Pro-inflammatory cytokines disrupt β-cell circadian clocks in diabetes
| Autor: | Jeong Heon Lee, Tracy K. Her, Matthew R. Brown, Kuntol Rakshit, Tamas Ordog, Naureen Javeed, Aleksey V. Matveyenko, Zhenqing Ye |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
medicine.medical_treatment Circadian clock 030209 endocrinology & metabolism Inflammation Type 2 diabetes Biology medicine.disease 3. Good health Proinflammatory cytokine Cell biology 03 medical and health sciences 0302 clinical medicine Cytokine medicine Glucose homeostasis Epigenetics medicine.symptom Transcription factor 030304 developmental biology |
| DOI: | 10.1101/705210 |
| Popis: | 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 ofBmal1(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. |
| Databáze: | OpenAIRE |
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