Individual and joint effects of trehalose and glutamate on diabetic retinopathy: a propensity score-matched case–control study

Guo, Chengnan; Xu, Yixi; Ma, Yange; Xu, Xin; Peng, Fang; Li, Hui; Jin, Dongzhen; Zhao, Shuzhen; Xia, Zhezheng; Lai, Mengyuan; Che, Mingzhu; Huang, Ruogu; Wang, Yanan; Jiang, Depeng; Cheng, Zheng; Mao, Guangyun

doi:10.1530/ec-21-0474

Cited by 3 publications

(1 citation statement)

References 44 publications

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“…Glu is associated with T2D, and studies have shown a 0.25 drop in Glu levels in diabetic subjects compared to non-diabetic controls (23). At the same time, studies have found that Glu is a risk factor for the incidence of DR (24), while another Korean study found that the intake of Glu did not affect the incidence of DR (25). We believe that in addition to the heterogeneity of the population, the metabolic interactions between amino acids should also be taken into account.…”

Section: Discussionmentioning

confidence: 99%

A new predictive model for the concurrent risk of diabetic retinopathy in type 2 diabetes patients and the effect of metformin on amino acids

Song

Luo²,

Huang³

et al. 2022

Front. Endocrinol.

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ObjectiveThis study established a model to predict the risk of diabetic retinopathy (DR) with amino acids selected by partial least squares (PLS) method, and evaluated the effect of metformin on the effect of amino acids on DR in the model.MethodsIn Jinzhou, Liaoning Province, China, we retrieved 1031 patients with type 2 diabetes (T2D) from the First Affiliated Hospital of Liaoning Medical University. After sorting the amino acids using the PLS method, the top 10 amino acids were included in the model. Multivariate logistic regression was used to analyze the relationship between different amino acids and DR. And then the effects of metformin on amino acids were explored through interaction. Finally, Spearman’s rank correlation analysis was used to analyze the correlation between different amino acids.ResultsAfter sorting by PLS, Gly, Pro, Leu, Lyr, Glu, Phe, Tyr, His, Val and Ser were finally included in the DR risk prediction model. The predictive model after adding amino acids was statistically different from the model that only included traditional risk factors (p=0.001). Metformin had a significant effect on the relationship between DR and 7 amino acids (Gly, Glu, Phe, Tyr, His, Val, Ser, p<0.05), and the population who are not using metformin and have high levels of Glu (OR: 0.44, 95%CI: 0.27-0.71) had an additive protection effect for the occurrence of DR. And the similar results can be seen in high levels of Gly (OR: 0.46, 95%CI: 0.29-0.75), Leu (OR: 0.48, 95%CI: 0.29-0.8), His (OR: 0.46, 95%CI: 0.29-0.75), Phe (OR: 0.24, 95%CI: 0.14-0.42) and Tyr (OR: 0.41, 95%CI: 0.24 -0.68) in population who are not using metformin.ConclusionsWe established a prediction model of DR by amino acids and found that the use of metformin reduced the protective effect of amino acids on DR developing, suggesting that amino acids as biomarkers for predicting DR would be affected by metformin use.

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Section: Discussionmentioning

confidence: 99%

A new predictive model for the concurrent risk of diabetic retinopathy in type 2 diabetes patients and the effect of metformin on amino acids

Song

Luo²,

Huang³

et al. 2022

Front. Endocrinol.

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Accumulation of branched-chain amino acids deteriorates the neuroinflammatory response of Müller cells in diabetic retinopathy via leucine/Sestrin2-mediated sensing of mTOR signaling

Gong,

Wang,

Luo

et al. 2024

Acta Diabetol

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Aims This study aimed to investigate branched-chain amino acid (BCAA) catabolism in diabetic retinopathy (DR). Methods Wild-type and db/db mice were fed BCAAs (5 or 10 mg/kg/day) for 12 weeks, and hyperglycemia-exposed Müller cells were treated with BCAAs (2 or 5 mmol/L) for 24 and 48 h. BCAA levels were measured using MS/MS. Western blotting was performed to detect proteins. Flow cytometry, oxygen consumption rate, and Cell Counting Kit-8 assays were used to evaluate Müller cell viability. Each experiment was conducted at least thrice. Results BCAAs and branched-chain α-keto acids (BCKAs) were increased in the retina and systemic tissues of diabetic mice, and these changes were further enhanced to approximately 2-fold by extra BCAAs compared to wild-type group. In vitro, BCAAs and BCKAs were induced in hyperglycemic Müller cells, and augmented by BCAA supplementation. The aberrant BCAA catabolism was accompanied by mTORC1 activation and subsequently induced TNF-ɑ, VEGFA, GS, and GFAP in retinas and Müller cells under diabetic conditions. The cell apoptosis rate increased by approximately 50%, and mitochondrial respiration was inhibited by hyperglycemia and BCAA in Müller cells. Additionally, mTORC1 signaling was activated by leucine in Müller cells. Knockdown of Sestrin2 or LeuRS significantly abolished the leucine-induced mTORC1 phosphorylation and protected Müller cell viability under diabetic conditions. Conclusions We found that BCAA catabolism is hindered in DR through mTORC1 activation. Leucine plays a key role in inducing mTORC1 by sensing Sestrin2 in Müller cells. Targeting Sestrin2 may ameliorate the toxic effects of BCAA accumulation on Müller cells in DR.

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Age-related driving mechanisms of retinal diseases and neuroprotection by transcription factor EB-targeted therapy

Abokyi,

Tse

2024

Neural Regeneration Research

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Retinal aging has been recognized as a significant risk factor for various retinal disorders, including diabetic retinopathy, age-related macular degeneration, and glaucoma, following a growing understanding of the molecular underpinnings of their development. This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches, focusing on the activation of transcription factor EB. Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies, such as exercise, calorie restriction, rapamycin, and metformin, in patients and animal models of these common retinal diseases. The review critically assesses the role of transcription factor EB in retinal biology during aging, its neuroprotective effects, and its therapeutic potential for retinal disorders. The impact of transcription factor EB on retinal aging is cell-specific, influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways. In vascular endothelial cells, transcription factor EB controls important processes, including endothelial cell proliferation, endothelial tube formation, and nitric oxide levels, thereby influencing the inner blood-retinal barrier, angiogenesis, and retinal microvasculature. Additionally, transcription factor EB affects vascular smooth muscle cells, inhibiting vascular calcification and atherogenesis. In retinal pigment epithelial cells, transcription factor EB modulates functions such as autophagy, lysosomal dynamics, and clearance of the aging pigment lipofuscin, thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization. These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis, neuronal synapse plasticity, energy metabolism, microvasculature, and inflammation, ultimately offering protection against retinal aging and diseases. The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases. Therefore, it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.

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Individual and joint effects of trehalose and glutamate on diabetic retinopathy: a propensity score-matched case–control study

Cited by 3 publications

References 44 publications

A new predictive model for the concurrent risk of diabetic retinopathy in type 2 diabetes patients and the effect of metformin on amino acids

A new predictive model for the concurrent risk of diabetic retinopathy in type 2 diabetes patients and the effect of metformin on amino acids

Accumulation of branched-chain amino acids deteriorates the neuroinflammatory response of Müller cells in diabetic retinopathy via leucine/Sestrin2-mediated sensing of mTOR signaling

Age-related driving mechanisms of retinal diseases and neuroprotection by transcription factor EB-targeted therapy

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