Yumnamcha Thangal, Guerra Michael, Singh Lalit Pukhrambam, Ibrahim Ahmed S
Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
Antioxidants (Basel). 2020 Dec 8;9(12):1244. doi: 10.3390/antiox9121244.
Diabetic retinopathy is a major cause of ocular complications in patients with type 1 and type 2 diabetes in developed countries. Due to the continued increase in the number of people with obesity and diabetes in the United States of America and globally, the incidence of diabetic retinopathy is expected to increase significantly in the coming years. Diabetic retinopathy is widely accepted as a combination of neurodegenerative and microvascular changes; however, which change occurs first is not yet understood. Although the pathogenesis of diabetic retinopathy is very complex, regulated by numerous signaling pathways and cellular processes, maintaining glucose homeostasis is still an essential component for normal physiological functioning of retinal cells. The maintenance of glucose homeostasis is finely regulated by coordinated interplay between glycolysis, Krebs cycle, and oxidative phosphorylation. Glycolysis is the most conserved metabolic pathway in biology and is tightly regulated to maintain a steady-state concentration of glycolytic intermediates; this regulation is called scheduled or regulated glycolysis. However, an abnormal increase in glycolytic flux generates large amounts of intermediate metabolites that can be shunted into different damaging pathways including the polyol pathway, hexosamine pathway, diacylglycerol-dependent activation of the protein kinase C pathway, and Amadori/advanced glycation end products (AGEs) pathway. In addition, disrupting the balance between glycolysis and oxidative phosphorylation leads to other biochemical and molecular changes observed in diabetic retinopathy including endoplasmic reticulum-mitochondria miscommunication and mitophagy dysregulation. This review will focus on how dysregulation of glycolysis contributes to diabetic retinopathy.
在发达国家，糖尿病视网膜病变是1型和2型糖尿病患者眼部并发症的主要原因。由于美国及全球肥胖和糖尿病患者人数持续增加，预计未来几年糖尿病视网膜病变的发病率将显著上升。糖尿病视网膜病变被广泛认为是神经退行性变和微血管变化的结合；然而，哪种变化先发生尚不清楚。尽管糖尿病视网膜病变的发病机制非常复杂，受众多信号通路和细胞过程调控，但维持葡萄糖稳态仍是视网膜细胞正常生理功能的重要组成部分。葡萄糖稳态的维持通过糖酵解、三羧酸循环和氧化磷酸化之间的协同相互作用进行精细调节。糖酵解是生物学中最保守的代谢途径，受到严格调控以维持糖酵解中间产物的稳态浓度；这种调节称为定时或调节性糖酵解。然而，糖酵解通量的异常增加会产生大量中间代谢产物，这些产物可被分流到不同的损伤途径，包括多元醇途径、己糖胺途径、蛋白激酶C途径的二酰甘油依赖性激活以及阿马多里/晚期糖基化终产物（AGEs）途径。此外，破坏糖酵解和氧化磷酸化之间的平衡会导致糖尿病视网膜病变中观察到的其他生化和分子变化，包括内质网 - 线粒体通讯障碍和线粒体自噬失调。本综述将聚焦于糖酵解失调如何导致糖尿病视网膜病变。
