Diabetic retinopathy (DR) is a leading cause of blindness in working age adults. DR has non-proliferative stages, characterized in part by retinal neuroinflammation and ischemia, and proliferative stages, characterized by retinal angiogenesis. Several systemic factors, including poor glycemic control, hypertension, and hyperlipidemia, increase the risk of DR progression to vision-threatening stages. Identification of cellular or molecular targets in early DR events could allow more prompt interventions pre-empting DR progression to vision-threatening stages.

Glia mediate homeostasis and repair. They contribute to immune surveillance and defense, cytokine and growth factor production and secretion, ion and neurotransmitter balance, neuroprotection, and, potentially, regeneration. Therefore, it is likely that glia orchestrate events throughout the development and progression of retinopathy. Understanding glial responses to products of diabetes-associated systemic dyshomeostasis may reveal novel insights into the pathophysiology of DR and guide the development of novel therapies for this potentially blinding condition.

In this article, first, we review normal glial functions and their putative roles in the development of DR. We then describe glial transcriptome alterations in response to systemic circulating factors that are upregulated in patients with diabetes and diabetes-related comorbidities; namely glucose in hyperglycemia, angiotensin II in hypertension, and the free fatty acid palmitic acid in hyperlipidemia. Finally, we discuss potential benefits and challenges associated with studying glia as targets of DR therapeutic interventions.

In vitro stimulation of glia with glucose, angiotensin II and palmitic acid suggests that: 1) astrocytes may be more responsive than other glia to these products of systemic dyshomeostasis; 2) the effects of hyperglycemia on glia are likely to be largely osmotic; 3) fatty acid accumulation may compound DR pathophysiology by promoting predominantly proinflammatory and proangiogenic transcriptional alterations of macro and microglia; and 4) cell-targeted therapies may offer safer and more effective avenues for DR treatment as they may circumvent the complication of pleiotropism in retinal cell responses.

Although several molecules previously implicated in DR pathophysiology are validated in this review, some less explored molecules emerge as potential therapeutic targets. Whereas much is known regarding glial cell activation, future studies characterizing the role of glia in DR and how their activation is regulated and sustained (independently or as part of retinal cell networks) may help elucidate mechanisms of DR pathogenesis and identify novel drug targets for this blinding disease.

糖尿病视网膜病变（DR）是工作年龄成年人失明的主要原因。DR具有非增殖期和增殖期，其部分特征在于视网膜神经炎症和缺血，以及增殖期，其特征在于视网膜血管生成。一些全身性因素，包括血糖控制不佳、高血压和高脂血症，会增加 DR 进展至危及视力阶段的风险。识别早期 DR 事件中的细胞或分子靶点可以采取更及时的干预措施，预防 DR 进展到威胁视力的阶段。

神经胶质细胞介导体内平衡和修复。它们有助于免疫监视和防御、细胞因子和生长因子的产生和分泌、离子和神经递质平衡、神经保护以及潜在的再生。因此，神经胶质细胞很可能在视网膜病变的发生和进展过程中协调事件。了解神经胶质细胞对糖尿病相关全身稳态失调产物的反应可能会揭示对 DR 病理生理学的新见解，并指导针对这种潜在致盲疾病的新疗法的开发。

在本文中，我们首先回顾了正常的神经胶质功能及其在 DR 发展中的假定作用。然后，我们描述了神经胶质转录组的改变，以响应糖尿病和糖尿病相关合并症患者上调的全身循环因子；即高血糖中的葡萄糖、高血压中的血管紧张素II和高脂血症中的游离脂肪酸棕榈酸。最后，我们讨论了将神经胶质细胞作为 DR 治疗干预目标进行研究的潜在益处和挑战。

用葡萄糖、血管紧张素 II 和棕榈酸对神经胶质细胞进行体外刺激表明：1）星形胶质细胞可能比其他神经胶质细胞对这些全身性动态平衡失调的产物更敏感；2）高血糖对神经胶质细胞的影响可能主要是渗透性的；3) 脂肪酸积累可能通过主要促进大胶质细胞和小胶质细胞的促炎症和促血管生成转录改变而加剧 DR 病理生理学；4) 细胞靶向疗法可能为 DR 治疗提供更安全、更有效的途径，因为它们可以避免视网膜细胞反应中多效性的并发症。

尽管之前与 DR 病理生理学有关的几种分子在本次综述中得到了验证，但一些较少探索的分子成为潜在的治疗靶点。尽管人们对神经胶质细胞激活了解甚多，但未来研究表征神经胶质细胞在 DR 中的作用以及如何调节和维持神经胶质细胞的激活（独立或作为视网膜细胞网络的一部分）可能有助于阐明 DR 发病机制并确定新的药物靶点致盲疾病。