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

点击翻译按钮获取中文摘要

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.