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.
Millions of Americans are exposed to shift work and many other environmental conditions that disrupt normal circadian rhythms. Environmental conditions associated with disrupted circadian rhythms greatly increase the risk for development of Type 2 diabetes and also significantly hinder the treatment and management of hyperglycemia in existing patients with diabetes. Thus the goal of the current proposal is to investigate mechanisms responsible for increased risk for diabetes in people experiencing daily disruptions in circadian rhythms.
|Vella, Adrian; Matveyenko, Aleksey (2018) Walking a fine line between ?-cell secretion and proliferation. J Biol Chem 293:14190-14191|
|Rakshit, Kuntol; Qian, Jingyi; Gaonkar, Krutika Satish et al. (2018) Postnatal Ontogenesis of the Islet Circadian Clock Plays a Contributory Role in ?-Cell Maturation Process. Diabetes 67:911-922|
|Javeed, Naureen; Matveyenko, Aleksey V (2018) Circadian Etiology of Type 2 Diabetes Mellitus. Physiology (Bethesda) 33:138-150|
|Xu, Jin; Jia, Yun-Fang; Tapadar, Subhasish et al. (2018) Inhibition of TBK1/IKK? Promotes Regeneration of Pancreatic ?-cells. Sci Rep 8:15587|
|Brown, Matthew R; Matveyenko, Aleksey V (2018) Physiological Glucocorticoid Replacement in Adrenal Insufficiency: Does It Fix the Broken Clock? J Clin Endocrinol Metab 103:3511-3513|
|Qian, Jingyi; Thomas, Anthony P; Schroeder, Analyne M et al. (2017) Development of diabetes does not alter behavioral and molecular circadian rhythms in a transgenic rat model of type 2 diabetes mellitus. Am J Physiol Endocrinol Metab 313:E213-E221|
|Sharma, Anu; Laurenti, Marcello C; Dalla Man, Chiara et al. (2017) Glucose metabolism during rotational shift-work in healthcare workers. Diabetologia 60:1483-1490|
|Javeed, Naureen; Matveyenko, Aleksey V (2017) ? cell self-renewal: Cyclin D2 to the rescue. Cell Cycle 16:1326-1327|
|Butler, Alexandra E; Matveyenko, Aleksey V; Kirakossian, David et al. (2016) Recovery of high-quality RNA from laser capture microdissected human and rodent pancreas. J Histotechnol 39:59-65|
|Thomas, Anthony P; Hoang, Jonathan; Vongbunyong, Kenny et al. (2016) Administration of Melatonin and Metformin Prevents Deleterious Effects of Circadian Disruption and Obesity in Male Rats. Endocrinology 157:4720-4731|
Showing the most recent 10 out of 20 publications