment. Moreover, non-invasive techniques, like optical coherence tomography, have allowed to detect new findings in the retinal layers, such as the hyperreflective intraretinal spots, which have been hypothesized to represent an in vivo marker of microglial activation, and early neural cell loss, confirming the hypothesis that neurodegeneration occurs early both in type 1 and 2 diabetes. These new emerging insights foster a better understanding of the pathogenesis of DR, which can no longer be considered as a pure retinal vascular complication of DM.

Diabetic Retinopathy–An Underdiagnosed and Undertreated Inflammatory, Neuro-Vascular Complication of Diabetes

“…The generated reparative enzymes, formerly termed "heat shock proteins" that resulted from retinal pigment epithelium non-lethal laser heating that have thus far been measured include reductions in thiobarbituric acid reactive substances (TBARS), increased glutathione (GSH) and superoxide dismutase 1 (SOD1) as well as a reduction in cytochrome c, caspase 3 expression and activity along with cleaved caspase 9, and increased Beclin 1, p62, and LC3b (131). Reductions in markers of inflammation have also been documented in human diabetic retinopathy (132,133), and micropulsed laser treatment has been demonstrated to improved early forms of macular edema with significant improvement in vision and without evidence of laser injury (133)(134)(135). When the macular edema is more severe, however, similar to the studies of intravitreal anti-VEGF injections, the studies of micropulsed laser demonstrate only minimal improvement in the edema and in vision (presumably because of the already established, irreversible neurodegeneration) (11,133).…”

Remodeling of Retinal Architecture in Diabetic Retinopathy: Disruption of Ocular Physiology and Visual Functions by Inflammatory Gene Products and Pyroptosis

“…Inhibiting ADM/NO signaling pathway in DR might downregulate NO in the retinal cultures treated with high glucose. Ruboxistaurin (PKC β inhibitor) downregulates ADM expression and activity, and electroretinography (ERG) showed that this change helped preserve the retinal functions suggesting that ADM/NO pathway could also serve as a potential therapeutic target for DR ( Midena and Pilotto, 2017 ).…”

Early Retinal Changes by OCT Angiography and Multifocal Electroretinography in Diabetes

“…It has been hypothesized that aggregates of activated microglial cells may be visualized in vivo at structural OCT as hyperreflective intraretinal foci (HRF), with specific features, in eyes with DM [11][12][13]. In diabetic eyes, the crosstalk among vessels, neurons, and glial cells in the retina is still partly unknown and we still lack a holistic approach which encompasses all retinal components [14,15]. A growing body of literature has been devoted to analyzing and interpreting both the new OCT and OCTA data [16,17].…”