Glucose Metabolic Characterization of Human Aqueous Humor in Relation to Wet Age-Related Macular Degeneration

Abstract

Purpose Energy compromise underpins wet age-related macular degeneration (wAMD) pathogenesis, but the relationship between glucose metabolism and the disease remains unclear. Here, we characterized aqueous humor (AH) to elucidate glucose-related metabolic signatures in patients with wAMD. Methods In total, 25 eyes of 25 patients with wAMD were divided into phakic (15 eyes), pseudophakic (10 eyes), and intravitreal injections of ranibizumab (13 eyes) wAMD groups. Twenty patients with cataract (21 eyes) served as controls. Ultrahigh-performance liquid chromatography tandem mass spectrometry was used to quantitatively characterize AH. Results Twenty-one metabolites related to glucose metabolism were identified in AH from 45 patients. Tricarboxylic acid (TCA)-related metabolic substrates, including citrate, were detected in AH and were significantly increased in AMD ( P < 0.01) and AMD pseudophakic groups ( P < 0.05). In contrast, α -ketoglutarate levels were decreased in the AMD group ( P < 0.05). The α -ketoglutarate/citrate ratio was significantly decreased, corresponding to 71.71% and 93.6% decreases in the AMD (phakic and pseudophakic) groups as compared with controls ( P < 0.001), revealing a significant positive correlation with glutamine. A lower mean glutamine and higher glutamate level were detected in AMD cases compared with controls. No significant differences were observed for lactic acid or other Krebs cycle metabolites. Intravitreal injection significantly alleviated mean central foveal thickness but did not significantly alter metabolites. Conclusions Compromised glucose TCA cycle and altered glutamine metabolism are implicated in the AH metabolism in wAMD. These findings highlight potential treatments for alleviating wAMD from a metabolic perspective.

Plasma Metabolomic Profiles Associated with Three-Year Progression of Age-Related Macular Degeneration

“…However, through excitotoxicity, it can result in neural cell damage or death, [34] which is thought to be mediated at least in part by oxidative stress [35]. Indeed, Charles-Messance et al [36] showed in a mouse model that glutamate alone is sufficient for inducing rod photoreceptor cell death and that this is due to the deregulation of glutamate homeostasis and glutamate excitotoxicity.…”

Role of glucose metabolism in ocular angiogenesis (Review)

“…In clinical samples, higher levels of the intermediates of the TCA cycle were similarly detected in patients with active nAMD. In a previous study, using ultrahigh-performance liquid chromatography-tandem mass spectrometry, the detection of energy metabolites in the aqueous humor of with AMD revealed that citrate and isocitrate levels were significantly increased in the AMD group, whereas succinate and α-ketoglutarate levels were significantly decreased compared with the control group ( 106 ). Low α-ketoglutarate levels contribute to the stabilization of HIF-1α and the secretion of VEGF-A, which further promotes progression to CNV ( 107 ).…”

“…Thus, the dysregulation of the TCA cycle may also be a driving force in nAMD. However, the underlying mechanisms require further investigation ( 106 ).…”

New insight of metabolomics in ocular diseases in the context of 3P medicine

“…Dysregulated lipid and glucose energy metabolism was speculated to be the driven force for wet AMD [ 83 ]. Hence, researchers conducted a targeted metabolomics study on the glucose metabolism and an untargeted metabolomics study [ 29 , 30 ]. The prior study analyzed the AH samples of 25 AMD patients and 25 controls via LC–MS [ 29 ].…”