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

项目总结 美国有3000多万人患有糖尿病，其中90%-95%患有2型糖尿病。糖尿病患者 视网膜病变是糖尿病最严重的并发症之一，是导致失明的主要原因。节食的同时， 运动和药物治疗一直是糖尿病治疗的基石，对控制血糖水平的影响 睡眠和代谢控制的昼夜节律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，存在黑素表达的功能障碍 糖尿病视网膜病变患者的固有光敏性视网膜神经节细胞(IpRGC)。这些ipRGC 是引导(同步)昼夜节律系统的关键部分，它影响褪黑激素的分泌和 调节睡眠/醒来时间和代谢生理学。最近的数据表明，患有糖尿病的人 视网膜病变表现为ipRGC功能异常和褪黑激素生理异常。新奇的假设 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 睡眠和昼夜节律紊乱，进一步对他们的代谢控制产生不利影响，并可能 加速疾病进展。此外，我们假设，补充褪黑激素将破坏这种恶性的 周而复始。这项拟议的研究将通过瞳孔测量全面检查2型患者的ipRGC功能。 糖尿病伴和不伴糖尿病视网膜病变。这些小组将提供一系列ipRGC功能。沉睡 持续时间和质量(通过腕部活动描记)、家庭脑电(EEG)、多导睡眠描记、夜间活动 褪黑激素分泌(由尿液6-硫氧基黑素测定)、昼夜节律(24小时采血 褪黑激素和皮质醇)和标准代谢结果(血红蛋白A1c、空腹血糖、24小时平均值 来自连续血糖监测的血糖水平)将是结果，并作为ipRGC的功能进行检查 功能。然后，糖尿病视网膜病变患者将被随机分配到每晚接受褪黑素治疗 补充剂或安慰剂，为期8周。初步结果将在研究结束时进行评估， 包括通过活动记录仪测量的睡眠和通过24小时激素采样评估的昼夜节律。 还将评估血糖参数(血红蛋白A1c、空腹血糖、24小时平均血糖水平 连续血糖监测)。这项拟议的研究将加深我们对 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。考虑到目前的疫情，这些数据将具有很高的相关性 糖尿病和糖尿病视网膜病变，并将提供潜在的治疗干预措施，导致改善疾病 这些患者的预后。

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.