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Free Radic Biol Med. 2018 May 1;119:69-74. doi: 10.1016/j.freeradbiomed.2018.02.022. Epub 2018 Feb 16.

Untimely oxidative stress in β-cells leads to diabetes - Role of circadian clock in β-cell function.

Author information

1
Diabetes and Beta Cell Biology Center, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pittsburgh, 200 Lothrop, BST-1058W, Pittsburgh, PA 15261, United States.
2
Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, United States.
3
Division of Cardiology, Department of Pediatrics, Children's Hospital of Pittsburgh and University of Pittsburgh, Pittsburgh, PA, United States.
4
Diabetes and Beta Cell Biology Center, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pittsburgh, 200 Lothrop, BST-1058W, Pittsburgh, PA 15261, United States. Electronic address: yechoorv@pitt.edu.

Abstract

Diabetes results from a loss of β-cell function. With the number of people with diabetes reaching epidemic proportions globally, understanding mechanisms that are contributing to this increasing prevalence is critical. One such factor has been circadian disruption, with shift-work, light pollution, jet-lag, increased screen time, all acting as potential contributory factors. Though circadian disruption has been epidemiologically associated with diabetes and other metabolic disorders for many decades, it is only recently that there has been a better understanding of the underlying molecular mechanisms. Experimental circadian disruption, via manipulation of environmental or genetic factors using gene-deletion mouse models, has demonstrated the importance of circadian rhythms in whole body metabolism. Genetic disruption of core clock genes, specifically in the β-cells in mice, have, now demonstrated the importance of the intrinsic β-cell clock in regulating function. Recent work has also shown the interaction of the circadian clock and enhancers in β-cells, indicating a highly integrated regulation of transcription and cellular function by the circadian clock. Disruption of either the whole body or only the β-cell clock leads to significant impairment of mitochondrial function, uncoupling, impaired vesicular transport, oxidative stress in β-cells and finally impaired glucose-stimulated insulin secretion and diabetes. In this review, we explore the role of the circadian clock in mitigating oxidative stress and preserving β-cell function.

KEYWORDS:

Bmal1; Circadian clock; Diabetes; Insulin; Islet; Nrf2; Oxidative stress; β-cell

PMID:
29458148
PMCID:
PMC5910243
[Available on 2019-05-01]
DOI:
10.1016/j.freeradbiomed.2018.02.022

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