糖尿病视网膜病变中的激素代谢负荷：糖尿病视网膜作为内分泌反应性靶器官

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中文摘要

糖尿病视网膜病变（DR）通常被解释为慢性高血糖和血管损伤的并发症。这一模型仍然是基础性的，但它不能完全解释某些患者中早期、快速或治疗抵抗的疾病。青春期、妊娠、绝经、阻塞性睡眠呼吸暂停、甲状腺功能障碍、慢性应激以及血糖控制的快速改善，是尽管进行标准风险评估但视网膜病变仍可能发生变化的临床情境。我们提出激素代谢负荷（HMB）假说，该假说将糖尿病视网膜视为内分泌反应性的神经和血管组织。在这一模型中，生长激素/胰岛素样生长因子-1（GH/IGF-1）、下丘脑-垂体-肾上腺（HPA）-糖皮质激素信号及相关糖皮质激素受体/盐皮质激素受体（GR/MR）平衡、甲状腺激素和性类固醇信号，通过受体和酶介导的途径作用于视网膜神经元、Müller胶质细胞、内皮细胞、周细胞和视网膜色素上皮细胞。这些轴可能与高血糖共同汇聚于氧化应激、核因子κB（NF-κB）介导的炎症、血管内皮生长因子（VEGF）信号、血视网膜屏障（BRB）功能障碍、神经退行性变和代谢记忆。HMB被提出作为额外的研究层面，而非替代已确立的DR风险评估，并且不应被用于证明广泛激素检测或超说明书内分泌治疗的合理性。这一假说产生了可检验的预测：多轴内分泌谱分析应能在标准变量之外改善风险预测；以所选轴特异性紊乱的更大程度、持续性或共现为特征的前瞻性指定内分泌-视网膜谱，应与不同的光学相干断层扫描（OCT）或光学相干断层扫描血管成像（OCTA）轨迹相关；尽管接受了足量抗VEGF治疗但仍持续存在或反应欠佳的糖尿病性黄斑水肿（DME），应富集所选内分泌信号；后期生物标志物选择的研究应检验匹配的内分泌纠正是否比非选择性干预具有更大的视网膜效应。这是一个针对特定表型的研究导向模型，包括快速非增殖性糖尿病视网膜病变、持续或反应欠佳的DME、青春期增殖性疾病、绝经后加速、甲状腺相关疾病以及伴有睡眠呼吸暂停的糖尿病视网膜病变。如果得到验证，这一框架可能支持更聚焦的内分泌-视网膜研究，并改善特定DR表型中精准预防研究的设计。

英文摘要

Diabetic retinopathy (DR) is usually interpreted as a complication of chronic hyperglycemia and vascular injury. This model remains fundamental, but it does not fully explain early, rapid, or treatment-resistant disease in some patients. Puberty, pregnancy, menopause, obstructive sleep apnea, thyroid dysfunction, chronic stress, and rapid improvement in glycemic control are clinical settings in which retinal disease may change despite standard risk assessment. We propose the Hormonal Metabolic Burden (HMB) hypothesis, which views the diabetic retina as an endocrine-responsive neural and vascular tissue. In this model, growth hormone/insulin-like growth factor-1 (GH/IGF-1), hypothalamic-pituitary-adrenal (HPA)-glucocorticoid signaling and related glucocorticoid receptor/mineralocorticoid receptor (GR/MR) balance, thyroid hormone, and sex steroid signaling act on retinal neurons, Müller glia, endothelial cells, pericytes, and retinal pigment epithelial cells through receptor- and enzyme-mediated pathways. These axes may converge with hyperglycemia on oxidative stress, nuclear factor kappa B (NF-κB)-mediated inflammation, vascular endothelial growth factor (VEGF) signaling, blood-retinal barrier (BRB) dysfunction, neurodegeneration, and metabolic memory. HMB is proposed as an additional research layer rather than a replacement for established DR risk assessment, and it should not be used to justify broad hormone testing or off-label endocrine treatment. This hypothesis generates testable predictions: multi-axis endocrine profiling should improve risk prediction beyond standard variables; prespecified endocrine-retinal profiles characterized by greater magnitude, persistence, or co-occurrence of selected axis-specific disturbances should be associated with distinct optical coherence tomography (OCT) or optical coherence tomography angiography (OCTA) trajectories; persistent or suboptimally responsive diabetic macular edema (DME) despite an adequate course of anti-VEGF therapy should be enriched for selected endocrine signals; and later-stage biomarker-selected studies should test whether matched endocrine correction has greater retinal effects than unselected intervention. It is a research-oriented model for selected phenotypes, including rapid nonproliferative diabetic retinopathy, persistent or suboptimally responsive DME, pubertal proliferative disease, postmenopausal acceleration, thyroid-linked disease, and diabetic retinopathy with sleep apnea. If validated, this framework may support more focused endocrine-retinal research and improve the design of precision prevention studies in selected DR phenotypes.