Identification of a metabolite that can prevent features associated with proliferative diabetic retinopathy

Abstract

Purpose: Proliferative diabetic retinopathy (PDR), which is characterized by neovascularization on the retinal surface and posterior vitreous, is the most advanced form of diabetic retinopathy (DR) and a major cause of blindness in the world. The absence of effective and sustainable therapeutic options can be attributed in part to an incomplete understanding of the disease and to the lack of animal models that fully recapitulate it. Metabolomics is a powerful and emerging technique for evaluating functional genomics and for studying diseases with underlying metabolic dysfunction such as DR. We hypothesized that if more complete metabolic profiles generated using highly sensitive metabolomic strategies were compared, dysregulated pathways with potential therapeutic interest could be identified.

Methods: Untargeted metabolomic analyses were performed on both blood and vitreous from diabetic patients and controls to identify local and circulating factors. Blood samples from diabetic patients with at least 20 years of disease were divided into three groups: Non-apparent DR; mild DR and PDR. Vitreous samples were divided into PDR and non-diabetic groups. Rodent models of neuronal dysfunction and preretinal neovascularization received intravitreal injections of candidate molecules or vehicle. The eyes were then analyzed by ERG, OCT, immunohistochemistry and mass spectrometry.

Results: A very clear demarcation between the metabolomic profiles from vitreous of PDR patients and controls was observed. In PDR samples amino-acids, acylcarnitines, succinate and allantoin were upregulated. Importantly, some of the identified metabolomic features were also observed in OIR mice. Inosine, a small molecule with putative neuroprotective properties, was upregulated in 33% of the diabetic patients with long-standing disease that had not developed PDR. In the rodent models, intravitreal inosine injections significantly limited the development of pathological features and were associated with a different metabolomic profile when compared to controls.

Conclusions: These results provide information regarding the global metabolic dysfunction associated with PDR. The selective upregulation of inosine in patients that do not develop PDR, along with its effects on prevention of hallmark features in animal models, suggests that inosine may be a potential therapeutic option for limiting disease progression.

Keywords: 499 diabetic retinopathy • 592 metabolism • 609 neovascularization