Metabolomic profiling could identify stage-specific diabetic retinopathy biomarkers

In a follow-up study, the researchers will perform aqueous and serum sampling to investigate dynamic changes in the ocular and blood metabolomes during DR progression. Image credit: ©Goffkein – stock.adobe.com

The authors of a recent study believe in the potential of metabolomic profiling for identifying stage-specific biomarkers of diabetic retinopathy (DR) in the vitreous.¹ The findings were described by first author John Kim Hiller, MD, PhD, from the Center for Eye Research and Innovative Diagnostics, Department of Ophthalmology, Institute of Clinical Medicine, Faculty of Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway.

“As researchers strive to untangle the molecular underpinnings of DR progression, the identification of robust biomarkers capable of distinguishing distinct stages of the disease has emerged as a pivotal pursuit.^2,3 In this context, the growing field of metabolomics offers a promising avenue, leveraging the dynamic interplay and effects of small molecules to illuminate the metabolic signatures associated with varying stages of DR,⁴” Hiller and his colleagues commented.

They theorised that because the vitreous humor contains metabolites sourced from both local ocular tissues and systemic circulation,⁵ these small-molecule chemicals may provide a dynamic reflection of cellular processes and may reveal the biochemical nuances characterising different stages of DR.⁶ They believe that the metabolomic fingerprint present in the vitreous environment may hold the key to unlocking molecular insights crucial for accurate disease stratification, prognosis and the tailoring of personalised therapeutic interventions.^4,6

In this study, they collected vitreous samples during therapeutic pars plana vitrectomy from 23 patients with varying health scenarios as follows: without diabetes (control, n=6), with diabetes and without retinopathy (DIA, n=5), non-proliferative DR (NPDR, n=5) and proliferative DR (PDR, n=7). The samples then were analysed using high-performance liquid chromatography coupled with high-resolution mass spectrometry.

Metabolomic results

The analyses of the principal components showed distinct metabolic signatures differentiating the patient groups, according to the investigators.

“The lysine, proline and arginine levels progressively increased from DIA to NPDR and PDR stages, highlighting their association with disease progression. Methionine and threonine showed notable increases in PDR compared to all other groups, while carnitine, a key metabolite in lipid metabolism, exhibited stage-specific increases, peaking in PDR. The detection of systemic and topical drugs, including metformin and tropicamide, in the vitreous further emphasises altered ocular permeability in DR,” Dr Hiller and colleagues reported.

The insights gained from this study will contribute to an increased understanding of the pathophysiological mechanisms underlying the progression from no DR via NPDR to full-blown PDR. They believe that identifying the changes in lysine, carnitine and proline metabolism observed may indicate disease progression and help contribute to development of innovative diagnostic tools and therapeutic targets, thereby contributing to the enhanced prevention and management of DR and its complications.

They also suggested that future research can validate the present findings in bodily fluids that can be accessed more easily such as the aqueous humor, tear fluid or serum to detect DR early and explore the protective role of metformin in the ocular environment, particularly in preventing the transition from NPDR to PDR.

The researchers are planning a longitudinal follow-up study that includes aqueous and serum sampling to investigate dynamic changes in the ocular and blood metabolomes during the progression of DR.

References

1. Hiller JK, Sandås EM, Rootwelt H, et al. Metabolomic biomarkers in vitreous humor: unveiling the molecular landscape of diabetic retinopathy progression. Int J Retin Vitr. 2025;11:58. https://doi.org/10.1186/s40942-025-00682-5

2. Safi H, Safi S, Hafezi-Moghadam A, Ahmadieh H. Early detection of diabetic retinopathy. Surv Ophthalmol. 2018;63:601–8.

3. Vujosevic S, Aldington SJ, Silva P, Henrnández C, Scanlon P, Peto T, et al. Screening for diabetic retinopathy: new perspectives and challenges. Lancet Diabetes Endocrinol. 2020;8:337–47.

4. Laíns Î, Gantner M, Murinello S, Lasky-Su JA, Miller JW, Friedlander M, et al. Metabolomics in the study of retinal health and disease. Prog Retin Eye Res. 2019;69:57–79.

5. Boulagnon C, Garnotel R, Fornes P, Gillery P. Post-mortem biochemistry of vitreous humor and glucose metabolism: an update. Clin Chem Lab Med CCLM. 2011;49:1265–70.

6. Midena E, Frizziero L, Midena G, Pilotto E. Intraocular fluid biomarkers (liquid biopsy) in human diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 2021; 259:3549-3560. doi: 10.1007/s00417-021-05285-y.