Abstract
Purpose:
Diabetic retinopathy (DR), a common microvascular complication of diabetes, is the leading cause of acquired blindness in the working-age population. Individuals with diabetes still develop DR despite appropriate glycemic and blood pressure control, highlighting the pressing need to identify useful biomarkers for risk stratification. The purpose of this review is to systematically summarize potential metabolic biomarkers and pathways of DR, which could facilitate developing an understanding of the disease mechanisms, as well as new therapeutic measures.
Methods:
We searched PubMed and Web of Science for relevant metabolomics studies on humans published before September 30, 2020. Information regarding authors, title, publication date, study subjects, analytical platforms, methods of statistical analysis, biological samples, directions of change of potential metabolic biomarkers, and predictive values of metabolic biomarker panels was extracted, and the quality of the studies was assessed. Pathway analysis, including enrichment analysis and topology analysis, was derived from integrating differential metabolites using MetaboAnalyst 3.0, based on the Kyoto Encyclopedia of Genes and Genomes and Human Metabolome Database.
Results:
We found nine studies focused on the identification of potential biomarkers. Repeatedly identified metabolites including l-glutamine, l-lactic acid, pyruvic acid, acetic acid, l-glutamic acid, d-glucose, l-alanine, l-threonine, citrulline, l-lysine, and succinic acid were found to be potential biomarkers of DR. It was observed that l-glutamine and citrulline changed in all biological samples. Dysregulation of metabolic pathways involved amino acid and energy metabolism.
Conclusions:
This review summarizes potential biomarkers and metabolic pathways, providing insights into new pathogenic pathways for this microvascular complication of diabetes.
Diabetic retinopathy (DR), one of the most common ocular complications of diabetes, is the leading cause of acquired blindness in the working-age population
1 and is becoming a global health concern. It is estimated that approximately one in three patients with diabetes suffers from DR, of whom 30% are affected by vision-threatening DR, including proliferative DR (PDR) and diabetic macular edema (DME).
2 It is well established that traditional risk factors for DR include long diabetes duration and poor glycemic and blood pressure control.
2 However, in clinical practice, some patients with diabetes still develop DR despite tight glycemic and blood pressure control, which may be related to metabolic memory. Diabetic patients are in a long-term hyperglycemic state, and in the later stage of stable glycemic control the target cells can still remember the earlier glycemic environment, which makes patients vulnerable to diabetes-related complications.
3 Therefore, identifying biomarkers for targeting screening and therapy for DR is necessary to prevent irreversible retinal damage among patients with diabetes.
Over the last few decades, huge advancements in retinal imaging have been made that have allowed for better visualization of the anatomy of the retina and choroid and improved our ability to diagnose DR. New imaging technologies, such as optical coherence tomography and optical coherence tomography angiography, can produce high-resolution images of the retina in a noninvasive manner.
4 In addition, recently developed molecular genetic technology can be used to identify disease mutation sites, which is helpful in furthering our understanding the genetic susceptibility of DR
5 and providing targets for gene treatment.
6 Proteomics techniques can also identify biomarkers associated with the development of DR.
7 However, several disadvantages of these methods should be acknowledged. First, imaging diagnosis is effective only if specific pathologic changes have been detected and confirmed.
8 Second, genomic and proteomic studies may provide limited correlation with disease phenotypes, and only a small fraction of patients would benefit from these therapies.
9
Metabolomics is a promising branch of omics for revealing the metabolic changes and underlying mechanism involved in the pathogenesis of diseases.
9 The retina is a highly metabolically active tissue, and the application of metabolomics in retinal diseases may achieve success in identifying useful biomarkers.
10 Although quite a few metabolomics studies have reported possible metabolic biomarkers and pathways of DR, a systematic summary is lacking.
In this effort, we aimed to summarize the metabolites that are significantly altered in DR and explore the metabolic pathways involved in the onset and progression of DR. The findings might move the care of patients with DR toward a personalized approach and lead to new therapeutic options.
In this review, nine metabolomics studies on DR were comprehensively reviewed, and the data of these studies were analyzed to identify valuable metabolic biomarkers and pathways involved in the pathology of DR. Several potential metabolites were summarized (observed in at least two studies), including l-glutamine, l-lactic acid, pyruvic acid, acetic acid, l-glutamic acid, d-glucose, l-alanine, l-threonine, citrulline, l-lysine, and succinic acid. Both l-glutamine and citrulline were especially observed to differ in all biological samples (plasma, vitreous, and AH). After analyzing the metabolic pathways of differential metabolites, we found that amino acid and energy metabolism significantly differed between patients with DR and controls.
Supported by a grant from the National Natural Science Foundation of China (81973061), by the Tang Scholar of Soochow University, and by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
Disclosure: X.-W. Hou, None; Y. Wang, None; C.-W. Pan, None