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

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.

Fig. 1. Interaction of β-cell clock with the central clock and environmental cues

The central clock is entrained by external cues, of which light is the primary entraining signal. Other entraining signals include activity, temperature and food. The central clock regulates the β-cell clock via neurohumoral outputs.

Fig. 2. Core clock and antioxidant gene oscillations in pancreatic islets

Relative gene expression of Bmal1, Per1 (core clock genes) and of anti-oxidant genes, Senstrin2 (Sesn2) and Peroxiredoxin 3 (Prdx3), are shown after normalization to house keeping genes, Tbp (TATA box binding protein) and topl (topoisomerases I). qRT-PCR from isolated islets that were collected every 4 h is shown. ZT is Zeitgeber time with ZT-0 being when lights are turned on at 7 A.M. Each time point represents islets collected from 4 mice. The gene expression data were fitted to a cosine function (using Acro software V3.5 Dr. Refinetti) and the cocinar parameters are presented below each panel.

Fig. 3

Circadian control of β-cell function. The intrinsic β-cell clock regulated many cellar process critical to normal function, including, glucose sensing and substrate metabolism, mitochondrial function, stress responses, insulin secretion by exocytosis and proliferation. Hence, circadian disruption leads to as failure of stimulus-secretion coupling, poor insulin secretion and diabetes.