Metabolomic Analysis of Serum from Diabetic Patients With and Without Retinopathy

Abstract

Purpose: : Diabetes is the most common cause of vision loss in Americans under the age of 55; the vast majority of these patients will have some form of diabetic retinopathy after 20 years of the disease. There is a small percentage of diabetic patients who manifest little retinopathy in spite of long-standing disease. We analyzed the serum of patients with 10 or more years of diabetes and compared metabolite profiles of patients with (PDR) and without (non/mild NPDR) severe retinopathy to identify metabolites present in either population. Such profiling may detect molecules present in long-standing diabetic patients that may be protective against the development of retinopathy; similarly, metabolites restricted to those patients with PDR may facilitate development of retinopathy. Further testing of identified metabolites was done using the mouse oxygen-induced retinopathy (OIR) model to determine metabolites of patients that would exacerbate or protect the development of obliteration or neovascularization in OIR.

Methods: : Metabolomic profiles from serum of patients with mild NPDR or PDR were generated and compared. Candidate molecules were chosen and identified by comparing the ESI-Q-TOF fragmentation pattern of the ion to that of an authentic model compound. Different concentrations of candidate metabolites were injected intraperitoneally or intraocularly in Bl6 mice at P7 and P12 under conditions of OIR; obliteration and tuft formation in the retinal vasculature was measured at P17.

Results: : We identified metabolites that are increased in patients with minimal retinopathy compared to patients with proliferative disease. We then tested whether these metabolites reduced vessel obliteration and tuft formation when Bl6 mice were pretreated with the compound before the animal is exposed to ischemic stress. At least one metabolite provided significant reduction in neovascularization and obliteration in the OIR model.

Conclusions: : We demonstrate that diabetic patients with minimal retinopathy have different metabolomic profiles compared to patients with significant diabetic retinopathy, which may explain why severe forms of the eye disease are observed in some patients but not in others. The identification of metabolites that may serve as biomarkers of disease progression and/or as protective agents under conditions of hypoxic stress may be very useful for developing therapeutic strategies for treating diabetic retinopathy.

Keywords: diabetic retinopathy • diabetes • metabolism