Manifestation of Pathology in Animal Models of Diabetic Retinopathy Is Delayed from the Onset of Diabetes

Abstract

Diabetic retinopathy (DR) is the most common complication that develops in patients with diabetes mellitus (DM) and is the leading cause of blindness worldwide. Fortunately, sight-threatening forms of DR develop only after several decades of DM. This well-documented resilience to DR suggests that the retina is capable of protecting itself from DM-related damage and also that accumulation of such damage occurs only after deterioration of this resilience. Despite the enormous translational significance of this phenomenon, very little is known regarding the nature of resilience to DR. Rodent models of DR have been used extensively to study the nature of the DM-induced damage, i.e., cardinal features of DR. Many of these same animal models can be used to investigate resilience because DR is delayed from the onset of DM by several weeks or months. The purpose of this review is to provide a comprehensive overview of the literature describing the use of rodent models of DR in type-1 and type-2 diabetic animals, which most clearly document the delay between the onset of DM and the appearance of DR. These readily available experimental settings can be used to advance our current understanding of resilience to DR and thereby identify biomarkers and targets for novel, prevention-based approaches to manage patients at risk for developing DR.

Keywords: diabetic retinopathy; hyperglycemia-induced mitochondrial adaptation; mitophagy; mouse models; protection; resistance to diabetic retinopathy.

Figure 1

DR pathogenesis involves loss of resilience, which is a prerequisite for the subsequent accumulation of damage within the retina. In both humans and experimental animals, a retinopathy-free period precedes the appearance of DR. Recent discoveries in both T1D and T2D mice indicate that the retinopathy-free period is associated with enhanced tolerance of insults that cause damage to the retina, such as increased mitochondrial oxidative stress and cytokine production [7]. Loss of resilience sets the stage for progressive accumulation of retinal damage, which indicates the existence of DR.

Figure 2

Mitophagy is an essential component of resilience. The onset of DM, i.e., enduring elevation of blood sugar, triggers mitochondrial adaptation, which includes enhanced clearance of dysfunctional mitochondria. Deterioration of this innate defense mechanism results in self-perpetuating progress damage of the retina, which manifests as DR.