Circulating Metabolites and Lipids Are Associated to Diabetic Retinopathy in Individuals With Type 1 Diabetes

Abstract

Omics-based methods may provide new markers associated to diabetic retinopathy (DR). We investigated a wide omics panel of metabolites and lipids related to DR in type 1 diabetes. Metabolomic analyses were performed using two-dimensional gas chromatography with time-of-flight mass spectrometry and lipidomic analyses using an ultra-high-performance liquid chromatography quadruple time-of-flight mass spectrometry method in 648 individuals with type 1 diabetes. Subjects were subdivided into no DR, mild nonproliferative DR (NPDR), moderate NPDR, proliferative DR, and proliferative DR with fibrosis. End points were any progression of DR, onset of DR, and progression from mild to severe DR tracked from standard ambulatory care and investigated using Cox models. The cohort consisted of 648 participants aged a mean of 54.4 ± 12.8 years, 55.5% were men, and follow-up was 5.1–5.5 years. Cross-sectionally, 2,4-dihydroxybutyric acid (DHBA), 3,4-DHBA, ribonic acid, ribitol, and the triglycerides 50:1 and 50:2 significantly correlated ( P < 0.042) to DR stage. Longitudinally, higher 3,4-DHBA was a risk marker for progression of DR ( n = 133) after adjustment ( P = 0.033). We demonstrated multiple metabolites being positively correlated to a higher grade of DR in type 1 diabetes and several triglycerides being negatively correlated. Furthermore, higher 3,4-DHBA was an independent risk marker for progression of DR; however, confirmation is required.

Diminished retinal complex lipid synthesis and impaired fatty acid β-oxidation associated with human diabetic retinopathy

“…In a lipidomic study of human erythrocytes' phospholipids, Koehrer et al (11) reported a higher level of PC and plasmenyl-choline in diabetic patients without retinopathy. In a study of 648 individuals with type 1 diabetes, 2,4-dihydroxybutyric acid (DHBA); 3,4-DHBA; ribonic acid; and ribitol were positively -and the triglycerides 50:1 and 50:2 were negatively -correlated with DR stage (9). Overall, our findings are aligned with these other studies that report a lower abundance of complex retinal lipids accompanying DR. ) in participants without diabetes and diabetics without retinopathy, higher unsaturated FFAs in participants without diabetes, and higher polyunsaturated longer-chain FAHFA in participants without diabetes, and their lower levels among diabetics with retinopathy.…”

“…While these studies have shed some light on the pathogenesis of diabetic kidney disease and diabetic neuropathy, the metabolic basis of DR remains poorly understood. As for other diabetes complications, hyperglycemia is widely accepted as an important driver of DR in diabetes (8), but recent studies suggest a prominent role of altered lipid metabolism in DR pathology (9)(10)(11)(12)(13)(14)(15). In diabetic animal models, remodeling of fatty acids (15), alterations in 12/15-lipoxygenase (10), and a significant decrease in glycerophospholipids (12) have been reported in retina.…”

Metabolomics in Diabetic Retinopathy: A Systematic Review

“…39 Another study, in conjunction with metabolomics and lipidomics, estimated the association between multiple metabolites and DR grading to identify risk markers for DR progression. 40 The ultimate goal of metabolomics research is to realize the integration of research results and previous research results to develop a powerful tool for in-depth study of diseases. 41 In future research, DR biomarkers should be non-invasive, rapid, and economical, 36 helping us better understand the complex pathogenesis of diseases.…”

Metabolomics in Retinal Diseases: An Update

“…To date, longitudinal analysis is still lacking in the area of metabolomics-based clinical studies of retinal diseases. Only one study has employed a longitudinal analysis to characterize associations between circulating metabolites (lipids) and DR. Curovic et al [88] performed serum metabolomic cross-sectional analyses and plasma lipidomic cross-sectional analyses, and identified a panel of differential metabolites (lipids), including 2,4-dihydroxybutyric acid (DHBA), 3,4-DHBA, ribonic acid, ribitol, and the triglycerides 50:1 and 50:2, which were significantly correlated (p < 0.042) to DR stage. Based on the follow-up information on DR status, differential metabolite (lipid)-specific Cox proportional hazards models were established for capturing association with any progression, onset of DR, and progression from mild to severe DR.…”