Role of Circadian Misalignment in Beta-cell Failure in Type 2 Diabetes

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Disruption of circadian rhythms due to common conditions such as sleep loss and shift work are becoming increasingly prevalent in modern societies with nearly 20% of the workforce in the United States exposed to some type of shift work. Individuals exposed to circadian disruption have increased risk for development of Type 2 diabetes (T2DM) and other metabolic diseases. However, the mechanisms underlying this association are still largely unknown. The loss of pancreatic beta-cell mass and function is a critical pathophysiological event precipitating development of hyperglycemia in T2DM. Thus, the long-term objectives of the current proposal are to delineate molecular mechanisms responsible for the loss of beta-cell function and mass in individuals exposed to conditions associated with circadian rhythm disruptions. To achieve these objectives studies in Specific Aim 1 will examine effects of chronic exposure to circadian misalignment in-vivo on the function of the beta-cell molecular circadian clock. To assess islet circadian clock function investigators will employ bioluminescence approach using a transgenic rat model with Per-1: luciferase gene reporter monitored by intensified charge-coupled device (ICCD) camera. Studies outlined in Specific Aim 2 will investigate the hypothesis that disrupted beta-cell circadian clock function compromises cellular defense response to oxidative stress resulting in the loss of beta-cell function and survival. Lastly, in the third Specific Aim, studies will address the hypothesis that circadian hormone melatonin plays a previously underappreciated role in the regulation of beta cell function, survival and defense response to oxidative stress. Thus, the activation of beta- cell melatonin receptor signaling has the potential to attenuate deleterious effects of circadian misalignment and oxidative stress on the beta-cell in T2DM. Taken together outlined specific aims will address a clinically relevant translation question related to understanding the role of the circadian system in regulation of pancreatic beta-cell function and survival in T2DM.