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: 10250519
• 负责人: Sirimon Reutrakul
• 金额: $ 66.06万
• 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/10250519
• 关键词: 6-sulfatoxymelatonin; Adult; Adverse effects; Affect; Blindness; Blood specimen; Cell physiology; Circadian Dysregulation; Circadian desynchrony; Clinical; Complications of Diabetes Mellitus; DR1 gene; Data; Diabetes Mellitus; Diabetic Retinopathy; Disease; Disease Outcome; Disease Progression; Electroencephalography; Epidemic; Etiology; Foundations; Functional disorder; Future; Glucose; Goals; Gold; Health; Home; Hormones; Hour; Human; Hydrocortisone; Individual; Interruption; Intervention; Knowledge; Lead; Light; Link; Measures; Melatonin; Metabolic; Metabolic Control; Monitor; Neural Retina; Neurohormones; Neuronal Dysfunction; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Outcome Measure; Participant; Patients; Pharmaceutical Preparations; Phase; Photosensitivity; Physiology; Pilot Projects; Placebos; Polysomnography; Preventive treatment; Randomized; Retinal Diseases; Retinal Ganglion Cells; Role; Salivary; Sampling; Serum; Severities; Signal Transduction; Sleep; Sleep disturbances; Suggestion; System; Testing; Therapeutic Intervention; United States; Urine; Work; Wrist; actigraphy; base; blood glucose regulation; circadian; circadian pacemaker; circadian regulation; control trial; diet and exercise; fasting glucose; glucose metabolism; glucose monitor; glycemic control; improved; 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.

项目总结