Plasma Metabonomic Profiling of Diabetic Retinopathy

Abstract

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of visual impairment in working-age adults. Patients with diabetes often develop DR despite appropriate control of systemic risk factors, suggesting the involvement of other pathogenic factors. We hypothesize that the plasma metabolic signature of DR is distinct and resolvable from that of diabetes alone. A nested populationbased case-control metabonomic study was first performed on 40 DR cases and 40 control subjects with diabetes using gas chromatography-mass spectrometry. Eleven metabolites were found to be correlated with DR, and the majority were robust when adjusted for metabolic risk factors and confounding kidney disease. The metabolite markers 2-deoxyribonic acid; 3,4-dihydroxybutyric acid; erythritol; gluconic acid; and ribose were validated in an independent sample set with 40 DR cases, 40 control subjects with diabetes, and 40 individuals without diabetes. DR cases and control subjects with diabetes were matched by HbA 1c in the validation set. Activation of the pentose phosphate pathway was identified from the list of DR metabolite markers. The identification of novel metabolite markers for DR provides insights into potential new pathogenic pathways for this microvascular complication and holds translational value in DR risk stratification and the development of new therapeutic measures.Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of visual impairment in working-age adults worldwide (1,2). The global prevalence of diabetes is rising and the number of people with diabetes is projected to increase by 54% in 2030, compared with 2010 (3). The public health burden of diabetes and DR would thus increase correspondingly. The major risk factors of DR are poor glycemic control and hypertension, as well as the duration of diabetes (4,5), but their relative importance varies between studies (2,6). Although the risks of DR progression and vision loss are reduced with intensive control of risk factors (7,8), many patients with diabetes continue to develop complications despite tight glycemic and blood pressure control. There is increasing evidence to suggest that "metabolic memory" is responsible for this observation. The term metabolic memory refers to the persistent epigenetic modifications caused by early exposure to hyperglycemia that, in turn, predispose individuals to the development of diabetes complications even after good glycemic control

Erythritol is a pentose-phosphate pathway metabolite and associated with adiposity gain in young adults

“…Several recent studies of erythritol loading reported no effect on glucose (32,33), consistent with our findings. A study in patients with diabetes reported that erythritol and enrichment of another PPP biomarker (ribose) were increased in patients with diabetic retinopathy, and suggested that polyol pathway flux may yield biomarkers of clinical risk in diabetes (34).…”

Human plasma metabolomics in age-related macular degeneration (AMD) using nuclear magnetic resonance spectroscopy

“…[22],[23],[24]. Metabolomics of human plasma has been used to characterize diabetic retinopathy[25],[26], open angle glaucoma[27] and anterior uveitis. [28] In AMD, investigators have used untargeted LC-MS metabolomics to investigate changes in the plasma of “wet” AMD patients (n = 26), compared to controls (n = 19).…”

Clinical Metabolomics and Glaucoma

“…In ophthalmology, metabolomics has been used to study various eye diseases including glaucoma [10][11][12][13][14][15][16] , age-related macular degeneration [17][18][19] , diabetic retinopathy [20][21][22] , keratoconus [23] , refractive error [24,25] , retinal detachment [26] , uveitis [27,28] , dry eye [29,30] , and other ocular surface diseases [31] . Analyses have been performed on tear fluid [23,[29][30][31][32] , aqueous humor [24,25,33,34] , vitreous humor [20,26,27,35,36] , cornea [37][38][39] , conjunctiva [40] , and lens [41,42] samples.…”