Sleep and Circadian Regulation in Diabetic Retinopathy: The Role of Intrinsically Photosensitive Retinal Ganglion Cells and Melatonin Supplementation

糖尿病视网膜病变中的睡眠和昼夜节律调节：本质光敏视网膜神经节细胞和褪黑激素补充剂的作用

• 批准号: 10701729
• 负责人: Sirimon Reutrakul
• 金额: $ 66.51万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701729
• 关键词: 6-sulfatoxymelatonin; Acceleration; Adult; Adverse effects; Affect; Blindness; Blood specimen; Cell physiology; Circadian Dysregulation; Circadian desynchrony; Clinical; Complications of Diabetes Mellitus; Continuous Glucose Monitor; DR1 gene; Darkness; Data; Diabetes Mellitus; Diabetic Retinopathy; Diet; Disease; Disease Outcome; Disease Progression; Electroencephalography; Epidemic; Etiology; Exercise; Foundations; Functional disorder; Future; Glucose; Goals; Health; Home; Hormones; Hour; Human; Hydrocortisone; Individual; Interruption; Intervention; Knowledge; Light; Link; Measures; Melatonin; Metabolic; Metabolic Control; Monitor; Neural Retina; Neurohormones; Neuronal Dysfunction; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Outcome Measure; Participant; Patients; Persons; Pharmaceutical Preparations; Phase; Physiology; Pilot Projects; Placebos; Polysomnography; Preventive treatment; Randomized; Randomized, Controlled Trials; Retinal Diseases; Retinal Ganglion Cells; Role; Salivary; Sampling; Serum; Severities; Signal Transduction; Sleep; Sleep disturbances; System; Testing; Therapeutic Intervention; United States; Urine; Work; Wrist; actigraphy; biomarker validation; blood glucose regulation; circadian; circadian pacemaker; circadian regulation; fasting glucose; glucose metabolism; glycemic control; improved; improvement on sleep; melanopsin; melatonin supplementation; novel; primary outcome; response; sleep pattern; sleep regulation; standard measure; treatment strategy; urinary; vascular abnormality

PROJECT SUMMARY Diabetes affects more than 30 million people in the United States, with 90-95% having type 2 diabetes. Diabetic retinopathy, one of the most serious complications of diabetes, is the leading cause of blindness. While diet, exercise and medications have been cornerstones of diabetes treatment to control glucose levels, the influence of sleep and circadian regulation on metabolic control are increasingly recognized as potential targets of future preventive treatment strategies. Recent work discovered that there is a dysfunction of the melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) in patients with diabetic retinopathy. These ipRGCs are a crucial part of entraining (synchronizing) the circadian system, which influences melatonin secretion and regulates sleep/wake timing and metabolic physiology. Recent data indicate that individuals with diabetic retinopathy show abnormalities in ipRGC function and abnormal melatonin physiology. The novel hypothesis we propose to test is that ipRGC dysfunction associated with type 2 diabetes and diabetic retinopathy leads to disturbances in sleep and circadian regulation, which further adversely affects their metabolic control and could accelerate disease progression. Further, we hypothesize that melatonin supplementation will disrupt this vicious cycle. The proposed study will comprehensively examine ipRGC function via pupillometry in patients with type 2 diabetes with and without diabetic retinopathy. These groups will provide a range of ipRGC function. Sleep duration and quality (via wrist actigraphy), at-home electroencephalography (EEG), polysomnography, nocturnal melatonin secretion (measured from urinary 6-sulfatoxymelatonin), circadian regulation (24-hour blood sampling for melatonin and cortisol) and standard metabolic outcomes (hemoglobinA1c, fasting glucose, 24-hour mean glucose levels from continuous glucose monitoring) will be the outcomes and examined as a function of ipRGC function. Then, patients with diabetic retinopathy will be randomized to receive nightly melatonin supplementation or placebo for 8 weeks. The primary outcomes will be assessed at the end of the study which include sleep as measured by actigraphy and circadian regulation as assessed by 24-hour hormone sampling. Glucose parameters will also be assessed (hemoglobinA1c, fasting glucose, 24-hour mean glucose levels from continuous glucose monitoring). The proposed study will advance our understanding of the relationship between ipRGC function and the nonvisual health of people with diabetes, and provide evidence of potential benefits of melatonin in patients with diabetic retinopathy. These data will be highly relevant given the current epidemic of diabetes and diabetic retinopathy, and will inform potential therapeutic interventions, leading to improve disease outcomes in these patients.

项目摘要 糖尿病影响美国超过3000万人，其中90-95%患有2型糖尿病。糖尿病 视网膜病是糖尿病最严重的并发症之一，是导致失明的主要原因。当节食时， 运动和药物一直是糖尿病治疗的基石，以控制血糖水平， 睡眠和昼夜节律调节对代谢控制的作用越来越被认为是未来的潜在目标。 预防性治疗策略。最近的研究发现，黑视素表达障碍， 在糖尿病性视网膜病变患者中的固有光敏视网膜神经节细胞（ipRGC）。这些IPRGC 是影响褪黑激素分泌的昼夜节律系统的关键部分， 调节睡眠/觉醒时间和代谢生理学。最近的数据表明，糖尿病患者 视网膜病变显示ipRGC功能异常和褪黑激素生理学异常。新的假设 我们建议测试的是，与2型糖尿病和糖尿病视网膜病变相关的ipRGC功能障碍导致 睡眠和昼夜节律调节紊乱，这进一步对他们的代谢控制产生不利影响， 加速疾病进展。此外，我们假设补充褪黑激素会破坏这种恶性的 周期这项拟议的研究将通过瞳孔测量法全面检查2型糖尿病患者的ipRGC功能。 糖尿病伴和不伴糖尿病性视网膜病变。这些组将提供一系列ipRGC功能。睡眠 持续时间和质量（通过腕关节活动记录仪），在家脑电图（EEG），多导睡眠图，夜间 褪黑激素分泌（从尿6-硫酸氧褪黑激素测量）、昼夜节律调节（24小时血液采样 褪黑激素和皮质醇）和标准代谢结果（血红蛋白A1 c，空腹血糖，24小时平均值 来自连续葡萄糖监测的葡萄糖水平）将作为结果，并作为ipRGC的函数进行检查 功能然后，糖尿病视网膜病变患者将随机接受夜间褪黑激素治疗 补充剂或安慰剂8周。将在研究结束时评估主要结局， 包括通过活动记录仪测量睡眠和通过24小时激素采样评估的昼夜节律调节。 还将评估血糖参数（血红蛋白A1 c、空腹血糖、24小时平均血糖水平， 连续葡萄糖监测）。这项拟议的研究将促进我们对以下关系的理解： ipRGC功能和糖尿病患者的非视觉健康，并提供证据表明 糖尿病视网膜病变患者的褪黑素这些数据将是高度相关的，鉴于目前的流行病， 糖尿病和糖尿病视网膜病变，并将告知潜在的治疗干预，导致改善疾病 这些患者的结果。

项目成果

The association between rest-activity parameters and hemoglobin A1c in patients with prediabetes.

糖尿病前期患者的休息活动参数与糖化血红蛋白之间的关联。

• DOI: 10.1080/07420528.2023.2215337
• 发表时间: 2023
• 期刊: Chronobiology international
• 影响因子: 2.8
• 作者: Paewponsong,Jirayupa;Gerber,BenS;Anothaisintawee,Thunyarat;Chirakalwasan,Naricha;Saetung,Sunee;Reutrakul,Sirimon
• 通讯作者: Reutrakul,Sirimon