Environmental conditions associated with disruption of circadian rhythms are becoming increasingly prevalent in today's society. Importantly, multiple strands of evidence suggest that disruption of circadian rhythms predisposes to Type 2 diabetes mellitus (T2DM), mediated through deleterious effects on pancreatic ?-cells. Epidemiological studies consistently show robust association between circadian disruption and increased prevalence of glucose intolerance, metabolic syndrome and T2DM. Our previous work in animal models demonstrated that either genetic or environmental disruption of the ?-cell circadian clock function increases the propensity for the development of diabetes by compromising regulation ?-cell function and mass. Moreover, recent preliminary data identified that the ?-cell circadian clock functions to regulate the cellular response to DNA damage. Thus, common diabetogenic stressors (e.g. glucolipotoxicity) disproportionately induce DNA damage and ?-cell failure in clock-disrupted ?-cells. These cumulative observations led us to develop three specific aims with an overall objective of elucidating the role of the circadian clock in the regulation of ?-cell response to DNA damage. Accordingly, Specific Aim 1 will test the hypothesis that the disruption of circadian rhythms (global and ?-cell specific) increases ?-cell vulnerability to DNA damage, and will also examine whether the circadian clock regulates DNA damage response through transcriptional control of the growth arrest and DNA-damage-inducible 45g (Gadd45g) gene in ?-cells.
Specific Aim 2 will test the hypothesis that neonatal (immature) ?-cells are characterized by repressed circadian clock function that increases their vulnerability to DNA damaged-induced diabetogenic injury. The follow up studies will use the genetic approach to induce circadian clock function in immature human ?-cells derived from induced pluripotent stem cells (iPSC), and will test the efficacy of this approach to improve the response to diabetogenic injury and functional maturation. Finally, Specific aim 3 will test the therapeutic potential of enhancing the ?-cell circadian clock function in order to prevent DNA damage-induced ?-cell attrition in circadian?disrupted adult ?-cells. This will be achieved by developing a novel mouse model of conditional ?-cell specific expression of Bmal1 and testing whether this approach results in attenuation of ?-cell failure in response to concomitant exposure to circadian disruption and diet-induced obesity. Taken together, outlined specific aims: 1) will uncover a novel molecular mechanism responsible for circadian disruption-induced susceptibility to ?-cell failure and 2) will use this knowledge to test a therapeutic approach to prevent ?-cell failure under diabetogenic conditions.
The incidence of Type 2 Diabetes Mellitus has reached an epidemic proportion with nearly 360 million people worldwide diagnosed with this debilitating disease. Type 2 diabetes is associated with severe health complications that afflict both the quality and the length of life and burden health care systems with direct global spending estimated at nearly $500 billion per year. Type 2 diabetes results partially due to impaired function and survival of pancreatic beta cells, which function to produce and secret insulin to maintain normal glucose levels. The goal of the current proposal is to investigate novel cellular mechanisms responsible for regulation of pancreatic beta cell function and survival in health and diabetes. More importantly, proposed studies will also test a novel therapeutic strategy to preserve beta cells under various diabetic conditions.
| 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 |
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