RT Journal Article
SR Electronic
T1 Pro-inflammatory cytokines disrupt β-cell circadian clocks in diabetes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 705210
DO 10.1101/705210
A1 Naureen Javeed
A1 Matthew R. Brown
A1 Kuntol Rakshit
A1 Tracy Her
A1 Zhenqing Ye
A1 Jeong Heon Lee
A1 Tamas Ordog
A1 Aleksey V. Matveyenko
YR 2019
UL http://biorxiv.org/content/early/2019/08/15/705210.abstract
AB Intrinsic β-cell circadian clocks are a prerequisite for the control of glucose homeostasis through regulation of β-cell function and turnover. However, little is known about the contributions of circadian clock disruption to the natural progression of β-cell failure in diabetes. To address this, we examined the effects of cytokine-mediated inflammation, common to the pathophysiology of Type 1 and Type 2 diabetes, on the physiological, molecular, and epigenetic regulation of circadian clocks in β-cells. Specifically, we provide evidence that the key diabetogenic cytokine IL-1β disrupts functionality of the β-cell circadian clock and circadian regulation of insulin secretion through impaired expression of the key transcription factor Bmal1, evident at the level of promoter activation, mRNA, and protein expression. Additionally, IL-1β-mediated inflammation was shown to augment genome-wide DNA-binding patterns of Bmal1 (and its heterodimer, Clock) in β-cells towards binding sites in the proximity of genes annotated to pathways regulating β-cell apoptosis, inflammation, and dedifferentiation. Finally, we identified that the development of hyperglycemia in humans is associated with compromised β-cell BMAL1 expression suggestive of a causative link between circadian clock disruption and β-cell failure in diabetes.